Dimethylformamide → 2-Bromo-5-hydroxy-N-[2-(4-hydroxyphenyl)ethyl]-4-methoxy-N-methylbenzamide

Temperature

80 °C

To a solution of 138 g 2-bromo-5-hydroxy-4-methoxy benzoic acid (B13) in MIBK (690 mL) was added thionyl chloride (106 g) and DMF (13 mL) and the reaction mixture was heated to 80° C. and stirred at this temperature until TLC analysis indicated the complete disappearance of B13. The resulting mixture was subjected to distillation to remove the excess thionyl chloride. After distillation of thionyl chloride, the resulting acid chloride solution was cooled to room temperature and was added to a solution of 100 g of N-methyl-N-(2-[4-hydroxyphenyl]ethyl) amine HBr (A12 HBr) and 94 g Na2CO3 in 1000 mL of MIBK and 600 mL H2O pre-cooled to 0° C. A solution of NaOH (82.5 g) in 165 mL H2O was added slowly to maintain the temperature under 5° C. The reaction mixture was stirred at this temperature until TLC analysis showed the complete disappearance of B13 acid chloride. The pH of the reaction mixture was brought to 10-11 by adding more NaOH and the resulting mixture was heated to 50° C. and stirred at this temperature for another 1 h. The reaction mixture was cooled to room temperature and the aqueous layer was separated. The organic layer was concentrated to ⅕th of its volume. 500 mL of heptane was added. The precipitate was collected by filtration to give 163 g (65% yield) of N-methyl-N-(2-[4-hydroxyphenyl]ethyl)-2-bromo-5-hydroxy-4-methoxy benzene carboxamide (C2).

1. distillationThe resulting mixture was subjected to distillation
2. customto remove the excess thionyl chloride
3. distillationAfter distillation of thionyl chloride
4. temperaturethe resulting acid chloride solution was cooled to room temperature
5. additionwas added to a solution of 100 g of N-methyl-N-(2-[4-hydroxyphenyl]ethyl) amine HBr (A12 HBr) and 94 g Na2CO3 in 1000 mL of MIBK and 600 mL H2O
6. temperaturepre-cooled to 0° C
7. additionA solution of NaOH (82.5 g) in 165 mL H2O was added slowly
8. temperatureto maintain the temperature under 5° C
9. stirringThe reaction mixture was stirred at this temperature until TLC analysis
10. additionby adding more NaOH
11. temperaturethe resulting mixture was heated to 50° C.
12. stirringstirred at this temperature for another 1 h
13. temperatureThe reaction mixture was cooled to room temperature
14. customthe aqueous layer was separated
15. concentrationThe organic layer was concentrated to ⅕th of its volume
16. addition500 mL of heptane was added
17. filtrationThe precipitate was collected by filtration

ORD record

ord-7efbb07eb16d40ab88b3af77b8b276e2

Source dataset

uspto-grants-2011_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07985879B2