4-Bromo-5-fluoro-1,2-benzenediamine

To a flask was added 5-fluoro-2-nitroaniline (8.9 g, 57 mmol), NBS (10 g, 56 mmol), and acetic acid (500 mL), and the reaction was heated to 110 °C. Intermediate 11C; 4-bromo-5 -fluorobenzene- 1 , 2-diamine; To a solution of 4-bromo-5-fluoro-2-nitroaniline (1.0 g, 4.3 mmol) in THF (9.0 mL), EtOH (9.0 mL) and Hstep 2: To a suspension of 96 (1.57 g, 6.74 mmol) in EtOH (16 mL) was added SnC¾ (3.82 g, 20.2 mmol). The reaction mixture was heated at reflux for 14 h, cooled to RT and concentrated in vacuo. The residue was partitioned between EtOAc (100 mL) and sat'd. aq. NaHCC>3 (200 mL). The resulting slurry was filtered through a pad of Celite® and the wet cake was washed with EtOAc (3 x 50 mL). The organic layer was washed sequentially with saturated NaHC03, water, and brine, dried (MgSO i), filtered and concentrated in vacuo to afford 600 mg (43percent) of 44oromo-5-fluorobenzene-l, 2-diamine (98) as yellow solid: MS (ESI) m/z = 205 [M+l]Step 1: (1 S, 5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-1 -carboxylic acid (830 mg; 3.47 mmol) is dissolved in DCM (12 ml) and HATU (1583 mg; 4.16 mmol) is added followed by the addition of DIPEA (1.48 ml; 8.67 mmol). Stirring at rt is continued for 10 min, followed by the addition of 4-bromo-5-fluorobenzene-1 , 2- diamine (880 mg; 4.16 mmol) and stirring is continued at rt for 16 h. The reaction mixture is quenched by the addition of water 20 ml) followed by the separation of the organic phase. The aqueous phase is extracted with DCM (15 ml) and the combined organic phases are washed with brine (20 ml), dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by preparative HPLC (conditions C) to give 1.362 g; 3.29 mmol) of tert-butyl (1S, 5R)-1-((2-amino-5-bromo-4-fluorophenyl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2- carboxylate as a slightly purple solid. LC-MS (conditions A): tR = 0.97 min; [M+H]+ = 414.09/416.09 (Br isotops4-Bromo-5-fluoro-1, 2-diaminobenzene 4-Bromo-5-fluoro-1, 2-diaminobenzene was prepared using an adaptation of the method of Bellamy et al. (Bellamy, F. D. et al., Tetrahedron Lett. 25:839 (1984)). A mixture of 4-bromo-3-fluoro-6-nitroaniline (320 mg, 1.36 mmol) and SnCl2 2H2 O (1.53 g, 6.81 mmol) dissolved in 7 mL ethyl acetate and 3 mL absolute ethanol under N2 was heated at 75 C. for 8 h. Some starting material had remained (by TLC) after only 1 h heating. All the starting material had reacted after 8 h as evidenced by TLC (silica gel, 3:1 hexanes:ethyl acetate). The reaction was allowed to cool to room temperature and poured into 50 mL H2 O. Sufficient sat'd NaHCO3 solution was added (foaming) to bring the pH to 5. The resulting mixture was extracted with 3*25 mL ethyl acetate and the combined organic extracts washed with 20 mL sat'd NaCl solution. The organic phase was dried (MgSO4), vacuum filtered and the solvent rotary evaporated to yield a white powder 277 mg (99%). 1 H NMR (CDCl3) delta3.22 (br s, 2H, NH2); 3.60 (br s, 2H, NH2); 6.50 (d, 1H, JHF =9.6 Hz, H-6); 6.83 (d, 1H, JHF =6.6 Hz, H-3).

Molecular Weight:205.03
XLogP3:1.4
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Exact Mass:203.96984
Monoisotopic Mass:203.96984
Topological Polar Surface Area:52
Heavy Atom Count:10
Complexity:122
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes