6-BROMO-3-CHLOROISOQUINOLINE

Add 50 g of 1, 3-dichloro-6-bromoisoquinoline to 500 mL of glacial acetic acid, and then add 14 g of red phosphorus.Hydrochloric acid 100 mL, then the system was heated to reflux, the reaction was about 5 h, and TLC confirmed the reaction was complete.After-treatment: cool to room temperature, suction filtration, add 500 mL of water to the filter cake.The mixture was adjusted to pH = 8 with 15percent aqueous ammonia, filtered, and the filtrate was extracted with ethyl acetate.The acetic acid phase is dried, added with water and alkali, extracted with ethyl acetate, and combined with all organic phases.Wash once with saturated brine, dry over anhydrous sodium sulfate, spin dry, The column was passed through 200-300 mesh silica gel, petroleum ether: ethyl acetate = 50:1 to 20:1.The product 3-chloro-6-bromoisoquinoline 30 g was obtained in a yield of 68.4percent.Example 80C Example 80C Add 100g of 6-Bromo-3-chloroisoquinoline (2.015 g, 8.309 mmol), tert-butyl6-(4, 4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)spiro[ chromane-2, 4'-piperidine ]-1 '-carboxylate (3. 971 g, 9.248mmol), tetrakis(triphenylphosphine)palladium(O) (1.031 g, 0.892 mmol), Na2C03 in water (1M) (30 mL, 30 mmol) and 1, 4-dioxane (56 g, 50 mL, 630 mmol) were combined, purged with argonand heated at 100 oc under nitrogen for 4 days. The reaction was cooled toRT, filtered througha pad of Celite, and washed with DCM. The filtrate was concentrated and the residue wasdissolved in DCM, washed with saturated aq. NaHC03, and then brine. The organic layer wasdried over Na2S04, filtered and concentrated. The residue was purified by ISCO silica gelchromatography ( 30% EtOAc I heptane) to afford a yellow solid (3.23 g, 79%). Analysis:LCMS: m/z = 465 (M + 1); 1HNMR (400 MHz, DMSO-d6) 8: 9.18 (s, 1H), 8.22-8.18 (m, 2H), 8.02-7.99 (m, 2H), 7.62-7.58 (m, 2H), 6.96 (d, 1H, J= 8.4 Hz), 3.74-3.71 (m, 2H), 3.22-3.18 (m, 2H), 2.87-2.84 (m, 2H), 1.88-1.84 (m, 2H), 1.75-1.71 (m, 2H), 1.61-1.53 (m, 2H), 1.41(s, 9H).6-Bromo-3-chloroisoquinoline (0.504 g, 2.0784 mmol), ethyl6-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)spiro[ 4H-1, 3-benzodioxine-2, 4'-piperidine]-1 '-carboxylate (0.962 g, 2.385mmol), tetrakis(triphenylphosphine)palladium(O) (0.242 g, 0.209 mmol), Na2C03 in water (1 M)(7 mL, 7 mmol) and 1, 4-dioxane (14 g, 12 mL, 160 mmol) were combined, purged with argonand heated at 100 oc under nitrogen for 20 h. The reaction was cooled toRT, filtered through apad of Celite, and washed with DCM. The filtrate was concentrated, the residue was dissolvedin EtOAc, and washed with saturated aqueous NaHC03 solution, then brine. The organic layerwas dried over MgS04, filtered and concentrated. The residue was purified by ISCO silica gelchromatography ( 30- 65% EtOAc I heptane) to give a white solid (649 mg, 68%). Analysis:mp: 92 oc; LCMS: m/z = 439 (M + 1); 1H NMR (400 MHz, DMSO-d6) 8: 9.20 (s, 1H), 8.24-8.19 (m, 2H), 8.01 (m, 2H), 7.71 -7.68 (m, 1H), 7.62 (m, 1H), 7.03 (d, 1H, J= 8.5 Hz), 4.98 (s, 2H), 4.09-4.03 (m, 2H), 3.57-3.44 (m, 4H), 1.92-1.82 (m, 4H), 1.21-1.18 (m, 3H).Step 2 To a mixture of Amixture of

Molecular Weight:242.50
XLogP3:3.8
Hydrogen Bond Acceptor Count:1
Exact Mass:240.92939
Monoisotopic Mass:240.92939
Topological Polar Surface Area:12.9
Heavy Atom Count:12
Complexity:165
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes