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

Temperature

16.5 °C

A mixture of methyl 2-methyl-6-nitrobenzoate (200.0 g, 1.02 moles, previously prepared), 1,3-dibromo-5,5-dimethylhydantoin (DBH, 162.0 g, 0.57 mole, from Aldrich Chemicals) and methyl acetate (1.20 L, from Aldrich Chemicals) was charged into a 3-L three-necked flask at about 20-25° C. under nitrogen. After the reaction mixture was refluxed for 0.5-1 hour, a solution of 2,2′-azobisisobutyronitrile (AIBN, 8.6 g, 52 mmol, from Aldrich Chemicals) in 100 mL of methyl acetate was charged over 15-30 minutes. The reaction mixture was refluxed for 6.5-8 hours until the amount of unreacted 2-methyl-6-nitrobenzoate was less than 5-10%. The reaction mixture was cooled to 15-18° C. and kept at 15-18° C. for 50-60 minutes. The solid was filtered, washed with cold (i.e., 5-10° C.) methyl acetate (2×100 mL) until there was less than 3% of methyl 2-bromomethyl-6-nitrobenzoate remained in the solid. Next, after heptane (1.00 L) was charged into the filtrate, the upper layer organic phase was washed with 2% of brine (2×500 mL) and deionized water (1-2×500 mL) until there was less than 0.5% (area percentage at 210 nm) of unreacted 5,5-dimethylhydantoin according to measurement by HPLC. After the solution was concentrated under a reduced pressure to remove about 1.80-1.90 L of methyl acetate, methyl tert-butyl ether (MTBE, 300 mL) was charged. After the reaction mixture was refluxed at 65-70° C. for 10-15 minutes, the solution was cooled to 50-55° C. over 0.5-1 hour and seeded with 500 mg of methyl 2-bromomethyl-6-nitrobenzoate at 45-50° C. The suspension was cooled to 20-25° C. and kept at 20-25° C. for 2-3 hours. The solids were collected by filtration, washed with 5-10° C. a cold mixture of heptane and MTBE in a volume ratio of 1:2 (2×100 mL), and dried to a constant weight at 20-25° C. under a vacuum at 100-120 ton. The yield of methyl 2-bromomethyl-6-nitrobenzoate was 185.2 g (66%), based on 200.0 g input of methyl 2-methyl-6-nitrobenzoate. The product was found to have a purity of >98% measured by HPLC based on area percentage, and a water content of <0.1% measured by Karl Fisher titration.

1. additionwas charged into a 3-L three-necked flask at about 20-25° C. under nitrogen
2. temperatureAfter the reaction mixture was refluxed for 0.5-1 hour
3. filtrationThe solid was filtered
4. washwashed with cold (i.e., 5-10° C.) methyl acetate (2×100 mL) until there
5. additionNext, after heptane (1.00 L) was charged into the filtrate
6. washthe upper layer organic phase was washed with 2% of brine (2×500 mL) and deionized water (1-2×500 mL) until there
7. concentrationAfter the solution was concentrated under a reduced pressure
8. customto remove about 1.80-1.90 L of methyl acetate, methyl tert-butyl ether (MTBE, 300 mL)
9. additionwas charged
10. temperatureAfter the reaction mixture was refluxed at 65-70° C. for 10-15 minutes
11. temperaturethe solution was cooled to 50-55° C. over 0.5-1 hour
12. customseeded with 500 mg of methyl 2-bromomethyl-6-nitrobenzoate at 45-50° C
13. temperatureThe suspension was cooled to 20-25° C.
14. waitkept at 20-25° C. for 2-3 hours
15. filtrationThe solids were collected by filtration
16. washwashed with 5-10° C.
17. additiona cold mixture of heptane and MTBE in a volume ratio of 1:2 (2×100 mL)
18. customdried to a constant weight at 20-25° C. under a vacuum at 100-120 ton

ORD record

ord-d4c06068588c4718ad21149d8734ae83

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08415485B2