5-broMo-2,4-diMethyl-pyriMidine

c) 5-bromo-2, 4-dimethylpyrimidine. A mixture of 5-bromo-4-chloro-2, 6- dimethylpyrimidine (2.73 g, 12.33 mmol), 4-methylbenzenesulfonohydrazide (4.19 mL, 37.0 mmol) and chloroform (40 mL) was heated at 90 °C for 16 hours. The solution was cooled and the solid filtered and washed with chloroform. LCMS revealed this solid (4.75g) was the desired intermediate. A mixture of this solid and 0.94M aqueous sodium carbonate (40 mL, 37.7 mmol) was heated at 90 °C for 1 .5 hours. The cooled solution was extracted with ethyl acetate 3 times, and the combined organics were washed with brine, dried (Na5-Bromo-2, 4-dimethylpyrimidine (B1.4) (0350) To a suspension of MnOTo a suspension of MnOTo a suspension of Mn02 (96 g, 1.1 mol) in 1.0 L CHCI3 was added a solution of BI .3 (47 g, 0.22 mol) in 1.0 L CHCI3dropwise at 0 °C. The mixture was stirred for 2 h at rt. After filtration and concentration, the residue was purified on 100-200 mesh silica gel column (PE:EA=100:0 to 50:50) to give the title compound (30 g, 73percent) as a yellow solid. LC-MS: [M+H] = 1891.To a solution of tetrahydropyran-4- amine (1.35 g, 13.4 mmol) in toluene (5 ml) was added 5-bromo-2, 4- dimethyl-pyrimidine (500 mg, 2.67 mmol), BINAP (333 mg, 0.53 mmol), Cs2C03 (1.74 g, 5.35 mmol) and Pd(OAc)2 (60 mg, 0.27 mmol) at rt under N2. The mixture was heated at 120 C for 3 h under a N2 atmosphere. H20 (10 ml) was added and the mixture was extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (5 ml), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by FCC (0 - 50 % MeOH in EtOAc) to give the title compound as a brown solid (Y = (1619) 90 %). H NMR (400 MHz, methanol-^) d ppm 7.98 (s, 1H), 4.02 - 3.99 (m, 2H), 3.62 - 3.54 (m, 3H), 2.51 (s, 3H), 2.39 (s, 3H), 2.05 - 1.92 (m, 2H), 1.66 - 1.56 (m, 2H). (B1.4) (0350) To a suspension of MnO2 (96 g, 1.1 mol) in 1.0 L CHCl3 was added a solution of B1.3 (47 g, 0.22 mol) in 1.0 L CHCl3 dropwise at 0 C. The mixture was stirred for 2 h at rt. After filtration and concentration, the residue was purified on 100-200 mesh silica gel column (PE:EA=100:0 to 50:50) to give the title compound (30 g, 73%) as a yellow solid. LC-MS: [M+H]+=189.1.To a suspension of MnO2 (96 g, 1.1 mol) in 1.0 L CHCl3 was added a solution of B16.4 (47 g, 0.22 mol) in 1.0 L CHCl3 dropwise at 0 C. The mixture was stirred for 2 h at rt. After filtration and concentration, the residue was purified on 100-200 mesh silica gel column (PE:EA = 100:0 to 50:50) to give the title compound (30 g, 73%) as a yellow solid. LC-MS: [MH]+ = 189.To a suspension of Mn02 (96 g, 1.1 mol) in 1.0 L CHCI3 was added a solution of BI .3 (47 g, 0.22 mol) in 1.0 L CHCI3dropwise at 0 C. The mixture was stirred for 2 h at rt. After filtration and concentration, the residue was purified on 100-200 mesh silica gel column (PE:EA=100:0 to 50:50) to give the title compound (30 g, 73%) as a yellow solid. LC-MS: [M+H] = 1891.Intermediate B1 (0351) A mixture of B1.4 (12 g, 64 mmol), bis(pinacolato)diboron (22.8 g, 89.6 mmol, 1.4 eq), KOAc (18.8 g, 192 mmol, 3.0 eq), and Pd(dppf)Cl2 (2.34 g, 3.2 mmol) in 200 mL of anhydrous dioxane was heated at 90 C. and stirred for 4 h under N2. The solvent was removed under reduced pressure, the residue was diluted with 300 mL mixed slovent (PE:EA=4:1), filtered and concentrated. The crude product was purified by flash column chromatography (PE:EA=2:1 to 1:1) to give the title compound (10 g, 66%) as a yellow oil. LC-MS: [M+H]+=235.1.A mixture of B16.5 (12 g, 64 mmol), bis(pinacolato)diboron (22.8 g, 89.6 mmol, 1.4 eq), KOAc (18.8 g, 192 mmol, 3.0 eq), and Pd(dppf)Cl2 (2.34 g, 3.2 mmol) in 200 mL of anhydrous dioxane was heated at 90 C and stirred for 4 h under N2. The solvent was removed under reduced pressure, the residue was diluted with 300 mL mixed solvent (PE:EtOAc = 4:1), filtered and concentrated. The crude product was purified by flash column chromatography (PE:EtOAc = 2:1 to 1:1) to give the title compound (10 g, 66%) as a yellow oil. LC-MS: [MH]+ = 235.A mixture of B1.4 (12 g, 64 mmol), bis(pinacolato)diboron (22.8 g, 89.6 mmol, 1.4 eq), KOAc (18.8 g, 192 mmol, 3.0 eq), and Pd(dppt)C12 (2.34 g, 3.2 mmol) in 200 mL of anhydrous dioxane was heated at 90 C and stirred for 4 h under N2. The solvent was removed under reduced pressure, the residue was diluted with 300mL mixed slovent (PE:EA = 4:1), filtered and concentrated. The crude product was purified by flash column chromatography (PE:EA = 2:1 to 1:1) to give the title compound (10 g, 66%) as a yellow oil. LC-MS: [M+H] = 235.1.b) methyl 3-((7-(2, 4-dimethylpyrimidin-5-yl)-3-sulfamoylquinolin-4-yl)amino)-5- isopropoxybenzoate. A mixture of methyl 3-((7-bromo-3-sulfamoylquinolin-4- yl)amino)-5-isopropoxybenzoate (250 mg, 0.506 mmol) bis(pinacolato)diboron (141 mg, 0.556 mmol), potassium acetate (174 mg, 1.770 mmol) [1 , 1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane adduct (20.65 mg, 0.025 mmol) and 1 , 4-dioxane (3 mL) was purged with nitrogen for 15 minutes, and then heated at 1 10 C for 30 minutes in a microwave reactor. 5- bromo-2, 4-dimethylpyrimidine (0.036 mL, 0.321 mmol), cesium carbonate (330 mg, 1 .01 1 mmol), [1 , 1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane adduct (20.65 mg, 0.025 mmol) and water (1 mL) were added to the mixture and this again purged with nitrogen for 15 minutes. The mixture was heated in a microwave reactor at 1 10 C for 30 min, then cooled and filtered. The filtrate was purified by reverse-phase preparative HPLC (ODS, acetonitrile/0.03% aqueous ammonia) to give the title compound (120 mg, 80% pure, 36%) as a brown solid. LCMS (ES+) m/e 522 [M+H]+.

Molecular Weight:187.04
XLogP3:1.7
Hydrogen Bond Acceptor Count:2
Exact Mass:185.97926
Monoisotopic Mass:185.97926
Topological Polar Surface Area:25.8
Heavy Atom Count:9
Complexity:97.1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes