2-amino-6-bromoanisole

A mixture of 1-bromo-2-methoxy-3-nitrobenzene (20.1 g, 86.6 mmol) and iron powder (33.4 g, 598 mmol) in acetic acid/water (1:1, 600 mL) was heated to 80°C for 1.5 hours. Step 2[00173j Int9 (5.12 g, 22.1 mmol) was dissolved in ethyl alcohol (150 mL) and water (50 mL). To this was added zinc (5.77 g, 88 mmol) and ammonium chloride (2.36 g, 44.1 mmol). The reaction was stirred for 1 hour, filtered and then concentrated. The crudematerial was dissolved in ethyl acetate and washed with water three times, the organic layer was then dried over sodium sulfate, filtered, concentrated and collected (4.3 g, 96percent). LC retention time 0.75 [J]. m/z: 201.8 (MHj.A mixture of 1-Bromo-2-methoxy-3-nitro-benzene (17.8 g, 0.0768 mol), SnCl3-Bromo-2-methoxy-phenylamine A mixture of l-Bromo-2-methoxy-3-nitro-benzene (17.8 g, 0.0768 mol), SnClTo a solution of bromo-2-methoxy-3-nitrobenzene 1 (lOg, 43.lmmol, 1.Oeq) in acetic acid (lOOmL), iron powder (12.03g, 215.5mmol, 5.Oeq) was added portion wise. Reaction mixture was stirred at 120°C for 4h. After completion of the reaction, the reaction mixture was filtered, concentrated in vacuo to obtain residue which was transferred into water and extracted with ethyl acetate. Organic layer combined, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to obtain 55.1 (8g, 91.87percent). MS(ES): m/z 203.49 [M+H]t (E)N-((dimethylamino)methyl ene)acetamideA mixture of l-bromo-2-methoxy-3-nitrobenzene from Step 1 (3 g, 11.64 mmol), zinc metal (7.61 g, 116 mmol) and ammonium chloride (6.22 g, 116 mmol) in EtOH (50 mL) and water (7.14 mL) was stirred at rt overnight. The reaction was then diluted with dichloromethane (200 mL), and filtered. The filtrate was washed with water (50 mL), dried (sodium sulfate), and concentrated. Redissolved this material in dichloromethane, and loaded onto a 80g silica gel column for purification by flash chromatography, eluting with 0-100percent EtOAc in hexanes. Afforded 3-bromo-2- methoxyaniline (2.11 g, 9.92 mmol, 85percent yield) as a colorless oil.In rt will come from step 11-bromo-2-methoxy-3-nitrobenzene (3 g, 11.64 mmol), zinc metal (7.61 g, 116 mmol) and ammonium chloride (6.22 g, 116 mmol) And water (7.14 mL) was stirred overnight. The reaction was then diluted with dichloromethane (200 mL) and filtered. The filtrate (50 mL) was washed with water, dried (sodium sulfate) and concentrated. The material was redissolved in methylene chloride and loaded onto a 80 g silica gel column column for purification by flash chromatography with 0-100percent EtOAc in hexanes.A solution of 3-bromo-2-methoxyaniline (2.11 g, 9.92 mmol, 85percent yield) was obtained as a colorless oil.suspension of l-bromo-2-methoxy-3-nitrobenzene (Intermediate 17, 4.45 g, 19.2 mmol) in15 mL EtOH and 20 mL 30percent NHPreparation 22Stepl[00236j To a slurry of 2-amino-6-bromophenol (4.00 g, 21.27 mmol) in methanol (2.152 mL, 53.2 mmol) and THF (10 mL) at room temperature was added triphenylphosphine (11.16 g, 42.5 mmol). After stirring for a few minutes, diisopropylazodicarboxylate (DIAD, 12.41 mL, 63.8 mmol) was then added dropwise via syringe over 5 minutes. After the addition was complete, the reaction was allowed to stir at room temperature for 1 h. The resulting mixture was then concentrated to remove the volatiles and the resulting residue was purified by silica gel flash chromatography using hexanes/ethyl acetate as the eluent. Fractions containing the major UV-active productwere combined and concentrated under vacuum to afford 2.35 g (55percent) of a dark brown oil as the desired product. HPLC (Method N) RT = 1.33 minutes. LCMS MH+ 202/204 (observed bromide isotope pattern).Step 4 To a slurry of 2-amino-6-bromophenol (4.00 g, 21.27 mmol) in methanol (2.152 mL, 53.2 mmol) and THF (10 mL) at rt was added triphenylphosphine (11.16 g, 42.5 mmol). After stirring for a few minutes, DIAD (12.41 mL, 63.8 mmol) was then added dropwise via syringe over ~5 min. (exothermic). After the addition was complete, the reaction which had warmed due to the exothermic reaction was allowed to stir at rt for ~1 h. The resulting mixture was then concentrated to remove the volatiles and the resulting residue was purified by silica gel flash chromatography using hexanes/ethyl acetate as the eluant. Fractions containing the major uv active product were combined and concentrated under vacuum to afford 2.35 g (55percent) of a dark brown oil as the desired product. HPLC (method N) RT = 1.33 min. LCMS MH+ 202/204 (observed bromide isotope pattern).To a slurry of 2-amine-6-bromophenol (4.00 g, 21.27 mmol) in methanol (2.152 mL, 53.2 mmol) and THF (10 mL) at rt was added triphenylphosphine (11.16 g, 42.5 Mmol).After stirring for several minutes, DIAD (12.41 mL, 63.8 mmol) (exotherm) was added dropwise via the syringe over about 5 minutes. After the addition was complete, the reaction, which had been heated by the exothermic reaction, was stirred for about 1 h at rt. The resulting mixture was then concentrated to remove the volatiles and the resulting residue was purified by flash chromatography on silica gel using hexane / ethyl acetate as the eluent. The fractions containing the major product of uv activity were combined and concentrated in vacuo to afford 2.35 g (55percent) of the desired product as a dark brown oil.[00162] Intermediate 9A. 3-Bromo-2-methoxyaniline: Potassium carbonate (6.47 g, 46.8 mmol) and methyl iodide (2.86 mL, 46.8 mmol) were added to a solution of 2- bromo-6-nitrophenol (5.10 g, 23.4 mmol) in DMF (100 mL) at room temperature and the resulting reaction mixture was stirred for 16 h. The reaction was quenched with water (100 mL) and diluted with EtOAc (500 mL). The aqueous layer was extracted with EtOAc. The combined organics were washed with saturated aHC03 solution and brine, dried over MgS04, filtered, and evaporated. The crude was dissolved in EtOH (100 mL) and zinc (15.30 g, 233.9 mmol) and ammonium chloride (12.52 g, 233.9 mmol) were added. The reaction mixture was stirred at room temperature for 6 h. The reaction was diluted with EtOAc, filtered through CELITE®, and evaporated. The crude was purified by flash chromatography (10-20percent EtOAc/hexanes) to give Intermediate 9A (4.6 g, 97percent) as a yellow oil. LCMS (ESI) m/z 202, 204 (M+H, M+2+H)+, RT = 1.38 min (Method A).

Molecular Weight:202.05
XLogP3:1.9
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:200.97893
Monoisotopic Mass:200.97893
Topological Polar Surface Area:35.2
Heavy Atom Count:10
Complexity:110
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes