N-[5-(Bromomethyl)-4-(4-fluorophenyl)-6-(1-methylethyl)-2-pyrimidinyl]-N-methylmethanesulfonamide

Preparation 3. [180] N-[5-bromomethyl-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide [181] N-[4-(4-fluorophenyl)-5-hydroxymethyl-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide (50.0 g) and 48percent hydrogen bromide (130.0 mL) were added to a reactor. The reaction mixture was stirred at 80°C for 15 hours. The reaction was monitored with thin layer chromatography (ethyl acetate/n-hexane =1:2). The reaction mixture was cooled to 20.similar.25°C, stirred for over 1 hour, and then filtered under reduced pressure. The resulting white solid was washed with water (500.0 mL) and then dried under reduced pressure to obtain N-[5-bromomethyl-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide as a white solid (55.3 g, yield 94percent).[182] Reference 5-Bromomethyl-4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine To the mixed solution of 5-hydroxymethyl-4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidine (15 g, 42.42 mmol) dissolved in anhydrous toluene (120 ml) and anhydrous acetonitrile (60 ml), phosphorus tribromide (5.4 g, 19.44 mmol) was slowly added dropwise at 10 to 20°C under nitrogen stream. After the reaction for 1 hour, saturated brine (100 ml) and distilled water (10 ml) were added to the reaction mixture, and the mixture was stirred for 10 minutes. After the aqueous layer was separated and discarded, the organic layer was sequentially washed with a saturated sodium hydrogencarbonate aqueous solution (50 ml) and distilled water (50 ml). The organic layer was dried with anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The obtained crude product was dispersed in hexane (100 ml), and the title compound (17.5 g, yield: 99percent) was obtained as a white solid by filtration. To a 1000 ml three-mouth bottle by adding 4 - (4 - fluorophenyl) -6 - isopropyl -2 - [(N - methyl - N - methanesulfonyl) amino] pyrimidine -5 - methanol (3) (70 g, 0.2 µM) and 420 ml dichloromethane, stirring under ice bath cooling to 0 - 10 °C, to the reaction system drop [...] phosphorus (59.0 g, 0 . 22 µM), stirring the reaction 1 h, TLC detection reaction is over. Add 250 ml water to stir liquid, organic layer respectively uses 200 ml 8percent sodium bicarbonate solution and 200 ml each wash once with purified water, collecting the organic phase and concentrated under reduced pressure to dry, the residue is added to 200 ml of petroleum ether beating at room temperature 2 h, filtering, the filter cake is dried to obtain the compound (4) a total of 75.4 g, yield 90.6percent. HPLC detection 98.9percent.Phosphorus tribromide (6.2 g, 0.023 mol) is added to a solution of the compound of formula (36) (16.2 g, 0.046 mol) in dichloromethane (180 ml). Stirring is carried out at room temperature for 1 hour and 150 ML of water are then added. The organic phase is separated off and dried (using NA2SO4). The salt mixture is filtered off and the filtrate is concentrated by evaporation. By that means, 15.7 G (82 percent) of the bromide (37) can be obtained in the form of a yellow powder. H NMR (300 MHz, CDCI3) : 1.36 (d, J = 6. 6 Hz, 6H); 3.40-3. 36 (m, 1H); 3.48 (s, 3H); 3.54 (s, 3H); 4.47 (s, 2H); 7.18 (dd, J = 8.8, 8.8 Hz, 2H); 7.78 (dd, J = 8.8, 5.3 Hz, 2H). 13C NMR (75 MHz, CDCI3) : 22.3, 28.0, 32.0, 33.5, 42. 8, 115. 9 (JF = 21.9 Hz), 119.6, 131.0 (JCF = 8.4 HZ), 133.8 (JCF = 3.5 Hz), 158.2, 163.8 (JCF = 250 Hz), 165.8, 177.6.b) Flow mode synthesis of PMDBR; Flow reactor is prepared by 30 min of medium pressure Hg-lamp stabilization within a quartz jacket with water cooling stabilization to 40 - 45 °C. Care must be taken to seal the reactor with aluminium foil against stray radiation. Starting PMDME (11.4 g, 38.6 mmol, 1 equiv.) and /V-bromosuccinimide (NBS) (2.1 equiv.) are dissolved in acetonitrile (100 mL), sealed and flushed for 10 min with nitrogen. Solution is pumped via a syringe pump through a pre-prepared flow reactor with the flow rate of 600 μΙ_ per minute (30 min retention time). When reaction mixture is collected (50 mL), water (70 mL) and MeOH (5 mL) are added and precipitate filtered. Precipitate is recrystallized form ethyl acetate to afford 7.1 g (89 percent yield) of PMDBR as yellow crystalline solid.4.5.1. Using low pressure Hg-lampA solution of N-[4-(4-fluorophenyl)-6-isopropyl-5-methylpyrimidin-2-yl]-N-methylmethanesulfonamide (7, 3.94 g, 11.69 mmol) and NBS (4.37 g, 24.50 mmol, 2.1 equiv) in acetonitrile (70 mL) was poured into the photochemical reactor. The solution was purged with nitrogen gas for 10 min and the reactor was sealed. The reaction mixture was agitated and irradiated for 68 h at ambient temperature. The dark-red colored reaction mixture was diluted with Ha) Synthesis of PMDBR PMDME (3.94 g, 11.7 mmol, 1 equiv.) and N-bromosuccinimide (NBS) (2.1 equiv.) were dissolved in 70 mL of acetonitrile. The mixture was irradiated with light of a wavelength λ = 254 nm for 68 hours at ambient temperature (about 20 °C). The obtained dark yellow solution was diluted with H

Molecular Weight:416.3
XLogP3:3.2
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:5
Exact Mass:415.03654
Monoisotopic Mass:415.03654
Topological Polar Surface Area:71.5
Heavy Atom Count:24
Complexity:506
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes