Ammonia → HCID 90088631, compound

In a 1 L round-bottomed flask, a solution of 2-(1H-benzo[d][1,2,3]triazol-1-yl)-2-((phenoxycarbonyl)amino)acetic acid (19.37 g, 62.0 mmol) in THF (135 mL) was cooled in ice/water bath and treated with oxalyl chloride (5.43 mL, 62.0 mmol) and 4 drops DMF (bubbling). The reaction mixture was stirred for 4 hours (until HPLC analysis showed complete conversion to acid chloride). Then a solution of (2-amino-3-methylphenyl)(3-fluorophenyl)methanone (7.11 g, 31.0 mmol) in THF (35 mL) was added with 5 mL THF rinse and the resulting solution was removed from ice/water bath and stirred at room temperature for 1.5 hours. The mixture was then treated with a solution of ammonia, 7M in MeOH (19.94 mL, 140 mmol) (slight exotherm, immediately a white precipitate formed and mixture was cooled in ice/water bath). After 15 mins another portion of ammonia, 7M in MeOH (19.94 mL, 140 mmol) was added and the resulting mixture was removed from ice/water bath and sealed under N2 and stirred overnight at room temperature. The reaction mixture was concentrated to ˜½ volume and the resulting mixture was diluted with AcOH (63 mL) and stir at room temperature for 4 hours (until HPLC analysis showed complete conversion). The reaction mixture was concentrated and the residue dilute with 500 mL water and to give an orange sticky precipitate. Hexane and Et2O was added and stir at room temperature for 1 hour to form an orange solid. Et2O was removed under a stream of nitrogen and the aqueous layer was decanted. The orange sticky residue was triturate with 40 mL iPrOH and stir at room temperature to give a white precipitate. The solid was filtered and washed with iPrOH, dried on filter frit under a stream of nitrogen to give benzyl (5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)carbamate (5.4 g, 41.7% yield). MS(ES):m/z=418.3 [M+H+]; HPLC: RT=3.075 min Purity=99%. (H2O/MeOH with TFA, CHROMOLITH® ODS S5 4.6×50 mm, gradient=4 min, wavelength=220 nm).

1. washrinse
2. customthe resulting solution was removed from ice/water bath
3. customimmediately a white precipitate formed
4. customthe resulting mixture was removed from ice/water bath
5. customsealed under N2
6. stirringstirred overnight at room temperature
7. concentrationThe reaction mixture was concentrated
8. additionthe resulting mixture was diluted with AcOH (63 mL)
9. stirringstir at room temperature for 4 hours (until HPLC analysis showed complete conversion)
10. concentrationThe reaction mixture was concentrated
11. additionthe residue dilute with 500 mL water
12. customto give an orange sticky precipitate
13. stirringstir at room temperature for 1 hour
14. customto form an orange solid
15. customEt2O was removed under a stream of nitrogen
16. customthe aqueous layer was decanted
17. customThe orange sticky residue was triturate with 40 mL iPrOH
18. stirringstir at room temperature
19. customto give a white precipitate
20. filtrationThe solid was filtered
21. washwashed with iPrOH
22. customdried
23. filtrationon filter frit under a stream of nitrogen

ORD record

ord-c24886764d724a69b0fb6c2580098a60

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09133139B2