反应详情

温度

2.5 °C

To a suspension of 2-amino-5-chloro-3-methylbenzoic acid (i.e. the product of Step A) (92.8 g, 500 mmol) in acetonitrile (500 mL) at 0-5° C. was added 1,4-diaza-bicyclo[5.4.0]undec-7-ene (DBU, 90 mL, 92 g, 600 mmol), and then dimethyl sulfate (57 mL, 76 g, 600 mmol) was added dropwise at 0-5° C. After stirring 3 h at this temperature, additional DBU (15 mL) and dimethyl sulfate (10 mL) were added. After stirring another 3 h at this temperature, more additional DBU (15 mL) and dimethyl sulfate (10 mL) were added. After stirring another 2 h at this temperature, concentrated hydrochloric acid (60 mL, 720 mmol) was added dropwise at 0-10° C. The resulting suspension was stirred for 30 minutes at 0-5° C., then filtered, and the solids were washed with ice-cold 2:1 water-acetonitrile (3×100 mL), and dried under nitrogen. The crude product was suspended in methanol (250 mL), water (1000 mL) was added, and the mixture was stirred at room temperature for 1 h. Then the solids were filtered, washed with 4:1 water-methanol (100 mL), then with water (3×100 mL), and dried under nitrogen to afford the title compound as a low-melting white solid, 87.6 g (87.8% yield). HPLC of the solid product showed 99.7 area % of the title ester.

1. additionwere added
2. additionwere added
3. additionwas added dropwise at 0-10° C
4. filtrationfiltered
5. washthe solids were washed with ice-cold 2:1 water-acetonitrile (3×100 mL)
6. customdried under nitrogen
7. additionwater (1000 mL) was added
8. stirringthe mixture was stirred at room temperature for 1 h
9. filtrationThen the solids were filtered
10. washwashed with 4:1 water-methanol (100 mL)
11. dry with materialwith water (3×100 mL), and dried under nitrogen