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0 °C

Under an argon atmosphere 1H-1,2,3-benzotriazol-1-yl{[(benzyloxy)carbonyl]amino}acetic acid (6.71 g, 20.6 mmol) was suspended in anhydrous methylene chloride (92 ml) and cooled to 0° C. in an ice bath. Oxalyl chloride (2.61 g, 20.6 mmol) was added dropwise to the suspension, followed by N,N-dimethylformamide (38 ml) added dropwise. After the addition the reaction was stirred at 0° C. in an ice bath for 30 minutes, until no more gas evolved. Then 1-(2-amino-4-bromophenyl)ethanone (4.0 g, 18.7 mmol) and 4-methylmorpholine (2.84 g, 28.0 mmol) were added dropwise in anhydrous methylene chloride (60 ml) under stirring in an ice bath. The reaction mixture was then allowed to warm to room temperature and stirred over night. Reaction was quenched with water (200 ml), then extracted with ethyl acetate (3×250 ml). The organic layers were combined, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give a residue. This residue was dissolved in tetrahydrofuran (120 ml) and methyl-alcohol (35 ml) and then ammonia gas was bubbled through for 2.5 hours. The reaction was then concentrated to a very viscous light brown oil. The oil was dissolved in acetic acid (120 ml) and ammonium acetate (4.3 g, 56.1 mmol) was added in one portion and stirred for 12 hours. The reaction was diluted with water (100 ml) and then basified to pH=10 with 25% sodium hydroxide under stirring in an ice bath. The aqueous solution was then extracted with ethyl acetate (3×500 ml) and the organic layers combined, dried over magnesium sulfate, filtered and the filtrate concentrated to give a residue. The residue was purified to silica gel column chromatography eluting with 40% ethyl acetate in hexanes to give the title compound 162b (4 g, 53%). 1H NMR (CDCl3, 300 MHz): δ 9.90 (s-br, 1H), 7.42-7.31 (m, 6H), 7.12 (d, 1H, 1.5 Hz), 7.06-7.03 (m, 1H), 5.18-5.08 (m, 3H), 2.50 (s, 3H) ppm.

1. additionadded dropwise
2. additionAfter the addition the reaction
3. stirringunder stirring in an ice bath
4. temperatureto warm to room temperature
5. stirringstirred over night
6. customReaction
7. customwas quenched with water (200 ml)
8. extractionextracted with ethyl acetate (3×250 ml)
9. dry with materialdried over magnesium sulfate
10. filtrationfiltered
11. concentrationthe filtrate was concentrated
12. customto give a residue
13. custommethyl-alcohol (35 ml) and then ammonia gas was bubbled through for 2.5 hours
14. concentrationThe reaction was then concentrated to a very viscous light brown oil
15. dissolutionThe oil was dissolved in acetic acid (120 ml)
16. stirringstirred for 12 hours
17. stirringunder stirring in an ice bath
18. extractionThe aqueous solution was then extracted with ethyl acetate (3×500 ml)
19. dry with materialdried over magnesium sulfate
20. filtrationfiltered
21. concentrationthe filtrate concentrated
22. customto give a residue
23. customThe residue was purified to silica gel column chromatography
24. washeluting with 40% ethyl acetate in hexanes