2-Amino-5-bromothiazole

To a mixture of sodium bicarbonate (5.8 kg, 69.04 mol, 3.00 equiv) in water (30 L) and dichloromethane (20 L) was added 5-bromo-l, 3-thiazol-2-amine hydrobromide (6 kg, 23.08 mol, 1.00 equiv) in batches. The resulting mixture was stirred at room temperature for 4 h and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to afford 5-bromo-l, 3-thiazol-2-amine as a gray solid (2.9 kg, 70percent).A suspension of 2-amino-5-bromothiazole hydrobromide (30.0 g, 116.35 mmol) and TEA (24.1 ml, 174.53 mmol) in THF (350 ml) was stirred at rt for 6 h. The resulting precipitate was removed by filtration and the filtrate was concentrated under reduced pressure yielding 2-amino-5-bromothiazole (17 g, 94.97 mmol). This material was immediately used for the next step without further purification.(a)at 0 ° C2-Aminothiazole (400 mg, 4 mmol) was dissolved in 16 mLAcetic acid solution, Bromine (408 μL, 8 mmol) was slowly added dropwise.The mixture was further stirred at room temperature for 2 hours, TLC reaction was monitored until the reaction was completed, The pH was adjusted to 7-8 with saturated NaHCO3, Ethyl acetate (20 mL x 3), washed with saturated saline and the organic layer was mixed, Dry over anhydrous sodium sulfate, filter and concentrate and purify by column chromatography5-Bromothiazol-2-amine(520 mg, 75percent yield).To a solution of 5-bromothiazol-2-amine (4.46 g, 24.9 mmol), di-ferf-butyl dicarbonate (6.52 g, 30 mmol) and 4-dimethylaminopyridine (0.304 g, 2.5 mmol) in dichloromethane (120 ml_) at room temperature was added triethylamine (6.3 g, 62.3 mmol) dropwise under nitrogen. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane (200 ml_) and washed with 1 N hydrochloric acid solution (50 ml_ x 2). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 10/1 ) to give ferf-butyl 5-bromothiazol-2-ylcarbamate as a white solid (4.04 g, 1 8.1 mmol, 73%); LCMS (ESI) m/z: 223.0 [M+H]+.Example 15, Step E [00157] To a solution of 15_1 (58 g, 0.223 mol) in DCM (580 mL) was added Boc20 (58.3 g, 0.268 mol) and K2C03 (62.0 g, 0.446 mol). The reaction solution was stirred at 20 C for 16 hours, filtered, concentrated in vacuo and purified by chromatography on silica gel to afford compound 15_2 (40 g, 64%) as a white solid.Example 15, Step E[00157] To a solution of 15_1 (58 g, 0.223 mol) in DCM (580 mL) was added Boc20 (58.3 g, 0.268 mol) and K2C03 (62.0 g, 0.446 mol). The reaction solution was stirred at 20 C for 16 hours, filtered, concentrated in vacuo and purified by chromatography on silica gel to afford compound 15_2 (40 g, 64%) as a white solid.To a solution of 153 5-bromothiazol-2-amine (46) (105g, 403.1mmol) in 154 THF (500mL) was added 155 DMAP (2.41g, 20mmol) and the solution became turbid. Then a solution of Boc2O (105.6g, 484.6mmol) in THF (50mL) was added to the above mixture slowly and the resulting mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluting with ethyl acetate in 74 petroleum ether 10-17%) to give 156 47 as an off-white solid (45.1g, yield=40%). 1H NMR (400MHz, CDCl3) delta 11.75 (br, 1H), 7.24 (s, 1H), 1.58 (s, 9H); LC/MS (ESI, m/z) 222.98 [M+H-56]+.Step a. To a solution of 2-amino-5-bromothiazole (73.06 mmol) and DMAP (3.6mmol) in THF (130 ml) was added (BOC)20 (73.06 mmol) at rt. The reaction mixture was stirred at rt for 6 h. Excess THF was removed under reduced pressure and the resulting residue was purified by column chromatography (0-5% EtOAc in Hexane) yielding tert-butyl (5- bromothiazol-2-yl)carbamate (52.1mmol). MS: ES+ 279.08; 1H MR (400 MHz, DMSO-d6) delta ppm 11.75 (s, 1H), 7.44 (s, 1H), 1.48 (s, 9H).To a solution of 2 -amino-5 -bromothiazole (13 g, 72.62 mmol) and DMAP (0.44 g, 3.63 mmol) in THF (130 ml) was added (Boc)20 (15.83 g, 72.62 mmol) at rt. The reaction mixture was stirred at rt for 6 h. Excess THF was removed under reduced pressure and the resulting residue was purified by column chromatography (0-5% EtOAc in Hexane) yielding tert-butyl (5-bromothiazol-2- yl)carbamate (14.5 g, 52.16 mmol). LCMS: Method C, 2.28 min, MS: ES+ 279.08; NMR (400 MHz, DMSO-d6) 5 ppm 11.75 (s, 1H), 7.44 (s, 1H), 1.48 (s, 9H).A solution of 2-amino-5-bromothiazole (1-21) (5.5 g, 30.72 mmol) in acetonitrile (50 mL) was treated with copper (II) bromide (3.43 g, 15.36 mmol) and isoamyl nitrite (4.9 mL, 36.87 mmol), and the resulting reaction mixture was heated at 60C for 4 hours. The volatiles were removed by evaporation, and the obtained residue was diluted with water (50 mL) , followed by extraction with ethyl acetate (25 mL x 2), The combined organic layers were washed with brine (50 mL) , dried over anhydrous Na2S04 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (60-120 mesh) using 10% EtOAc in hexanes to give the desired product 1-22 (5.05 g, 68%) as a yellow liquid; LCMS : m/z 243.6 [M+2].Step I: 2, 5-dibromothiazole (1-22) A solution of 2-amino-5-bromothiazole (1-21) (5.5 g, 30.72 mmol) in acetonitrile (50 mL) was treated with copper(II) bromide (3.43 g, 15.36 mmol) and isoamyl nitrite (4.9 mL, 36.87 mmol), and the resulting reaction mixture was heated at 60 C. for 4 hours. The volatiles were removed by evaporation, and the obtained residue was diluted with water (50 mL), followed by extraction with ethyl acetate (25 mL*2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (60-120 mesh) using 10% EtOAc in hexanes to give the desired product 1-22 (5.05 g, 68%) as a yellow liquid; LCMS: m/z 243.6 [M++2].To a solution of 2-amino-5-bromothiazole (12.58g, 70mmol) in a mixture of phosphoric acid (106ml of an 86% solution in water), and cone, nitric acid (19.2ml) cooled at - 50C was added over 45 mins a solution of sodium nitrite (7.59g, 1 lOmmol) in water (26ml). 30 After the addition was complete the mixture was stirred at -50C for 15 mins, then hypophosphorous acid (38.8ml) added dropwise over 30 mins keeping the temperature below O0C. The mixture was stirred at O0C for 150 mins then allowed to warm to room temperature overnight. The mixture was poured into a solution of NaOH (85g) in water (400ml). 5N NaOH EPO

Molecular Weight:179.04
XLogP3:1.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:177.92003
Monoisotopic Mass:177.92003
Topological Polar Surface Area:67.2
Heavy Atom Count:7
Complexity:70
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes