1-Bromo-3-fluoro-2-methylbenzene

Colorlessto light yellow liquid

To a solution of benzyl (25)-2-(cyanomethyl)-4-[2-[[(25) -1 - methy lpyrrolidin-2 -y l]methoxy ] -6, 7, 8 , 9-tetrahy dro-577-pyrimido [4, 5-c] azepin-4-y 1] pi perazine- 1 - carboxylate (150 mg, 289 pmol, 1.0 eq) and l-bromo-3-fluoro-2- methyl-benzene (109 mg, 577 pmol, 2.0 eq) in toluene (3.0 mL) was added RuPhos (53.9 mg, 1 15 pmol, 0.4 eq), CS2CO3 (235 mg, 722 pmol, 2.5 eq) and Pd2(dba)3 (52.9 mg, 57.7 pmol, 0.2 eq), the reaction mixture was stirred at 90 C for 12 hours under N2. After completion, the reaction mixture was filtered through a celite, the filter cake was washed with ethyl acetate (10 mL), and adjusted with 1N HC1 aqueous to pH~3, then the organic layer was separated, and the aqueous was adjusted with Na2C03 solid to pH~8, extracted with ethyl acetate (2 x 10 mL), the organic layer was washed with saturated brine (1 x 20 mL), dried over Na2S04, filtered and concentrated. The residue was purified by reverse phase flash (Cl 8, 0.l%FA in water, 30%-50% MeCN). The product benzyl (2S)-2-(cyanomethyl)-4-[8-(3-fluoro-2-methyl-phenyl)-2-[[(2S)-l - methylpyrrolidin-2- yl]methoxy]-5, 6, 7, 9-tetrahydropyrimido[4, 5-c]azepin-4-yl]piperazine-l -carboxylate (1 10 mg, 175 pmol, 61% yield, 100% purity) was obtained as brown oil. LCMS [ESI, M+l]: 628. (0609) [0358] NMR (400 MHz, chloroform-d) d 7.44 - 7.31 (m, 5H), 7.1 1 - 7.02 (m, I II), 6.81 (d, J = 8.4 Hz, 1H), 6.73 (t, J= 8.6 Hz, 1H), 5.20 (s, 2H), 4.73 - 4.61 (m, 1H), 4.45 - 4.32 (m, III), 4.18 - 4.13 (m, 4H), 3.83 (br d, J= 13.2 Hz, 1H), 3.65 (br d, J- 12.4 Hz, 1H), 3.41 - 3.1 8 (m, 4H), 3.14 - 3.05 (m, 1H), 3.00 - 2.63 (m, 6H), 2.48 (s, 3H), 2.36 - 2.21 (m, 1H), 2.13 - 1.94 (m, 6H), 1.89 - 1.73 (m, 3H).1-Bromo-3-fluoro-2-methylbenzene (8.0 g, 42.3 mmol), Bromosuccinimide (9.0 g, 50.8 mmol), Azobisisobutyronitrile (300 mg) was dissolved in dry carbon tetrachloride (100 mL)Heat under reflux for 16 hours under nitrogen.The reaction was cooled to room temperature and filtered, Imidazole (8.7 g, 126.9 mmol) and potassium carbonate (17.5 g, 126.9 mmol) were added to the filtrate, Heat under reflux for 5 hours under nitrogen.LC-MS showed the reaction was complete, The reaction solution was filtered, The filtrate was concentrated, The residue was purified by flash silica gel column chromatography to give 1- (2-bromo-6-fluorobenzyl) -1H-imidazole (6.0 g).

Molecular Weight:189.02
XLogP3:3.1
Hydrogen Bond Acceptor Count:1
Exact Mass:187.96369
Monoisotopic Mass:187.96369
Heavy Atom Count:9
Complexity:94.9
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes