METHYL 5-BROMO-2-(METHYLSULFANYL)-4-PYRIMIDINECARBOXYLATE, 97

Yellow solid

Preparation 30: Methyl 5-bromo-2-(methylthio)pyrimidine-4-carboxylate A solution of 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (7.64 g, 30.7 mmol) in MeOH (60 mL) was treated with sulfuric acid (2 mL) and boiled for 24 hours. The mixture was poured onto ice water and extracted with DCM. The DCM phase was washed with saturated aqueous sodium hydrogen carbonate solution, dried and evaporated to give the title compound (6.42 g, 80percent). Preparation 29 (1052) Methyl 5-bromo-2-(methylthio)pyrimidine-4-carboxylate (1053) A solution of 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (7.64 g, 30.7 mmol) in MeOH (60 ml_) was treated with sulfuric acid (2 ml_) and heated to reflux for 24 hours. The mixture was poured onto ice water and extracted with DCM. The organic layer was washed with saturated aqueous NaHC03, dried (MgS04) and concentrated in vacuo to afford the title compound (6.42 g, (1054) 80percent). (1055) Th ion ly chloride (3.1 mL, 43.8 mmol) was added dropwise to 5-bromo-2-(methylthio)pyrimidine-4- carboxylic acid (1.3) (5.5 g, 22.2 mmoL) in methanol (50 mL) at 0 °C. The resultingmixture was stirred at 85 °C for 1 h, cooled to rt, and then poured into aq. NaHCO3 solution (100 mL). The mixture was extracted with CH2CI2 (3 x 100 mL). washed with water (50 mL), brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was recrystallized from petroleum ether to afford the title compound (4.6 g, 79percentyield) as a yellow solid. LC-MS: [MH] = 262.7.A solution of 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (110 g, 0.44 mol) in methanol (1.1 L) was cooled to 0°C with stir, and thionyl chloride (50 mL, 0.66 mol) was added dropwise thereto. The resultant reaction mixture was slowly heated, and the reaction was allowed to proceed under reflux for four hours. The completion of the reaction was confirmed by LC/MS and TLC, and the reaction mixture was cooled to room temperature. The volatiles were removed through evaporation under reduced pressure, and the residue was dissolved in ethyl acetate (1 L). The resultant solution was washed three times with 10percent aqueous sodium carbonate solution (200 mL) and then twice with saturated brine (200 mL). The resultant organic phase was dried over anhydrous magnesium sulfate, and solid was separated by filtration. The filtrate was then concentrated under reduced pressure, and the resultant crude product was purified by silica gel column chromatography to yield the title compound (88 g, 75percent).Methyl 5-bromo-2-(methylthio)pyrimidine-4-carboxylate (2631 mg, 10.0 mmol) and 1-ethynyl-3, 5-dimethoxybenzene (1622 mg, 10.0 mmol) were dissolved in dried THF (50 mL). The gas was exchanged with N2, Et3N (2:8 mL, 20.0 mmol), Pd(PPh3)2Cl2 (702 mg, 1.0 mmol), PPh3 (525 mg, 2.0 mmol) and CuI (190 mg, 1.0 mmol) were added successively under N2, the mixture was heated to 90 C. and stirred overnight. After the reaction was completed, the mixture was cooled to room temperature, added with a saturated aqueous solution of NaHCO3 (100 mL), extracted twice with EtOAc (100 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtrated, concentrated, and separated by silica gel column chromatography (PE:EA 4:1) to obtain compound methyl 5-((3, 5-dimethoxyphenyl)ethynyl)-2-(methylthio)pyrimidine-4-carboxylate (2.5 g, yield: 73%). MS m/z (ESI): 345.2 [M+H]+.3-ethynyl-2, 4-difluoro-1, 5-dimethoxybenzene (10.0 g, 50.5 mmol) and methyl 5-bromo-2-methylthio-pyrimidine-4-carboxylate (130 g, 49.5 mmol) were dissolved in DMF (100 mL), then CuI (479 mg, 2.52 mmol), Pd(PPh3)4 (2.91 g, 2.52 mmol) and Et3N (35.0 mL, 252.5 mmol) were added, the mixture was heated to 100 C. for 1.5 h under N2. The reaction was completed, the mixture was cooled to room temperature, a saturated aqueous NH4Cl solution was added to quench the reaction, then the mixture was extracted for three times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtrated and concentrated to obtain a crude product, then the crude product was separated by silica gel column chromatography (PE:EA:DCM=10:2:1) to obtain the target product (15.4 g, yield: 82%). 1H NMR (400 MHz, CDCl3) delta 8.82 (s, 1H), 6.69 (t, J=8.0 Hz, 1H), 4.03 (s, 3H), 3.90 (s, 6H), 2.63 (s, 3H).A solution of methyl 5-bromo-2-methylsulfanylpyrimidine-4-carboxylate (25 g, 95 mmol) in THF (375 mL) was cooled to -78C with stirring under a nitrogen atmosphere. DIBAL-H (84 mL, 143 mmol, 1.7 M in toluene) was added dropwise to the solution. The reaction mixture was stirred at -78C for four hours. The completion of the reaction was monitored by TLC and the reaction was quenched by dropwise addition of methanol at - 78C. The solution was allowed to warm slowly to 0C. The solution was diluted with ethyl acetate and filtered under reduced pressure through a Celite pad. The filtrate was washed with saturated brine (200 mL) twice. The resulting organic phase was dried over anhydrous magnesium sulfate, and the solid was filtered out. The filtrate was concentrated to give a mixture (25 g, crude product) of the title compounds. The crude product was used in the subsequent reaction without further purification

Molecular Weight:263.11
XLogP3:1.9
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:3
Exact Mass:261.94116
Monoisotopic Mass:261.94116
Topological Polar Surface Area:77.4
Heavy Atom Count:13
Complexity:193
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes