5-BROMO-3-IODO-1H-PYRROLO[2,3-B]PYRIDINE

Preparation of 5-bromo-3-iodo-lH-pyrrolo [2, 3-6] pyridine (Intermediate A)[0442] To a stirred solution of 5-bromo-lH-pyrrolo[2, 3-.pound.]pyridine (10 g, 50.76 mmol) in 500 mL of acetone N-idodosuccinamide was added and the reaction mixture was stirred for 20 min at room temperature. The product was crashed out as white solid was filtered and washed with lOOmL acetone. Resulting solid was dried under vacuum to afford 5-bromo-3-iodo-lH- pyrrolo[2, 3-6]pyridine (16.34 g, 100percent) as a light yellow powder. 1H NMR (DMSO-d , 300MHz) δ 8.51 (d, J= 2.1 Hz, 1H), 8.22 (s, 1H), 8.02 (d, J= 1.2 Hz, 1 H), 8.00 (d, J= 5.1 Hz, 2H), 7.44 (dd, J= 8.7 Hz, 0.6 Hz, 2H), 2.35 (s, 3H); MS ESI (m/z): 322/324 (M+l)To a stirred solution of 5-bromo-lH-pyrrolo[2, 3-Z?]pyridine (10 g, 50.76 mmol) in 500 mL of acetone N-idodosuccinamide was added and the reaction mixture was stirred for 20 min at room temperature. The product was crashed out as white solid was filtered and washed with lOOmL acetone. Resulting solid was dried under vacuum to afford 5- bromo-3-iodo-lH-pyrrolo[2, 3-Z?]pyridine (16.34 g, 100percent) as a light yellow powder. To a solution of 5-bromo-1H-pyrrolo[2, 3-b]-pyridine (commercial product, 1 g, 5.10 mmol) in 200 ml of CHTo a solution of 5-bromo-lH-pyrrolo[2, 3-b]pyridine (9.0 g, 0.046mol) and KOH (5.16 g, 0.092 mol) in DMF (90 mL) was added ITo a solution of bromide 24 (10.00 g, 51 mmol) in DMF (330 mL) was added KOH (10.70 g, 191 mmol, pellets) and the reaction mixture was stirred for about 20 min. The mixture was then cooled in an ice-bath and iodine (11.55 g, 45.62 mmol) was added portionwise over 10 min. When the addition was complete the reaction mixture was stirred at room temperature for 3.5 h, diluted with EtOAc (500 mL) and washed with saturated brine solution (500 mL). The aqueous layer was extracted with EtOAc (4x 200 mL), The combined organic solutions were dried (MgS04) and concentrated to afford 45 as a pale yellow solid (15.62 g, 95percent) ; 1H NMR (400 MHz, DMSO) No. 7. 78 (s, 1H), 7.84 (D, J= 2. 2 Hz, 1H), 7.93 (bs, NH), 8. 29 (d, J= 2.0 Hz, 1H).To a solution of 5-bromo-1H-pyrrolo[2, 3-b]pyridine (5.0 g, 25.38 mmol) in dichloromethane (400 mL) was added N-iodosuccinimide (6.28 g, 27.91 mmol). The mixture was stirred at 25°C for 1 h. The product precipitated as a white solid. The solid was isolated by filtration and washed with acetone (50 mL) to give 5-bromo-3-iodo-1H-pyrrolo[2, 3- b]pyridine (7.3 g, 22.61 mmol, 89percent yield) as a white solid. LCMS (ESI) [M+H] = 322.9.To a solution of 5-Bromo-1H-pyrrolo[2, 3-b]pyridine (2.0 g, 10.2 mmol) in Acetone (20 mL) NIS (2.7 g, 12.0 mmol) was added at 25 °C and stirred for 1 h. The 5-bromo -1H-pyrrolo [2, 3-b] pyridine (2.0g, 10 . 2mmol) adding 20 ml acetone, stirring to dissolve, then adding N-iodo succinimide (2.7g, 12 . 0mmol), stir at room temperature reaction 1h. After the reaction is ended, evaporating solvent under reduced pressure, ethyl acetate (20 ml) to dissolve, then with saturated sodium thiosulfate solution (2×30 ml) and saturated salt water (2×30 ml) washing, the organic phase is dried with anhydrous sodium sulfate, concentrated, that is, getting white solid (2.9g, 88.0percent).6.28 g (27.9 mmol) of N-iodosuccinimide are added portionwise to a solution of 5 g (25.4 mmol) of 5-bromo-1H-pyrrolo[2, 3-b]pyridine in 100 ml of acetone. The mixture is stirred for 1 hour at ambient temperature then cooled to0°C. The precipitate is filtered off, rinsed with a small amount of cold acetone and dried under vacuum for several hoursto give 7.18 g of a white solid. The compound is used in the next step without further purification. Yield: 88percent.To a solution of 5-bromo-1H-pyrrolo [2, 3-b] pyridine (100 mg, 0.51 mmol) in acetone (10 mL) was added N-iodosuccinimide (125.6 mg, 0.56 mmol) . The mixture was stirred at rt for 1.5 h and filtered, the filter cake was washed with acetone to give a gray solid product (150 mg, 86.1) .