DICHLOROQUINOLINE(2,5-)

Step 2: Preparation of compound 181-3 [00625] To a solution of compound 181-2 (19 g, 106 mmol) in DCM (250 mL) was added POClGeneral procedure: To solution of 5-methoxyquinoline 2a (104 mg, 0.66 mmol) in CHStep 2: Preparation of compound 181-3 [00625] To a solution of compound 181-2 (19 g, 106 mmol) in DCM (250 mL) was added POCl3 (32 g, 212 mmol). The mixture was heated to 40 C and stirred for 1.5 h. Saturated aqueous NaHCO3 (aq, 500 mL) was added and the mixture was stirred at 15 C for 10 min, then the aqueous phase was extracted with ethyl acetate (300 mL*3).The combined organic phase was washed with brine (500 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, PE/EA=50/1~20/1) to provide compound 181-3 (9.8 g, 40%) as a white solid.General procedure: To solution of 5-methoxyquinoline 2a (104 mg, 0.66 mmol) in CH2Cl2 (3 mL) was added meta-chloroperoxybenzoic acid (195 mg, 1.13 mmol) at 0 C for 30 min. The mixture was allowed to warm to room temperature and stirred for additional 3 h. The reaction is queched with 4 N NaOH and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure to give the crude N-oxide, which was directly used for the next step without purification. To solution of the resulting N-oxide in CH2Cl2 (2.5 mL) was adeed phosphorus oxychloride (0.09 mL, 0.99 mmol). The reaction mixture was refluxed at 60 C for 3 h, allowed to cool to room temperature and poured into ice-water. The resulting mixture was treated with 4 N aqueous NaOH until pH reached to around 10. The organic phase was extracted with CH2Cl2 (3 x 5 mL), washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (EtOA/CH2Cl2/Hexane = 1:2:4) to give 5-methoxy-2chloroquinoline 4a (40.1 mg, 32%)General procedure: 2-Chloro-5-methoxyquinoline [0085] After 5-methoxyquinoline (104.3 mg, 0.655 mmol) was dissolved in dichloromethane (3 mL), meta-chloroperbenzoic acid (mCPBA; 195 mg, 1.13 mmol) was added thereto at 0 C., and the resulting mixture was stirred for 30 min. After the stirring for 30 min, the reaction temperature was increased from 0 C. to room temperature, followed by further stirring for 3 hr. The completion of the reaction was confirmed by TLC (EtOAc/MC/Hexane=1:2:4). When the reaction was completed, the reaction mixture was extracted with an aqueous solution of 4 N NaOH and dichloromethane, to thereby separate an organic layer. The organic layer was dried over anhydrous MgSO4 and filtered. The resulting filtrate was concentrated under reduced pressure, to thereby generate a white solid. The thus generated solid was dissolved in dichloromethane (2.5 mL) and added with phosphorous oxychloride (POCl3; 0.09 mL, 0.992 mmol). The resulting mixture was subjected to distillation under reflux at 60 C. for 3 hr. The completion of the reaction was confirmed by TLC (EtOAc/CHCl3/Hexane=1:2:10). When the reaction was completed, the reactant was cooled down to room temperature, followed by further cooling down with the gentle addition of ice. The pH of the resulting mixture was then adjusted to 10 by dropwise addition of an aqueous solution of 4 N NaOH. When the pH was adjusted to 10, the reaction mixture was extracted with distilled water and dichloromethane, to thereby separate an organic layer. The organic layer was dried over anhydrous MgSO4 and filtered. The resulting filtrate was concentrated under reduced pressure and purified by column chromatography (EtOAc/CHCl3/Hexane=1:2:10, R.f: 0.6), to thereby obtain 2-chloro-5-methoxyquinoline (40.1 mg, 32%) as a white solid. [0086] 1H NMR (CDCl3, 300 MHz) delta 4.01 (s, 3H), 6.88 (dd, J=7.2, 1.5 Hz, 1H), 7.35 (d, J=8.7 Hz, 1H), 7.59-7.67 (m, 2H), 8.51 (d, J=8.7 Hz, 1H)To a solution of iPr2NH (0.157 mL, 1.10 mmol) in THF (5 mL) at -20 OC was added dropwise a solution of 1.6 M n-BuLi in hexane (0.687 mL, 1.10 mmol). The resulting solution was stirred at 0 C. for 30 min, then cooled to -78 C. To the solution was added dropwise a solution of To a solution of iPr2NH2 (0.157 mL, 1.10 mmol) in THF (5 mL) at -20 C. was added dropwise a solution of 1.6 M BuLi in hexane (0.687 mL, 1.10 mmol). The resulting solution was stirred at 0 C. for 30 min, then cooled to -78 C. To the solution was added dropwise a solution of

Molecular Weight:198.05
XLogP3:3.8
Hydrogen Bond Acceptor Count:1
Exact Mass:196.9799046
Monoisotopic Mass:196.9799046
Topological Polar Surface Area:12.9
Heavy Atom Count:12
Complexity:163
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes