6-BROMO-2(1H)-QUINOLONE

Beige Solid

6-Bromo-2(1 /-/)-quinolinone. The solution of the compound from Example 6 a) (6.0 g, 22.2 mmol) in concentrated HSulfuric acid (29.0 mL, 544 mmol) was added to (E)-N-(4-bromophenyl)-3-ethoxyacrylamide (11.2 g, 45.9 mmol) at 0°C under NPart B. Preparation of 6-Bromoquinolin-2( 1 H)-one.; [00793] The product from Part A (395mg, 1.542mmol) was added in portions to H[00535] Part B. Preparation of 6-Bromoquinolin-2(lH)-one.; [00536] The product from Part A (395mg, 1.542mmol) was added in portions to HTo a mixture of ethyl 3, 3-diethoxypropionate (62 g, 326 mmol) and water (100 ml) was added NaOH (16.0 g) while stirring. Stirring at 110° C. (open flask). After 40 min the mixture was homogeneous, heating was interrupted, and the mixture was allowed to cool to room temperature. The mixture was acidified (approx 35 ml conc. HCl, pH 3-2) and extracted (4.x.dichloromethane). The combined extracts were washed with brine (1.x.50 ml), dried (magnesium sulfate), and concentrated. 48 g of an oil was obtained. [0850] To the oil was dropwise added thionyl chloride (80 ml). The mixture was stirred at reflux (80° C.) for 1 h 30 min. After careful concentration the residue weighted 48 g (theoretical wheight should be 43 g). The acid chloride was kept overnight at -20° C. [0851] This product is mixed with dichloromethane (70 ml) and 5/7 of this solution (approx 230 mmol) was added to a solution of 4-bromoaniline (34.5 g, 201 mmol) and pyridine (50 ml) in dichloromethane (150 ml), and the mixture was shaken at room temperature over night. The mixture was filtered, and the resulting solid was washed with dichloromethane, and dried, to yield 21 g of N-(4-bromophenyl)-3-ethoxyacrylamide as colorless solid. To the filtrate was added a mixture of water (700 ml) and concentrated hydrochloric acid (50 ml). A solid precipitated upon shaking, and was filtered off, washed with dichloromethane and AcOEt, and dried. Additional 14.4 g of product were obtained. [0852] The filtrates were extracted (3.x.dichloromethane), washed once with brine, dried, and concentrated. Additional 18 g of product resulted. Total yield: 53.4 g. [0853] This product (58.8 g; 218 mmol) was mixed with ice-cold concentrated sulfuric acid (390 ml) and the mixture was stirred first at 0° C. for 15 min (until almost all acrylamide had dissolved) and then at room temperature for 4 h. The mixture was then poured into ice water (3 l) and allowed to stand overnight. The mixture was filtered, and the solid was washed with water. The solid was transferred into a flask with the aid of acetonitrile, ethanol, and dichloromethane, and the suspension was concentrated under reduced pressure. The residue was resuspended in acetonitrile (300 ml), heated to reflux, and allowed to stand at room temperature overnight. Filtration and drying of the solid under reduced pressure yielded 31.3 g (64percent) of 6-bromo-2-quinolone as a yellow solid. [0854] This quinolone (6.28 g, 28.0 mmol) was mixed with copper(I) cyanide (5.02 g, 56.1 mmol) and NMP (15 ml), and the mixture was stirred under reflux (202° C.) for 6 h, and then at room temperature overnight. Water (150 ml) was added, the mixture was filtered, and the solid was washed with water. The solid was resuspended in 1 N hydrochloric acid (200 ml) and iron(III) chloride hexahydrate (17.8 g) was added. The resulting mixture was stirred at room temperature for 3 d, filtered, and the solid was washed once with water, stripped with ethanol, and dried under reduced pressure, to yield 4.33 g (91percent) of 6-cyano-2-quinolone as a gray solid. Treatment of the product with POCl3 and then with 1-isopropylpiperazine as described in the General Procedure (B) yielded the title compound. [0855] 1H NMR (DMSO-d6) δ1.31 (d, J=7 Hz, 6H), 3.10 (m, 2H), 3.52 (m, 5H), 4.79 (m, 2H), 7.49 (d, J=8 Hz, 1H), 7.71 (d, J=8 Hz, 1H), 7.86 (d, J=8 Hz, 1H), 8.23 (d, J=8 Hz, 1H), 8.35 (s, 1H), 10.73 (br s, 1H); HPLC-MS: m/z 281 (MH+); Rt=1.62 min.This compound was prepared using the General Procedure (B) from 1-isopropylpiperazine and 2-chloro-6-(1-pyrazolyl)quinoline. The required 2-chloro-6-(1-pyrazolyl)quinoline was prepared by treatment of 6-(1-pyrazolyl)-2-quinolone with POCl3. 6-(1-Pyrazolyl)-2-quinolone was prepared in the following way: [0873] A mixture of 6-Bromo-2(1 /-/)-quinolinone. The solution of the compound from Example 6 a) (6.0 g, 22.2 mmol) in concentrated H2SO4 (30 mL) was heated in 100 0C EPO Sulfuric acid (29.0 mL, 544 mmol) was added to (E)-N-(4-bromophenyl)-3-ethoxyacrylamide (11.2 g, 45.9 mmol) at 0C under N2 (g). The mixture was stirred for 3 h at room temperature. The reaction was quenched by transferring the reaction mixture to ice fragments. At this point, the color of the reaction mixture turned to pink. After the ice melted, the quenched mixture was filtered and washed with sufficient H2O to afford bromoquinoline 6 (9.10 g, 89 %) as a pink solid:General procedure: In a round bottom flask were added (pyridine or quinoline or isoquinoline) of nitrogen oxides (1.0eq.), PyBrOP (2.0eq.), Sodium acetate (3.0 eq.), Water (10 to 20.0 eq.), Adding 1, 2-dichloroethane (substrate concentration 0.25 mol / L), And then heated to 60 ~ 85 degrees reaction, TLC followed the reaction until the end of the reaction (6 to 14 h).After completion of the reaction, petroleum ether: ethyl acetate = 5: 1 ~ 1: 1 as the mobile phase, Column chromatography gave the compounds shown in Table 1, Yield 45-92%.A mixture of the following reagents were divided into three equal batches; To a stirred solution of N-(4-bromophenyl)cinnamamide, 21 (25.0 g, 82 mmol) in chlorobenzene (125 mL) was added A1C13 (49.5 g, 372 mmol) in portions at 0 C and the mixture was stirred for 15 min. The resulting reaction mixture was heated to 90 C and was stirred for 2 h. The progress of the reaction was monitored by TLC (TLC system: 30 % EtOAc/Pet ether, Rf value: 0.01). After completion of reaction, reaction mixture was quenched with ice cold water, filtered and washed with diethyl ether to afford 6-bromoquinolin-2(lH)-one, 22 as a brown solid. LC-MS: 97.1 % at 215 nm (m/z = 224.0, [M+H]+).

Molecular Weight:224.05
XLogP3:2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:1
Exact Mass:222.96328
Monoisotopic Mass:222.96328
Topological Polar Surface Area:29.1
Heavy Atom Count:12
Complexity:227
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes