反应详情

To a suspension of 5-chloro-2-fluoro-4-methyl-N-(methylsulfonyl)benzamide (Preparation 14, 118 g, 0.45 mol) in 1,2-dichloroethane (1.25 L) was added N-bromosuccinimide (91 g, 0.51 mol) and benzoyl peroxide (5 g, 20 mmol) and the mixture heated to reflux for 18 hours. N-bromosuccinimide (30 g, 0.17 mol) was then added and the solution heated 24 hours more. A further portion of N-bromosuccinimide (20 g, 0.11 mol) was added and the solution heated for 3 hours, then cooled and washed with water (1 L) containing aqueous sodium thiosulphate solution (200 mL, 0.5 M). The organic layer was washed with water (500 mL), dried over sodium sulphate and concentrated in vacuo to yield a crude solid. To a solution of this crude solid in EtOAc (1 L) was added diisopropylethylamine (130 mL, 0.75 mol) and diethyl phosphite (27.6 g, 0.2 mol) and the mixture stirred for 5 hours under nitrogen, then washed with aqueous hydrochloric acid (1 L, 2 M), dried over magnesium sulphate and evaporated to yield a dark solid. Trituration with diethyl ether (200 mL) gave the first crop of title compound as a tan solid (68 g). The filtrate was purified by silica gel chromatography eluting with 10% EtOAc in DCM containing acetic acid (1%), followed by crystallization from acetonitrile (130 mL) to yield the second crop of the title compound (30 g).

1. temperaturethe mixture heated
2. temperatureto reflux for 18 hours
3. temperaturethe solution heated 24 hours more
4. temperaturethe solution heated for 3 hours
5. temperaturecooled
6. washwashed with water (1 L)
7. additioncontaining aqueous sodium thiosulphate solution (200 mL, 0.5 M)
8. washThe organic layer was washed with water (500 mL)
9. dry with materialdried over sodium sulphate
10. concentrationconcentrated in vacuo
11. customto yield a crude solid
12. washwashed with aqueous hydrochloric acid (1 L, 2 M)
13. dry with materialdried over magnesium sulphate
14. customevaporated
15. customto yield a dark solid