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Stage #1: for 2 h; Heating / reflux Stage #2: With ammonia In water
IP 14c. 6-bromo-2-chloro-4-methylquinoline 25 mL of phosphorus oxychloride was added to 2.7 g (11.34 mmol) of 6-bromo-4-methyl-1H-quinolin-2-one (Example 1b) and the reaction mixture was refluxed for 2 hours. After cooling, the mixture was added batchwise to 250 mL of 10percent NH3 solution, and the precipitate formed was filtered off, washed with water, and dried in the circulating air dryer at 30° C. Yield: 2.7 g (93percent of theoretical); C10H7BrClN (M=256.526); calc.: molpeak (M+H)+: 256/258/260 (BrCl); found: molpeak (M+H)+: 256/258/260 (BrCl); Rf value: 0.95 (silica gel, DCM/MeOH 9:1).
93%
for 2 h; Heating / reflux
1.43a. 6-bromo-2-chloro-4-methylquinoline 25 mL of phosphorus oxychloride is added to 2.7 g (11.34 mmol) of 6-bromo-4-methyl-1H-quinolin-2-one (Example 1b) and the reaction mixture is refluxed for 2 hours. After cooling, the mixture is added batchwise to 250 mL of 10percent NH3 solution, the precipitate formed is filtered off, washed with water, and dried in the circulating air dryer at 30° C. Yield: 2.7 g (93percent of theoretical); C10H7BrClN (M=256.526); calc.: molpeak (M+H)+: 256/258/260 (BrCl); found: molpeak (M+H)+: 256/258/260 (BrCl); Rf value: 0.95 (silica gel, DCM/MeOH 9:1).
86%
Stage #1: at 100℃; for 0.0833333 h; Microwave irradiation Stage #2: With sodium hydrogencarbonate In waterCooling with ice
[0604] (c) 6-Bromo-2-chloro-4-methylquinoline: 6-Bromo-4-methylquinolin-2(lH)-one (0.13 g, 0.546 mmol) was placed in a microwave vial and treated with POCI3 (0.4 rnL, 3.78 mmol). The reaction was heated in the microwave at 100 0C for 5 min. The reaction was poured into a beaker containing ice, neutralized using sat. NaHCO3 and then transferred to a separatory funnel using EtOAc. The organic layer was washed with water, dried (Na2SO4), filtered and concentrated to yield the desired product (0.12 g, 86percent).
[0603] (b) 6-Bromo-4-methylquinolin-2(lH)-one: N-(4-Bromophenyl)-3- oxobutanamide (0.73 g, 2.85 mmol) was dissolved in cone. H2SO4 (7 mL) and heated to 120 0C via oil bath for 1 hour. The reaction mixture was cooled to room temperature, transferred to a beaker containing ice and the resulting precipitates were filtered off. The desired product was isolated as a tan solid (0.4 g, 60percent).
52%
at 120℃; for 1 h;
IP 14b. 6-bromo-4-methyl-1H-quinolin-2-one A solution of 50.0 g (195 mmol) of N-(4-bromophenyl)-3-oxobutyramide in 217 mL of concentrated sulfuric acid was heated to 120° C. for 1 hour. After cooling to RT, the reaction solution was added to 1.5 L of ice water, stirred for 30 minutes, and the precipitate formed was filtered and washed with 4 L of water. Subsequently it was dried at 35° C. in the circulating air dryer until a constant weight was achieved. Yield: 24.0 g (52percent of theoretical); C10H8BrNO (M=238.081); calc.: molpeak (M+H)+: 238/240 (Br); found: molpeak (M+H)+: 238/240 (Br); HPLC-MS: 4.8 minutes (method B).
52%
at 120℃; for 1 h;
1b.6-bromo-4-methyl-1H-quinolin-2-one A solution of 50.0 g (195 mmol) of N-(4-bromophenyl)-3-oxobutyramide in 217 mL of concentrated sulfuric acid is heated to 120° C. for 1 hour. After cooling to RT, the reaction solution is added to 1.5 L of ice water, stirred for 30 minutes, and the precipitate formed is filtered and washed again with 4 L of water. Subsequently it is dried at 35° C. in the circulating air dryer until the weight is constant. Yield: 24.0 g (52percent of theoretical); C10H8BrNO (M=238.081); calc.: molpeak (M+H)+: 238/240 (Br); found: molpeak (M+H)+: 238/240 (Br); HPLC-MS: 4.8 min (method B).
[0603] (b) 6-Bromo-4-methylquinolin-2(lH)-one: N-(4-Bromophenyl)-3- oxobutanamide (0.73 g, 2.85 mmol) was dissolved in cone. H2SO4 (7 mL) and heated to 120 0C via oil bath for 1 hour. The reaction mixture was cooled to room temperature, transferred to a beaker containing ice and the resulting precipitates were filtered off. The desired product was isolated as a tan solid (0.4 g, 60%).
52%
With sulfuric acid; at 120.0℃; for 1.0h;
IP 14b. 6-bromo-4-methyl-1H-quinolin-2-one A solution of 50.0 g (195 mmol) of N-(4-bromophenyl)-3-oxobutyramide in 217 mL of concentrated sulfuric acid was heated to 120 C. for 1 hour. After cooling to RT, the reaction solution was added to 1.5 L of ice water, stirred for 30 minutes, and the precipitate formed was filtered and washed with 4 L of water. Subsequently it was dried at 35 C. in the circulating air dryer until a constant weight was achieved. Yield: 24.0 g (52% of theoretical); C10H8BrNO (M=238.081); calc.: molpeak (M+H)+: 238/240 (Br); found: molpeak (M+H)+: 238/240 (Br); HPLC-MS: 4.8 minutes (method B).
52%
With sulfuric acid; at 120.0℃; for 1.0h;
1b.6-bromo-4-methyl-1H-quinolin-2-one A solution of 50.0 g (195 mmol) of N-(4-bromophenyl)-3-oxobutyramide in 217 mL of concentrated sulfuric acid is heated to 120 C. for 1 hour. After cooling to RT, the reaction solution is added to 1.5 L of ice water, stirred for 30 minutes, and the precipitate formed is filtered and washed again with 4 L of water. Subsequently it is dried at 35 C. in the circulating air dryer until the weight is constant. Yield: 24.0 g (52% of theoretical); C10H8BrNO (M=238.081); calc.: molpeak (M+H)+: 238/240 (Br); found: molpeak (M+H)+: 238/240 (Br); HPLC-MS: 4.8 min (method B).
With sulfuric acid;
B. 6-Bromo-4-methyl-2-(1H)-quinolinone A mixture of 3.00 g (0.0117 moles) of N-(4-bromophenyl)-3-oxobutyramide and 6 ml concentrated sulfuric acid was stirred and heated to 95-100 C. (H2 O bath) for 11/2 hours. The resulting solution was poured onto an ice/H2 O mixture to yield a white crystalline product. The crystals were collected and taken up in 200 ml absolute ethanol. The volume was reduced to 150 ml followed by chilling; crystals were isolated (0.71 g 25.6%), mp 292-299 C. Anal. Calcd. for C10 H8 BrNO: C, 50.45; H, 3.39; N, 5.88; Br, 33.56. Found: C, 50.28; H, 3.44; N, 5.83; Br, 33.68. A TLC of the product on silica showed Rf 0.18 with ethyl acetate eluent.
With sulfuric acid;
B. 6-Bromo-4-methyl-2-(1H)-quinolinone A mixture of 3.00g (0.0117 moles) of N -(4-bromophenyl)-3-oxobutyramide and 6 ml concentrated sulfuric acid was stirred and heated to 95-100C (H2O bath) for 11/2 hours. The resulting solution was poured onto an ice/H2O mixture to yield a white crystalline product. The crystals were collected and taken up in 200 ml absolute ethanol. The volume was reduced to 150 ml followed by chilling; crystals were isolated (0.71g 25.6%), mp 292-299C. Anal . Calcd. for C10H8BrNO: C, 50.45; H, 3.39; N, 5.88; Br, 33.56. Found: C, 50. 28; H, 3.44; N, 5.83; Br, 33.68. A TLC of the product on silica showed Rf0.18 with ethyl acetate eluent.
IP 14c. 6-bromo-2-chloro-4-methylquinoline 25 mL of phosphorus oxychloride was added to 2.7 g (11.34 mmol) of 6-bromo-4-methyl-1H-quinolin-2-one (Example 1b) and the reaction mixture was refluxed for 2 hours. After cooling, the mixture was added batchwise to 250 mL of 10% NH3 solution, and the precipitate formed was filtered off, washed with water, and dried in the circulating air dryer at 30 C. Yield: 2.7 g (93% of theoretical); C10H7BrClN (M=256.526); calc.: molpeak (M+H)+: 256/258/260 (BrCl); found: molpeak (M+H)+: 256/258/260 (BrCl); Rf value: 0.95 (silica gel, DCM/MeOH 9:1).
93%
With trichlorophosphate; for 2h;Heating / reflux;
1.43a. 6-bromo-2-chloro-4-methylquinoline 25 mL of phosphorus oxychloride is added to 2.7 g (11.34 mmol) of 6-bromo-4-methyl-1H-quinolin-2-one (Example 1b) and the reaction mixture is refluxed for 2 hours. After cooling, the mixture is added batchwise to 250 mL of 10% NH3 solution, the precipitate formed is filtered off, washed with water, and dried in the circulating air dryer at 30 C. Yield: 2.7 g (93% of theoretical); C10H7BrClN (M=256.526); calc.: molpeak (M+H)+: 256/258/260 (BrCl); found: molpeak (M+H)+: 256/258/260 (BrCl); Rf value: 0.95 (silica gel, DCM/MeOH 9:1).
86%
[0604] (c) 6-Bromo-2-chloro-4-methylquinoline: 6-Bromo-4-methylquinolin-2(lH)-one (0.13 g, 0.546 mmol) was placed in a microwave vial and treated with POCI3 (0.4 rnL, 3.78 mmol). The reaction was heated in the microwave at 100 0C for 5 min. The reaction was poured into a beaker containing ice, neutralized using sat. NaHCO3 and then transferred to a separatory funnel using EtOAc. The organic layer was washed with water, dried (Na2SO4), filtered and concentrated to yield the desired product (0.12 g, 86%).
With sodium iodide;copper(l) iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 110.0℃;
1c. 6-iodo-4-methyl-1H-quinolin-2-one A mixture of 5.0 g (21.0 mmol) of <strong>[89446-19-5]6-bromo-4-methyl-1H-quinolin-2-one</strong> and 400 mg (2.1 mmol) of CuI in 21 mL 1,4-dioxane is evacuated and gassed with argon. Then 6.3 g (42.0 mmol) of NaI and 0.45 mL (4.2 mmol) of N,N'-dimethylethylenediamine are added, the mixture is evacuated again and gassed with argon before being heated overnight to 110 C. HPLC analysis of the mixture shows approximately 20% reaction. Therefore another 400 mg (2.1 mmol) of CuI, 6.3 g (42.0 mmol) of NaI, 0.45 mL (4.2 mmol) of N,N'-dimethylethylenediamine, and 21 mL of 1,4-dioxane are added and this mixture is heated overnight again to 110 C. To complete the reaction, the above procedure is repeated another three times. After cooling, the suspension is combined with 10% NH3 solution and water and the precipitated product is filtered off. This is then washed with 10% NH3 solution, water, isopropanol, DIPE, EtOAc, and DCM and dried overnight in the air. The product, which still contains approximately 20% educt, is further reacted without purification. Yield: 3.0 g (40% of theoretical); C10H8INO (M=285.081); calc.: molpeak (M+H)+: 286; found: molpeak (M+H)+: 286; HPLC-MS: 5.0 min (method B).
6-Bromo-4-methyl-2(1H)-quinolinone (Compound 757, Structure 16c of Scheme XXX, Where R=H, R1=Methyl) This compound was prepared in a similar fashion as that described in Example 1, General Procedure I by Knorr reaction of 4-bromoaniline and ethyl acetoacetate. Compound 757 was isolated as a white solid: 1H NMR (400 MHz, DMSO-d6) 11.7 (s, 1H), 7.86 (d, J=2.1, 1H), 7.66 (dd, J=7.5, 2.1, 1H), 7.27 (d, J=7.5, 1H), 6.45 (s, 1H), 2.41 (s, 3H).
C. 6-Bromo-2-chloro-4-methylquinoline A 0.46 g, (0.0019 mole) sample of 6-bromo-4-methyl-2-(1H)-quinolinone was dissolved in 3.0 ml POCl3 under N2 with stirring and heated to reflux for 2 hours. The solution solidified into a purple gum; 2.0 ml of extra POCl3 was added to dissolve the solid. The solution was then slowly poured onto a vigorously stirred slurry of 8 ml concentrated NH4 OH and approximately 75 g of ice. An immediate pink crystalline solid formed. The slurry was transferred to a separatory funnel and extracted with five 30 ml portions of CH2 Cl2. The extracts were washed with two 40 ml portions of water and dried over MgSO4. The solvent was removed under vacuum, leaving a rusty red crystalline solid, 0.48 g (97%). The product was taken up in hot absolute ethanol, Norite A decolourising carbon added, and filtered through Celite to yield a yellow liquid. Slow cooling of the ethanolic solution gave very fine, pink crystals, m.p. 139.1-139.80 C. TLC showed Rf 0.25 on silica with 1:1 hexane:CH2 Cl2 eluent. Anal. Calcd. for C10 H7 BrClN: C, 46.82; H, 2.75; N, 5.46; Br, 31.15; Cl, 13.82. Found: C, 46.97; H, 2.79; N, 5.42; Br, 31.08; Cl, 13.79.
C. 6-Bromo-2-chloro-4-methylquinoline A 0.46g, (0.0019 mole) sample of 6-bromo-4-methyl-2(1 H)-quinolinone was dissolved in 3.0 ml POCl3 under N2 with stirring and heated to reflux for 2 hours. The solution solidified into a purple gum; 2.0 ml of extra POCl3 was added to dissolve the solid. The solution was then slowly poured onto a vigorously stirred slurry of 8 ml concentrated NH4OH and approximately 75g of ice. An immediate pink crystalline solid formed. The slurry was transferred to a separatory funnel and extracted with five 30 ml portions of CH2Cl2. The extracts were washed with two 40 ml portions of water and dried over MgSO4.The solvent was removed under vacuum, leaving a rusty red crystalline solid, 0.48g (97%). The product was taken up in hot absolute ethanol, Norite A decolourising carbon added, and filtered through Celite to yield a yellow liquid. Slow cooling of the ethanolic solution gave very fine, pink cystals, m.p. 139. 1-139. 80C. TLC showed Rf0.25 on silica with 1:1 hexane:CH2Cl2 eluent. Anal . Calcd. for C10H7BrClN: C, 46.82; H, 2.75; N, 5.46; Br, 31.15; Cl, 13.82. Found: C, 46.97; H, 2.79; N, 5.42; Br, 31.08; Cl, 13.79.
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