[0784]MS (ESI, pos. ion) m/z: 322.9 [M+1]To a solution of commercially available 5-bromo-1H-pyrrolo[2, 3-b]pyridine (5.60 g, 28.4 mmol) in CHA mixture of 5-Bromo-1H-pyrrolo[2, 3-b]pyridine (50 g, 252.5 mmol) and N-iodosuccinimide (13.6 g, 60.6 mmol) in dichloroethane (200 ml) was stirred at 95° C. overnight. The reaction was allowed to cool to room temperature and saturated Na[0235] Step 1 : 5-Bromo-3-iodo-lH-pyrrolo[2, 3-]pyridine: N-Iodosuccinimide (6.75 g, 30.0 mmol) was added to a solution of 5-bromo-lH-pyrrolo[2, 3-]pyridine (5.39 g, 27.4 mmol) in acetone (130 mL) and stirred for 1 h at rt. The resulting solid was collected by vacuum filtration and washed with acetone to afford 6.65 g (75percent) of the desired product as an off-white to gray solid. 1H NMR (400 MHz, DMSO-^) δ ppm 12.4 (br. s, 1H), 8.32 (s, 1 H), 7.87 (s, 1H), 7.81 (s, 1H)Into a 500 mL round bottomed flask were added 5-bromo-1H-pyrrolo[2, 3-b]pyridine (10.11 g, 51.3 mmol) and 250 ml acetone. N-iodosuccinimide (NIS, 12.7 g, 56.4 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The precipitate was collected and washed with cold acetone to afford 12. 2 g (74percent) of the title compound as a tan powder. Into a 500 mL round bottomed flask were added 5-bromo-1H-pyrrolo[2, 3-b]ρyridine (10.11 g, 51.3 mmol) and 250 ml acetone. N-iodosuccinimide (NIS, 12.7 g, 56.4 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The precipitate was collected and washed with cold acetone to afford 12. 2 g (74percent) of the title compound as a tan powder. Synthesis of Compounds:; Method 1:; Step 1: Synthesis of 5-bromo-3-iodo-1H-pyrrolo[2, 3-b]pyridine.; Into a 500 mL round bottomed flask were added 5-bromo-1H-pyrrolo[2, 3-b]pyridine (10.11 g, 51.3 mmol) and 250 ml acetone. N-iodosuccinimide (NIS, 12.7 g, 56.4 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The precipitate was collected and washed with cold acetone to afford 12.2 g (74percent) of the title compound as a tan powder. Step-1: 5-Bromo-3-iodo-lH-pyrrolor2, 3-blpyridine 5-Bromo-lH-pyrrolo[2, 3-b]pyridine (5 g, 25 mmol) was dissolved in anhydrous acetone (75 ml) and added N-Iodo succinimide (6.18 g, 27.5 mmol) under nitrogen atmosphere and stirred at RT for 2 h. The reaction was monitored by TLC (10percent Ethyl acetate in hexane). The reaction mixture was cooled to RT and filtered, washed with cold acetone (50 ml) and dried under vacuum to afford 7.05 g (87percent yield) of 5-bromo-3-iodo-lH-pyrrolo[2, 3-b]pyridine. LCMS: m/z = 324.6 (M+l); HPLC: 91.11percent in method B.Step 1: (0558) To a solution containing compound 6 (2.0 g, 10.15 mmol) dissolved in N, N-dimethylformamide (78.93 mL, 1015.05 mmol) was added 1-iodopyrrolidine-2, 5-dione (2.28 g, 10.15 mmol) and the solution was allowed to stir at room temperature for 2 hours. Upon completion, the reaction mixture was poured into a saturated aqueous sodium thiosulfate solution and extracted with ethyl acetate (3×150 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and then evaporated to dryness to give 3.15 grams of compound 7 in about 95percent purity.

Molecular Weight:322.93
XLogP3:2.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:1
Exact Mass:321.86026
Monoisotopic Mass:321.86026
Topological Polar Surface Area:28.7
Heavy Atom Count:11
Complexity:155
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes