3-benzyl-6-bromo-2-chloroquinoline

Phosphoric trichloride (1.225 mol) was added dropwise at 10°C to DMF (0.525 mol). Then intermediate 1 (0.175 mol) was added at room temperature. The mixture was stirred overnight at 80°C, poured out on ice and extracted with DCM. The organic layer was dried (MgS04), filtered, and the solvent was evaporated. The product was used without further purification, yielding 77.62 g of intermediate 2 (67percent).Example A2; Preparation of intermediate 2; The reaction was carried out twice. POC13 (1.225 mol) was added dropwise at 10 °C to DMF (0.525 mol). Then intermediate 1 (0.175 mol) was added at room temperature . The mixture was stirred overnight at 80 °C, poured out on ice and extracted with CH2CI2. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated, yielding 77.62 g (67percent) of intermediate 2. The product was used without further purification.b) Preparation of intermediate 11; The reaction was carried out twice. POClb. Preparation of intermediate 10; The reaction was carried out twice . POClb) Preparation of intermediate 5; The reaction was carried out twice. POClIntermediate 2 The reaction was carried out twice . POCI3 (1.225 mol) was added dropwise at 10 POCl3 (129 g, 0.840 mol) was added dropwise into DMF (32.6 ml, 0.420 mol) at 0°C. After 1h of vigorous agitation under room temperature, compound 1 (32 g, 0.105 mol) and CH3CN (50mL) was added into the mixture, followed by being stirred overnight at 80°C. After solvent was partially removed, the residue was poured out into ice water (300mL) with rapid stirring and crude compound 2 precipitates gradually. Then the solid was filtrated and washed with portions of cold CH3OH. Finally, compound 2 (25g, 71percent) can be recrystallized from CH2Cl2 and CH3OH.The reaction was carried out twice . POClThe reaction was carried out twice. POC13 (1.225 mol) was added dropwise at [10C] to DMF (0.525 mol). Then intermediate compound 1 (prepared according [A1)] (0.175 mol) was added at room temperature. The mixture was stirred overnight at [80C, ] poured out on ice and extracted with CH2C12. The organic layer was dried [(MgS04), ] filtered, and the solvent was evaporated. The product was used without further purification. Yielding : (77.62g ; Yield=67percent).b) Preparation of intermediate compound 4b; The reaction was carried out twice. POClExample A2; Preparation of intermediate 2. Phosphoric trichloride (1.225 mol) was added dropwise at 10°C to DMF (0.525 mol). Then intermediate 1 (0.175 mol) was added at room temperature. The mixture was stirred overnight at 80°C, poured out on ice and extracted with DCM. The organic layer was dried (MgSOPreparation of3-Benzyl-6-bromo-2-chloro-quinoline; Phosphorus oxychloπde (30.0 g, 196 9 mmol) was added dropwise to JV, JV-Dimethylformamide (14 34 g, 196.18 mmol) at 5 Preparation of 3-benzyl-6-bromo-2-chloroquinoline; 3-Benzyl-6-bromo-lH-qumoline-2-one (0 87 g, 2.8 mmol) and freshly distilled phosphorous oxychloπde (5 mL) were refluxed togethei for 30 mm The reaction was poured into ice-water mixture, basified with saturated sodium bicarbonate solution to pH 8-8 5 and extracted with ethyl acetate (3 * 50 mL). The organic fractions were combined, washed with brme (50 mL), dried over anhydrous sodium sulfate, filtered and the solvents were evaporated under reduced pressure to obtain the crude product as a gum, General procedure: Two four-neck fl asks were evacuated at120 C for 1 h. The fl asks were fi lled with argon and cooled to25 C. Diethylamine (1.46 g, 0.02 mol), THF (50 mL), andN, N, N, N-tetramethylethylenediamine (2.32 g, 0.02 mol) wereplaced in the fi rst fl ask equipped with a thermometer and cooledto -20 C. Then 2.5 M n-butyllithium (8 mL, 0.02 mol) wasadded to the resulting solution, and the mixture was stirred for30 min and cooled to -78 C. The corresponding 3-benzyl-2-chloroquinoline 5 (0.015 mol) was placed in the second fl ask anddissolved in THF (50 mL). Then the mixture was cooled to-50 C. The fi rst fl ask was connected to the second fl ask bya rubber tube, and the content of the fi rst fl ask was poured intothe second one. After the completion of the ixing of the reagents, the reaction mixture was allowed to stand for 1 h and cooled to-78 C. Compound 6 was placed in the third fl ask and then itwas diluted with toluene to 50 mL and cooled to -78 C. Theresulting cold solution of compound 6 in toluene was added tothe reaction mixture. The mixture was kept for 3 h at -78 C, treated with concentrated hydrochloric acid (10 mL, 0.108 mol), and heated to 25 C. The reaction mixture was concentrated todryness, dissolved in chloroform (100 mL), and washed with water(3×30 mL). The aqueous layer was separated, and the chloroformlayer was dried over magnesium sulfate and concentrated. Thedry residue was twice suspended in toluene (50 mL) and thenfi ltered off . The resulting product was dried to constant weight.1-(6-Bromo-2-chloroquinolin-3-yl)-4-dimethylamino-2-(naphthalen-1-yl)-1-phenylbutan-2-ol (2). The yield of a mixture of twodiastereomers of 3'HCl was 3.62 g (40.5%), the (1R*, 2R*)/(1R*, 2S*) diastereomeric ratio was 60 : 40.A mixture of diastereomer hydrochlorides was obtained aswhite or beige crystals with m.p. 219.4-228.1 C (with decomp.).The chromatographic retention time tchr((1R*, 2R*)-2) = 16.03 min, tchr((1R*, 2S*)-2 = 17.35 min.1H NMR of the base (1R*, 2R*)-2 (CDCl3), delta: 1.95-2.05(s, 7 H, CH2-CH2, Me); 2.07-2.16 (m, 1 H, CH2-CH2);2.23-2.32 (m, 1 H, CH2-CH2); 2.48-2.57 (m, 1 H, CH2-CH2); 5.8-5.82 (s, 1 H, CH); 7.36-7.46 (m, 5 H, CHarom);7.48-7.53 (m, 2 H, CHarom); 7.56-7.62 (m, 2 H, CHarom);7.74-7.84 (m, 3 H, CHarom); 7.77-7.91 (m, 1 H, CHarom);8.24-8.30 (d, 1 H, CHarom, J = 7.2 Hz); 8.50-8.58 (m, 2 H, CHarom); 9.17 (s, 1 H, OH). 13C NMR of the base (1R*, 2R*)-2(CDCl3), delta: 34.0 (1 C), 44.5 (2 C), 55.5 (1 C), 56.0 (1 C), 82.0(1 C), 119.3 (1 C), 124.6 (2 C), 125.0 (1 C), 125.4 (1 C), 126.7(1 C), 127.3 (1 C), 127.7 (2 C), 128.2 (1 C), 128.4 (1 C), 129.3(1 C), 129.6 (2 C), 131.6 (2 C), 132.6 (1 C), 134.8 (1 C), 135.0(2 C), 138.5 (1 C), 139.2 (1 C), 141.1 (1 C), 144.0 (1 C), 152.1 (1 C).1H NMR of the base (1R*, 2S*)-2 (CDCl3), delta: 1.95-2.00(s, 5 H, CH2-CH2, Me); 2.00-2.10 (m, 5 H, CH2-CH2);6.00-6.05 (s, 1 H, CH); 6.85-6.95 (m, 3 H, CHarom); 7.15-7.20(m, 2 H, CHarom); 7.25 (s, 1 H, CHarom); 7.45-7.50 (m, 1 H, CHarom); 7.55-7.6 (m, 1 H, CHarom); 7.65-7.75 (m, 3 H, CHarom); 7.80-7.85 (m, 1 H, CHarom); 7.95-8.15 (m, 3 H, CHarom); 8.65-8.71 (m, 1 H, CHarom); 9.35 (s, 1 H, -OH).13C NMR of the base (1R*, 2S*)-2 (CDCl3), delta: 33.0 (1 C), 44.5(2 C), 53.5 (1 C), 56.0 (1 C), 82.0 (1 C), 124.5 (1 C), 124.8 (2 C), 125.6 (1 C), 126.0 (1 C), 126.8 (1 C), 127.2 (1 C), 127.2 (1 C), 127.3 (1 C), 127.5 (1 C), 127.8 (1 C), 128.0 (1 C), 128.2 (2 C), 129.6 (1 C), 129.8 (2 C), 134.0 (1 C), 134.5 (2 C), 140.0 (2 C), 141.0 (1 C), 146.0 (1 C), 152.0 (1 C).MS, found: m/z 559.92 [M + H]+; C31H28BrClN2O; calculatedM + H = 560.00.

Molecular Weight:332.62
XLogP3:5.8
Hydrogen Bond Acceptor Count:1
Rotatable Bond Count:2
Exact Mass:330.97634
Monoisotopic Mass:330.97634
Topological Polar Surface Area:12.9
Heavy Atom Count:19
Complexity:293
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes