| 73% | With bromine; In chloroform; at 20℃;Cooling; | Example IB. 4-Bromo-2-trichloroacetylpyrrole[00119] To a solution of Example IA (21.2 g, 99 mmol) in CHCl3 (100 mL), cooled in an ice-bath, bromine (17 g, 106 mmol) was added dropwise. The resulting solution was stirred at ambient temperature for 10 min and then poured into water. The organic phase was separated, washed with saturated aq. NaHCO3 (50 mL) and water (50 mL), dried (MgSO4) and evaporated under reduced pressure. Recrystallization of the residue from hexane gave the product 4-bromo-2- trichloroacetylpyrrole (Example IB, 21 g, 73%) as an off-white solid. LC-MS, [M- H]+ = 289. 1H NMR (DMSO-d6, 300MHz): δ 12.9 (brs, IH), 7.55 (s, IH), 7.31 (s, IH). |
| 60% | With bromine; iodine; In Carbon tetrachloride; at 0℃; for 0.666667h; | Preparation 5; 6-bromo-4-chloropyrrolo[l,2-b]pyridazine-3-carboxamideStep 1 : l-(4-Brom -lH-pyrrol-2-yl)-2,2,2-trichloroethanone[00173] To a 100 mL 3-neck round bottom equipped with a dropping funnel was added trichloroacetyl pyrrole (50 g, 236.4 mmol) and CC14 (1.0 L). After trichloroacetyl pyrrole was dissolved, the reaction was cooled to 0 C and iodine (0.176 g) was added to the reaction. At this time, a solution of bromine (12 mL) in CC14 (100 mL) was added dropwise very slowly to the reaction through a dropping funnel over 20 minutes and the resulting mixture was stirred at 0 C for additional 20 minutes. The resulting mixture was transferred into a separatory funnel and washed with 10% a2S203 solution, saturated aHC03 solution and brine (2x). The organic layer was dried and concentrated to give 50 g (60%) of the title compound as a white solid. LCMS (condition A): m/z = 287.8, 289.8, 290.8 -ve. XH NMR (400MHz, CDC13) δ ppm: 12.8 (1H, br.s), 7.56 (1H, m), 7.33 (1H, m). |
| 60% | With bromine;iodine; In Carbon tetrachloride; at 0℃; for 0.666667h; | To a 100 niL 3-neck round bottom equipped with a dropping funnel was added trichloroacetyl pyrrole (50 g, 236.4 mmol) and CC14 (1.0 L). After trichloroacetyl pyrrole was dissolved, the reaction was cooled to 0 C and iodine (0.176 g) was added to the reaction. At this time, a solution of bromine (12 mL) in CC14 (100 mL) was added dropwise very slowly to the reaction through a dropping funnel over 20 minutes and the resulting mixture was stirred at 0 C for additional 20 minutes. The resulting mixture was transferred into a separatory funnel and washed with 10% a2S203 solution, saturated NaHCC solution and brine (2x). The organic layer was dried and concentrated to give 50 g (60%) of the title compound as a white solid. LCMS (condition A): m/z = 287.8, 289.8, 290.8 -ve. XH NMR (400MHz, CDC13) δ ppm: 12.8 (1H, br.s), 7.56 (1H, m), 7.33 (1H, m). |
| 57% | With bromine; In chloroform; at 0 - 20℃; | Synthesis of 4-Bromo-2-trichloroacetylpyrrole (20) via Scheme 4; Bromine (2.12 g, 10 mmol) was added dropwise to a stirred solution of 2- trichloroacetylpyrrole (19, 1.71 g, 10.7 mmol) in CHCl3 (15 mL) at 0 C. The mixture was then stirred at 0 C for 20 min and at rt for 5 min before quenched with water. The organic layer was washed with sat. NaHCO3 and water, dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel using hexane/ethyl acetate (90: 10 to 75:25) to give 20 as a white solid (1.65 g, 57%). 1H NMR (CDCl3, 500 MHz) δ 9.21 (br. s, IH), 7.35 (dd, J = 1 .5, 2.5 Hz, I H), 7.15 (dd, J = I .5, 2.5 Hz, I H); mp 135-137 C (lit.,16 136-138 0C ). |
| 45% | With bromine; In dichloromethane; at 0 - 20℃; for 0.166667h;Inert atmosphere; | To a stirring solution of pyrrole 2a (9.6 g, 0.045 mol) in CH2Cl2 (100 mL) at 0 C, was addeddropwise a solution of bromine (2.55 mL, 0.05 mol) in CH2Cl2 (20 mL). The mixture wasallowed to warm to r.t. and stirred for 10 min before being poured onto water and the organiclayer extracted from CH2Cl2 (3 x 40 mL). The combined organic extracts were washed withsat. aq. sodium bicarbonate (50 mL), water (50 mL), and dried (MgSO4). The solvent wasremoved in vacuo to give the crude product which was purified by flash chromatography (1:19EtOAc:petroleum ether) to afford the title compound 2d (6 g, 45%) as a silvery, metallic solid.Rf = 0.17 (1:19 EtOAc:petroleum ether). m.p. 134-136 C. (lit. m.p. 140-143 C). |
| With bromine; In chloroform; at 0 - 20℃; for 0.666667h; | SYNTHETIC EXAMPLES Example 1 4-Bromo 2-trichloracetyl pyrrole: A solution of 2-trichloracetyl pyrrole (10.6 g, 50 MMOL) in CHC13 (10 mL) was cooled to 0 C and to this solution bromine (8.53 g, 53.5 MMOL) was added in a dropwise fashion. The reaction mixture was stirred for 10 minutes at 0 C then 30 minutes at room temperature. The solution was diluted with H20 and extracted with CHC13, washed with saturated NAHCO3 solution, dried over anhydrous NA2SO4 then concentrated in vacuo. The crude product was recrystallized from hexane and the product was obtained as white crystalline solid (8.0 g). HPLC Rt 5.66 min and MS 287.9 as M-1 peak. |
| With N-Bromosuccinimide; In acetonitrile; at 0 - 20℃;Large scale; | Example 1 A solution of Compound 1 in acetonitrile (1238.0 kg, 264.9 kg after correction) was charged into a 5000 L glass-lined reactor at a temperature of 20-30 C. The mixture was added with stirring over about 2 h and then cooled to 0 C. NBS (221.8 kg) was charged into the mixture at intervals of 20-30 min at 0-20 C. The mixture was cooled to 0-5 C and reacted until the content of Compound 8 was < 1.0%. Purified water (2650.0 kg) was added over about 1.5 - 2.5 h at 0-20 C. The mixture was cooled to 0-5 C and then stirred for about 1 h for crystallization. The mixture was filtered and the filter cake was rinsed with water. |
| With bromine; at 0℃; | 4-Bromopyrrole-2-carboxylic acid (3) is prepared by bromination of the commercially available 2-trichloroacetylpyrrole (6), which selectively gives the 4- bromo-2-trichloroacerylpyrroIe (7); |
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