5-Bromo-2-chloro-4-methylpyrimidine

A mixture of 5-Bromo 2, 4-dichloropyrimidine (0.4 g) and lron(lll)acetylacetonate (0.062 g) in Tetrahydrofuran (10 mL) was cooled to 0 °C. Methyl magnessium bromide (3 M solution in Diethylether) (0.76 mL) was added dropwise and the mixture stirred for 2 h. Saturated Aminonium Chloride solution was added and the mixture extracted with Ethyl acetate (2 X 20 mL). The organic extracts were dried over anhydrous Sodium sulphate and evaporated under reduced pressure to get a residue which was purified by Silica gel flash column chromatography eluting with a gradient of Ethyl acetate and n-heptane to afford the desired product (0.220 g, 60 percent) as a white solid. I H NMR (300 MHz, CDCI3) 6 8.52 (5, 1 H), 2.57 (5, 3H).Tert-butyl nitrite (16 g, 155 mmol) was added dropwise to a mixture of 5-bromo-4-methyl-2-pyrimidinylamine (5 g, 26.59 mmol), and benzyltriethylammoniumchloride (27 g, 118.54 mmol) in dichloromethane (200 mL). The reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was diluted with HA fourth exemplary Intermediate D, Intermediate D-4, may be used to synthesize compounds of formula I, wherein R1 is heteroaryl substituted with two R4 substituents. A mixture of sodium (111 mg, 4.82 mmol, 1.00 equiv) in methanol (772 mg, 24.1 mmol, 975. pL, 5.00 equiv) was stirred at 25 C for 0.5 h. To this solution was added 5-bromo-2-chloro-4- methyl-pyrimidine (1.00 g, 4.82 mmol, 1.00 equiv) and the mixture was stirred at 25 C for 2 h. The reaction was quenched upon the addition of water (5 mL). The aqueous phase was extracted with ethyl acetate (10.0 mL c 3) and the combined organic phase was washed with brine (10.0 mL x 3), dried over anhydrous Na2S04, filtered and concentrated in vacuo to afford 5-bromo-2- methoxy-4-methyl-pyrimidine (500 mg, 2.46 mmol, 51.1% yield) as a red oil. LCMS: [M+l] 203.1.Step 1: Preparation of l-(4-(2-chl oro-4-methylpyrimi din-5 -yl)phenyl)pyrrolidin-2-one. [0836] l-(4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one (2.08 g, 7.23 mmol), To a stirred solution of (2-methyl-[l, l*-biphenyl]-3-yl)methanol (7.1 g, 0.036 mol) in DMF (60 mL) at 0C, sodium hydride (1.73 g, 60% in minerali oil, 0.043 mol) was added and stirred at room temperature for 30 minutes. To this mixture, 5- bromo-2-chloro-4-methylpyrimidine (5 g, 0.024 mol) was added and allowed to stir at room temperature for 16h. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was then dried over sodium sulfate, filtered and evaporated to give crude product. The crude product was purified on column chromatography (silicagel, 100-200) using 10% ethyl acetate in hexane as eluent to afford 5-bromo-4- methyl-2-((2-methyl-[l, -biphenyl]-3-yl)methoxy)pyrimidine as off-white solid (Yield: 1.5 g, 17%). LCMS (ES) m/z = 369.01 [M+H]+; MR (400 MHz, CDC13): delta 2.31 (s, 3H), 2.58 (s, 3H), 5.47 (s, 2H), 7.21-7.23 (m, 2H), 7.25-7.30 (m, 2H), 7.35 (m, 1H), 7.39-7.43 (m, 2H), 7.49 (m, 1H), 8.47 (s, 1H). HPLC purity 214 nm, 99.78%.

Molecular Weight:207.45
XLogP3:2.3
Hydrogen Bond Acceptor Count:2
Exact Mass:205.92464
Monoisotopic Mass:205.92464
Topological Polar Surface Area:25.8
Heavy Atom Count:9
Complexity:101
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes