6-BROMO-4-IODOQUINOLINE

4.1.9 To a solution of 5 (11.0 g, 45.6 mmol) in anhydrous THF (150 mL) was added 2 M HCl in EtTo a solution of 6-bromo-4-chloroquinoline (3 g, 12.4 mmol) in anhydrous THF (50mL) was added 2M HCl in diethylether (7.4 mL, 14.8 mmol). The reaction was stirred at rt for30 min and concentrated in vacuo to provide 6-bromo-4-chloro-quinoline hydrochloride as anoff-white solid (3.46 g). [0 157] To a suspension of 6-bromo-4-chloro-quinoline hydrochloride (3 .46 g) inpropionitrile (100 mL) was added anhydrous sodium iodide (9.3 g, 62 mmol). The reaction was refluxed for 96 h, then cooled down tort. The mixture was treated with 10percent aq. K2C03 (50 mL), followed by 5percent aq. Na2S03 (20 mL), and then extracted with DCM (50 mL x 3). The combinedorganic phases were washed with brine (50 mL), dried over anhydrous Na2S04 and concentratedin vacuo to give the title compound as an off-white solid (3.4 g, 82.3percent). The title compound was characterized by LC-MS and 1 H NMR as shown below:LC-MS (ESI, pos. ion) m/z: 334 [M+Ht;1H NMR (400 MHz, CDCh) 8 (ppm): 7.78-7.83 (m, 1H), 7.89-7.93 (d, J = 8.9 Hz, 1H), 7.98-8.02(m, 1H), 8.21 (s, 1H), 8.44-8.47 (d, J = 4.5 Hz, 1H).To 6-bromo-4-chloroquinoline (3g, 12.4mmol) anhydrous THF (50 ml) is added to solution 2M HCl ether solution of (7.4 ml, 14 . 8mmol). Reaction solution stirring the mixture at room temperature for 30 minutes, concentrated under reduced pressure, to obtain 6-bromo-4-chloroquinoline hydrochloride is a kind of white solid (3.46g). The 6-bromo-4-chloroquinoline hydrochloride (3.46g) suspended in propionitrile (100 ml) in, and adding anhydrous sodium iodide (9.3g, 62mmol). Reaction liquid reflux 96 hours, cooling to room temperature, and for sequentially 10percent K Following the general procedure [43], a dry 500mL, single-neck round bottomed flask equipped with a magnetic stirring bar was charged with 6-bromo-4-chloroquinoline 4a (10.0g, 41.2mmol), and 170mL of dry THF. The solution was treated with 2N HCl in EtCompound 49b (350 mg, 1.05 mmol), cyclopropylboronic acid (99 mg, 1.15 mmol), [1, 1'-bis(diphenylphosphino)ferrocene]dichloropalladium (153 mg, 209 mumol) and potassium carbonate (433 mg, 3.14 mmol) were added to 30 mL of 1, 4-dioxane under an argon atmosphere. The reaction solution was stirred at 80C for 16 hours. The reaction solution was cooled and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by CombiFlash rapid preparation instrument with elution system B to obtain the title product 49c (110 mg), yield: 42.30%. MS m/z (ESI): 250.1[M+1].4-((3-fluorophenyl) amino) butyronitrile (142 mg, 0.8 mmol), Under the protection of nitrogen, the General procedure: To a stirred solution of 10 (1.00g, 4.00mmol) and K2CO3 (1.66g, 12.00mmol) in acetonitrile (20mL) was added dropwise diethylamine solution (1.20g, 16.00mmol) at room temperature for 2h. The solvent was evaporated in vacuo and the residue was then dissolved in EtOAc (50mL) and washed with water (20mL×3), the organic layers were washed with brine, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to provide the 11a (0.83g, 84.7% yield) as an off-white liquid. (0041) Then, a mixture of 11a (0.83g, 3.43mmol), bis(pinacolato)diboron (0.96g, 3.77mmol), PdCl2(dppf)-CH2Cl2 (0.084g, 0.103mmol) and potassium acetate (0.67g, 6.86mmol) in anhydrous 1, 4-dioxane (15mL) was purged with argon and heated at 100C for 2.5h. The reaction was then treated with 6 (1.20g, 3.60mmol), 2.0M aqueous Na2CO3 (5mL) and another portion of PdCl2(dppf)-CH2Cl2 (0.084g, 0.103mmol), then heated at 110C for 12h under argon. The reaction mixture was cooled to room temperature, filtered, and concentrated. The final compound was purified by MPLC (ISCO CombiFlash purification system) (MeOH/DCM, eluted from 0% to 10%), The fractions were collected, concentrated to afford 12a (0.72g, 57.2% yield).General procedure: To a stirred solution of 10 (1.00g, 4.00mmol) and K2CO3 (1.66g, 12.00mmol) in acetonitrile (20mL) was added dropwise diethylamine solution (1.20g, 16.00mmol) at room temperature for 2h. The solvent was evaporated in vacuo and the residue was then dissolved in EtOAc (50mL) and washed with water (20mL×3), the organic layers were washed with brine, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to provide the 11a (0.83g, 84.7% yield) as an off-white liquid. (0041) Then, a mixture of 11a (0.83g, 3.43mmol), bis(pinacolato)diboron (0.96g, 3.77mmol), PdCl2(dppf)-CH2Cl2 (0.084g, 0.103mmol) and potassium acetate (0.67g, 6.86mmol) in anhydrous 1, 4-dioxane (15mL) was purged with argon and heated at 100C for 2.5h. The reaction was then treated with 6 (1.20g, 3.60mmol), 2.0M aqueous Na2CO3 (5mL) and another portion of PdCl2(dppf)-CH2Cl2 (0.084g, 0.103mmol), then heated at 110C for 12h under argon. The reaction mixture was cooled to room temperature, filtered, and concentrated. The final compound was purified by MPLC (ISCO CombiFlash purification system) (MeOH/DCM, eluted from 0% to 10%), The fractions were collected, concentrated to afford 12a (0.72g, 57.2% yield).General procedure: To a stirred solution of 10 (1.00g, 4.00mmol) and K2CO3 (1.66g, 12.00mmol) in acetonitrile (20mL) was added dropwise diethylamine solution (1.20g, 16.00mmol) at room temperature for 2h. The solvent was evaporated in vacuo and the residue was then dissolved in EtOAc (50mL) and washed with water (20mL×3), the organic layers were washed with brine, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to provide the 11a (0.83g, 84.7% yield) as an off-white liquid. (0041) Then, a mixture of 11a (0.83g, 3.43mmol), bis(pinacolato)diboron (0.96g, 3.77mmol), PdCl2(dppf)-CH2Cl2 (0.084g, 0.103mmol) and potassium acetate (0.67g, 6.86mmol) in anhydrous 1, 4-dioxane (15mL) was purged with argon and heated at 100C for 2.5h. The reaction was then treated with 6 (1.20g, 3.60mmol), 2.0M aqueous Na2CO3 (5mL) and another portion of PdCl2(dppf)-CH2Cl2 (0.084g, 0.103mmol), then heated at 110C for 12h under argon. The reaction mixture was cooled to room temperature, filtered, and concentrated. The final compound was purified by MPLC (ISCO CombiFlash purification system) (MeOH/DCM, eluted from 0% to 10%), The fractions were collected, concentrated to afford 12a (0.72g, 57.2% yield).General procedure: To a stirred solution of 10 (1.00g, 4.00mmol) and K2CO3 (1.66g, 12.00mmol) in acetonitrile (20mL) was added dropwise diethylamine solution (1.20g, 16.00mmol) at room temperature for 2h. The solvent was evaporated in vacuo and the residue was then dissolved in EtOAc (50mL) and washed with water (20mL×3), the organic layers were washed with brine, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to provide the 11a (0.83g, 84.7% yield) as an off-white liquid. (0041) Then, a mixture of 11a (0.83g, 3.43mmol), bis(pinacolato)diboron (0.96g, 3.77mmol), PdCl2(dppf)-CH2Cl2 (0.084g, 0.103mmol) and potassium acetate (0.67g, 6.86mmol) in anhydrous 1, 4-dioxane (15mL) was purged with argon and heated at 100C for 2.5h. The reaction was then treated with 6 (1.20g, 3.60mmol), 2.0M aqueous Na2CO3 (5mL) and another portion of PdCl2(dppf)-CH2Cl2 (0.084g, 0.103mmol), then heated at 110C for 12h under argon. The reaction mixture was cooled to room temperature, filtered, and concentrated. The final compound was purified by MPLC (ISCO CombiFlash purification system) (MeOH/DCM, eluted from 0% to 10%), The fractions were collected, concentrated to afford 12a (0.72g, 57.2% yield).

Molecular Weight:333.95
XLogP3:3.5
Hydrogen Bond Acceptor Count:1
Exact Mass:332.86501
Monoisotopic Mass:332.86501
Topological Polar Surface Area:12.9
Heavy Atom Count:12
Complexity:165
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes