1-Hydroxybenzotriazole → 2-Bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoic acid methyl ester

Temperature

0 °C

Diisopropylethylamine (8.4 mL, 48.2 mmol) was added dropwise to a cooled (˜0° C.) solution of 2-bromo-1,4-benzenedicarboxylic acid, 1-methyl ester (Example 2; 5.00 g, 19.3 mmol), HBTU (7.31 g, 19.3 mmol), 3-hydroxybenzylamine HCl salt (Example 7; 3.37 g, 21.2 mmol), and HOBT (2.6 g, 19.2 mmol) in N,N-dimethylformamide (50 mL). The solution was allowed to stir at ˜0° C. for 1 h, then at room temperature for 4 h, and it was then concentrated to remove most of the N,N-dimethylformamide. The residue was partitioned between ethyl acetate and 1 M HCl (200 mL each). The ethyl acetate layer was washed with 1 M HCl (2×100 mL) and the combined aqueous layers were extracted with ethyl acetate (50 mL). The combined ethyl acetate layers were washed with saturated sodium hydrogen carbonate solution (2×100 mL), and brine, then dried (MgSO4), filtered, evaporated and recrystallized from hot ethyl acetate (˜60 mL) and hexanes (15 mL) to give 2-bromo-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoic acid, methyl ester (5.15 g, 73%) as white crystals.

1. waitat room temperature for 4 h
2. concentrationit was then concentrated
3. customto remove most of the N,N-dimethylformamide
4. customThe residue was partitioned between ethyl acetate and 1 M HCl (200 mL each)
5. washThe ethyl acetate layer was washed with 1 M HCl (2×100 mL)
6. extractionthe combined aqueous layers were extracted with ethyl acetate (50 mL)
7. washThe combined ethyl acetate layers were washed with saturated sodium hydrogen carbonate solution (2×100 mL), and brine
8. dry with materialdried (MgSO4)
9. filtrationfiltered
10. customevaporated
11. customrecrystallized from hot ethyl acetate (˜60 mL) and hexanes (15 mL)

ORD record

ord-3f2459ae14e24ebc96ade305654082a8

Source dataset

uspto-grants-2004_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06803384B2