7-BROMO-4-CHLOROTHIENO[3,2-D]PYRIMIDINE

7-Bromo-4-chloro-thieno[3, 2-d]pyrimidine (192): A solution of 7-bromo-3H-thieno[3, 2-d]pyrimid-4-one (191, 153.0 mg, 0.66 mmol) in phosphorus oxychloride (2 mL) was refluxed under NDimethylformamide (25.8 mL, 0.33 mol) and dichloromethane (150 mL) were placed in a reaction vessel, to which a dilution of oxalyl chloride (46.4 mL, 0.53 mol) in dichloromethane (150 mL) was then added over about 30 min. Subsequently, 7- bromothieno[3, 2-d]pyrimidin-4(3H)-one (35 g, 0.15 mol) was added, and heated under reflux for 3 hrs. Thereafter, the reaction mixture was quenched before water was added carefully. The Organic layer thus formed was isolated, while the aqueous layer was extracted with dichloromethane. The organic layers were pooled and dried over anhydrous sodium sulfate, and the dried organic layer was subjected to vacuum filtration and vacuum distillation, followed by desiccation with a nitrogen gas to obtain the desired compound (30.5 g, 85percent). 'H-NMR^OOMHz, DMSO-dDimethylformamide (25.8 mL, 0.33 mol) and dichloromethane (150 mL) were added to a reactor. Oxalyl chloride (46.4 mL, 0.53 mol) diluted with dichloromethane (150 mL) at room temperature was added to the reactor for about 30 minutes. 7-bromothieno[3, 2-d]pyrimidin-4(3H)-one (35 g, 0.15 mol) was added thereto, and then, the reaction solution was heated to reflux for 3 hours. The temperature of the reaction solution was lowered and water was carefully added thereto. The organic layer was separated, and the aqueous layer was subjected to extraction using dichloromethane. The extracted organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered and distilled under reduced pressure, and dried with nitrogen gas to obtain the title compound (30.5 g, 85percent). Step 1 -3 7-bromo-4-chlorothieno[3, 2-d1pyrimidine 7-bromothieno[3, 2-d]pyrimidin-4(3H)-one (5.9 g) was dissolved in POCl7-bromothieno[3, 2-d]pyrimidin-4(3H)-one (5.9 g) was dissolved in POClStep 3: 7-bromothieno[3, 2-d]pyrimidin-4(3H)-one (5.9 g) was dissolved in POClDimethylformamide (25.8 mL, 0.33 mol) and dichloromethane (150 mL) were added to a reactor. Oxalyl chloride (46.4 mL, 0.53 mol) diluted with dichloromethane (150 mL) at room temperature was added to the reactor for about 30 minutes. 7-bromothieno[3, 2- d]pyrimidin-4(3H)-one (35 g, 0.15 mol) was added thereto, and then, the reaction solution was heated to reflux for 3 hours. The temperature of the reaction solution was lowered and water was carefully added thereto. The organic layer was separated, and the aqueous layer was subjected to extraction using dichloromethane. The extracted organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered and distilled under reduced pressure, and dried with nitrogen gas to obtain the title compound (30.5 g, 85percent). 1H-NMR Spectrum (300 MHz, DMSO-: δ 9.16 (s, 1H), 8.79 (s, 1H)A solution of 7-bromo-3H-thieno[3, 2-d]pyrimid-4-one (126, 0.94 g, 4.1 mmol) in phosphorus oxychloride (4 mL) under NTo a solution of 3H-thieno[3, 2-d]pyrimid-4-one (82, 0.98 g, 6.4 mmol) in acetic acid (3.4 mL) was added a solution of bromine (1 mL) in acetic acid (3 mL). The compound of (9.2 g, 37 mmol), 4, 4, 5, 5-tetramethyl-2-(4, 9, 9-trimethyl-9H-fluoren-2-yl)-1, 3, 2-dioxaborolane (12.4 g, 37 mmol), tetrakis(triphenylphosphine)palladium(0) (2.2 g, 1.85 mmol) and sodium carbonate (5.9 g, 55.5 mmol) were added to 160 mL of 1, 4-dioxane and 40 mL of water in a 500 mL three-neck round bottom flask. The resulting mixture was purged with nitrogen for 5 min and refluxed overnight under nitrogen. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography (eluent: ethyl acetate/dichloromethane 1/200, v/v) to give 7-bromo-4-(4, 9, 9-trimethyl-9H-fluoren-2-yl)thieno[3, 2-d]pyrimidine as a white solid (10.4 g, 67percent).