5-Bromo-2-benzoxazolamine

To a stirred solution of 2-amino-4-bromophenol (3) (59.6 g, 0.317 mol) in methanol (600 mL) at roomtemperature, solid bromine cyanide (40.3 g, 0.38 mol, 1.2 eq) was added carefully in portions and the resultingmixture was stirred at 35 oc for 6 h. (Note: the bromine cyanide is very toxic, the reagent and reaction should be5 handled carefully in the fume hood). The reaction mixture was quenched by addition of saturated aqueousNa2C03 solution and the pH value was adjusted to 7-8. The mixture was then concentrated in vacuo to removethe methanol. The residue was dissolved in ethyl acetate (600 mL), washed with water (100 mL x 2) and brine(100 mL), dried over MgS04 and filtered. The filtrate was concentrated in vacuo to afford the desired product 4(65.2 g, 96.5percent yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): i5 7.62 (s, 2H), 7.37 (d, J = 1.9 Hz, 10 lH), 7.30 (d, J = 8.3 Hz, lH), 7.11 (dd, J = 8.3, 2.1 Hz, lH); 13C NMR (100 MHz, DMSO-d6): i5 163.7, 147.1, 145.7, 122.2, 117.7, ll5.4, 110.0.[00227] Preparation of compound 2:[00228] 1. 2-Amino-4-bromophenol (12574 g) and methanol (100.6 L, 79.6 kg) were charged to anappropriately sized reactor and stirredat room temperature (-18 to 20°C).[00229] 2. A solution of cyanogen bromide (8500 g) was prepared in methanol (25.1 L, 19.9 kg) in a separate 50 gallon reactor; this solution was charged to the starting material reaction mixture via an additional funnel (total reaction volume -150 L, 40 gal).[00230] 3. The reaction mixture was heated for -15 hours at 37 °C. [00231] 4. The reaction was monitored by HPLC until it was complete.[00232] 5. Upon completion, the reaction mixture was cooled to 18 - 20 °C.[00233] 6. 40percent Sodium carbonate solution (12.41 Kg of Na[0217] Preparation of compound 2: 1. 2-Amino-4-bromophenol (12574 g) and methanol (100.6 L, 79.6 kg) were charged to anappropriately sized reactor and stirredat room temperature (-18 to 20°C). 2. A solution of cyanogen bromide (8500 g) was prepared in methanol (25.1 L, 19.9 kg) in a separate 50 gallon reactor; this solution was charged to the starting material reaction mixture via an additional funnel (total reaction volume -150 L, 40 gal). 3. The reaction mixture was heated for -15 hours at 37 °C. 4. The reaction was monitored by HPLC until it was complete. 5. Upon completion, the reaction mixture was cooled to 18 - 20 °C. 6. 40percent Sodium carbonate solution (12.41 Kg of Na2C03 in 30.2 Lwater) was added at ambienttemperature and the mixture was stirred for ∼1 hour. 7. Solvent was distilled under vacuum at 30 - 40 °C to remove most of the methanol. 8. Water (50.2 L, 50.2 kg) was charged. 9. Ethyl acetate (125 L, 113kg) was addedand the resulting mixture was stirred for ∼10 minutes. 10. The agitation was stopped and the layers were allowed to separate. 11. The lower aqueous phase was drained. 12. Water (50 L, 50kg) was added to the organic layer in the reactor and the resulting mixture was stirred for at least 20 minutes. 13. The agitation was stopped and the layers were allowed to separate. 14. The lower aqueous phase was drained and combined with the aqueous phase from step 11. 15. Brine (7.0 Kg of NaCl in25 kg of H20)was addedand the resulting mixture was stirred for ∼10 minutes. 16. The agitation was stopped and the layers were allowed to separate. 17. The lower aqueous phase was drained and combined with the aqueous phases from step 14. 18. Magnesium sulfate (1.9 Kg) was added and the resulting mixture was stirred for at least 15 minutes. 19. The mixture was filtered into a cleaned reactor using lum in-line filter. 20. The reactor and filter lines were washed with ethyl acetate (12 L). 21. Distillation was carried out under vacuum at 30- 40 °C to minimum steerable volume (∼2 volumes, ∼25 L). 22. Heptane (63 L, 43 kg) was added. 23. Distillation was carried out under vacuum at 30- 40 °C to minimum stirrable volume (∼2 volumes, ∼25 L). 24. Steps 22 & 23were repeated one more time. 25. Heptane (32 L) was added and the resulting mixture was stirredforat least 3 hours at ambienttemperature (18 °C to 20 °C). 26. The reaction was monitored by HPLC. 27. A solidwas collected by vacuum filtration and washed with heptane (2 x 13 L, 8.9kg). 28. The solid was dried in a vacuum oven at ∼47 °C to constant weight to give brown to light brown color solid (13510 g, 95percent yield; HPLC purity 97.2percent; 'HNMR (DMSO-d6, 300 MHz) δ 7.6 (s, 2H), 7.38-7.28 (m, 2H), 7.15-7.08 (1H)).Add 188g of compound 3 to 2L of methanol (Me(10), Keep the temperature at about 30°C, slowly add 120g of Bromide (BrCN), and react at room temperature for 8 hours after the addition.Then use saturated sodium carbonate solution to adjust the pH of the reaction solution to 8-9, then keep 40 °C to concentrate the methanol, It was extracted 3 times with 2 L of ethyl acetate, washed 3 times with 2 L of brine, dried over anhydrous sodium sulfate and concentrated to give 150 g of compound 4 in a yield of 70percent.Preparation of 5-bromobenzoxazol-2-amine: 5.0 g (0.027 mol) of 2-amino-4-bromophenol, Thiocyanic acid according to 3.1g (0.040mol), Was added to a 100 ml round bottom flask, Then, 25 ml of 0.040 mol of hydrochloric acid was added, Reflow 6h.Let cool.Ethyl acetate 30 ml x 3 Extraction acid aqueous phase, Combine organic phase, Dried over anhydrous sodium sulfate for 12 h.The product was evaporated to dryness and dissolved in 40 ml of methanol.8.9 g (0.040 mol) of lead oxide was added, Reflux 8h, Hot filter, Get a black liquid.Recovery solvent, Column separation, Dichloromethane: methanol = 80: 1, Pale yellow solid, 1.72 g, M.p. 144 to 146 ° C, Yield: 29.02percent.

Molecular Weight:213.03
XLogP3:2.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:211.95853
Monoisotopic Mass:211.95853
Topological Polar Surface Area:52
Heavy Atom Count:11
Complexity:155
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes