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With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 4 h;
Step 2: 1-tert-butyl 3-methyl 2-(5-bromopyrimidin-2-yl)malonate Ex.46a (1.88 g, crude) was dissolved in CH2CI2 (20 mL). The mixture was cooled to 0°C and trifluoroacetic acid 99percent (10 mL) was added dropwise. The reaction mixture was allowed to rise rt and stirred at this temperature for 4h. The solvent was removed under reduced pressure. Toluene was added and the solution wasevaporated to dryness. The residue was diluted with EtOAc and sat. sodium bicarbonate solution. The two phases were partitionated. The organic layer was washed with brine, dried over Mg504 and the solution was concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel eluting with a gradient of Heptane/EtOAc from [100:0] to [60:40]. The desired fractions were combined and concentrated to obtain methyl 2-(5-bromopyrimidin-2-yl)acetate Ex.46b (405 mg, 34percent,calculated over two steps) as yellow oil.
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; for 3.25h;Inert atmosphere;
Step 1: sodium hydride (60percent in mineral oil) (310 mg, 7.76 mmol) was added portionwise to a stirred solution of <strong>[42726-73-8]tert-butyl methyl malonate</strong> (1.05 mL, 6.20 mmol) in dry DMF (25 mL) at 0°C and under N2 atmosphere. The solution was stirred at rt for 15mm and 2-chloro-5-bromopyrimidine (1.0 g, 5.17 mmol) wasadded portionwise. The reaction mixture was stirred at 50°C for 3h. After cooling to rt, sat. NH4CI and water was added to quench the reaction. The solution was acidified up to pH = 3 by the addition of 2N HCI. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Mg504, filtered and the solution was concentrated to dryness affording 1 -tert-butyl 3-methyl 2-(5-bromopyrimid in-2-yl)malonate Ex.46a. Thecrude material was considered to be suitable for the next synthetic step.