5-chloro-3,4-dihydro-1H-quinolin-2-one

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In the same manner as in Reference Example 1, 60% sodium hydride in oil was added portionwise to a solution of 5-chloro-3,4-dihydrocarbostyril in DMF, the resultant mixture was stirred for 30 minutes, 1-bromo-3-chloropropane was then added, and the resultant mixture was further stirred at 80°-90° C. for 8 hours. The DMF was distilled off under reduced pressure, and the residue was extracted with chloroform. The extract was washed with water and dried (anhydrous magnesium sulfate), the chloroform was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 5-chloro-1-(3-chloropropyl)-3,4-dihydrocarbostyril as a pale yellow oil. The DMF was distilled off under reduced pressure the residue was extracted with chloroform The extract was washed with water dried (anhydrous magnesium sulfate) the chloroform was distilled off under reduced pressure the residue was purified by silica gel column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In the same manner as in Reference Example 1, 60% sodium hydride in oil was added portionwise to a solution of 5-chloro-3,4-dihydrocarbostyril in DMF, the resultant mixture was stirred for 30 minutes, 1-bromo-3-chloropropane was then added, and the resultant mixture was further stirred at 80°-90° C. for 8 hours. The DMF was distilled off under reduced pressure, and the residue was extracted with chloroform. The extract was washed with water and dried (anhydrous magnesium sulfate), the chloroform was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 5-chloro-1-(3-chloropropyl)-3,4-dihydrocarbostyril as a pale yellow oil. The DMF was distilled off under reduced pressure the residue was extracted with chloroform The extract was washed with water dried (anhydrous magnesium sulfate) the chloroform was distilled off under reduced pressure the residue was purified by silica gel column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In the same manner as in Reference Example 1, 60% sodium hydride in oil was added portionwise to a solution of 5-chloro-3,4-dihydrocarbostyril in DMF, the resultant mixture was stirred for 30 minutes, 1-bromo-3-chloropropane was then added, and the resultant mixture was further stirred at 80°-90° C. for 8 hours. The DMF was distilled off under reduced pressure, and the residue was extracted with chloroform. The extract was washed with water and dried (anhydrous magnesium sulfate), the chloroform was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 5-chloro-1-(3-chloropropyl)-3,4-dihydrocarbostyril as a pale yellow oil. The DMF was distilled off under reduced pressure the residue was extracted with chloroform The extract was washed with water dried (anhydrous magnesium sulfate) the chloroform was distilled off under reduced pressure the residue was purified by silica gel column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In the same manner as in Reference Example 1, 60% sodium hydride in oil was added portionwise to a solution of 5-chloro-3,4-dihydrocarbostyril in DMF, the resultant mixture was stirred for 30 minutes, 1-bromo-3-chloropropane was then added, and the resultant mixture was further stirred at 80°-90° C. for 8 hours. The DMF was distilled off under reduced pressure, and the residue was extracted with chloroform. The extract was washed with water and dried (anhydrous magnesium sulfate), the chloroform was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 5-chloro-1-(3-chloropropyl)-3,4-dihydrocarbostyril as a pale yellow oil. The DMF was distilled off under reduced pressure the residue was extracted with chloroform The extract was washed with water dried (anhydrous magnesium sulfate) the chloroform was distilled off under reduced pressure the residue was purified by silica gel column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 42.5 g of 5-chloro-3,4-dihydrocarbostyril was suspended in 250 ml of dioxane and 44.3 g of NaBH4 was added to the suspension. Then 67 ml of acetic acid (d=1.05) was added dropwise to the mixture at room temperature. After heat-refluxing the resulting mixture for 2 hours the solvent was removed under reduced pressure. Water was added to the residue and insoluble materials were removed by filtration followed by washing with diethyl ether. The residue was extracted with diethyl ether, dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain 36.0 g of 5-chloro-1,2,3,4-tetrahydroquinoline having a boiling point of 116° to 120° C./0.2 mmHg. After heat-refluxing the resulting mixture for 2 hours the solvent was removed under reduced pressure Water was added to the residue and insoluble materials were removed by filtration by washing with diethyl ether The residue was extracted with diethyl ether dried over anhydrous sodium sulfate distilled under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 45 g of 5-amino-3,4-dihydrocarbostyril was suspended in 250 ml of a 15% hydrochloric acid and 250 ml of water having dissolved therein 20 g of sodium nitrite was added dropwise to the mixture followed by stirring at room temperature for 1 hour. The resulting solution was added dropwise to a solution prepared by dissolving 41.2 g of cuprous chloride in 120 ml of concentrated hydrochloric acid at room temperature while stirring. After completion of the addition, the mixture was heated on a water bath at 50° to 60° C. for 1 hour while stirring. After allowing the mixture to cool to precipitate crystals, they were collected by filtration and washed with water. The wet crystals were dissolved in chloroform and insoluble materials were removed by filtration. The residue was dried over anhydrous sodium sulfate. After removal of the solvent the residue was dissolved with heating and the solution was treated with activated carbon while hot. The ethanolic solution thus-treated was concentrated under reduced pressure. Recrystallization of the concentrate from ethanol gave 31.5 g of 5-chloro-3,4-dihydrocarbostyril having a melting point of 193° to 194° C. dissolved The resulting solution was added dropwise to a solution prepared while stirring After completion of the addition the mixture was heated on a water bath at 50° to 60° C. for 1 hour while stirring to cool to precipitate crystals, they were collected by filtration washed with water The wet crystals were dissolved in chloroform insoluble materials were removed by filtration The residue was dried over anhydrous sodium sulfate After removal of the solvent the residue was dissolved with heating the solution was treated with activated carbon while hot The ethanolic solution thus-treated was concentrated under reduced pressure Recrystallization of the concentrate from ethanol

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 5-chloro-3,4-dihydroquinolin-2(1H)-one (147-4; 1 g, 0.0055 mol) and cyclopropylboronic acid (0.95 g, 0.0110 mol) in tetrahydrofuran (30 mL) was added potassium phosphate (3.4 g, 0.0165 mol) and S-Phos (0.45 g, 0.0011 mol). Reaction mass was purged with argon for 20 min. Then catalyst palladium acetate (0.123 g, 0.00055 mol) was added and allowed to stir at 120° C. for 12 h. The reaction mixture was filtered through CELITE bed and filter bed was thoroughly washed with ethyl acetate. The collected organic part was concentrated under vacuum to afford the crude compound, which was purified by silica gel column chromatography to obtain title compound. MS (M+1): 188.1. Reaction mass was purged with argon for 20 min The reaction mixture was filtered through CELITE bed filter bed was thoroughly washed with ethyl acetate The collected organic part was concentrated under vacuum to afford the crude compound, which was purified by silica gel column chromatography

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 5-chloro-3,4-dihydroquinolin-2(1H)-one (143-4; 1.8 g, 0.0099 mol) and nickel bromide (2.15 g, 0.0099 mol) in N-methyl-2-pyrrolidone (10 mL) was added sodium cyanide (0.97 g, 0.0198 mol) portion wise at room temperature. Reaction mixture was heated at 200° C. for 10 min under microwave irradiation. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to obtain the title compound. MS (M−1): 171.2. Reaction mixture extracted with ethyl acetate (2×100 mL) The combined organic layer was washed with saturated aqueous sodium chloride solution dried over sodium sulphate concentrated under vacuum

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 5-chloro-3,4-dihydroquinolin-2(1H)-one (143-4; 0.4 g, 0.022 mol) in N,N-dimethylformamide (10 mL) was added N-bromosuccinimide (0.47 g, 0.0026 mol) portion wise at 0° C. Reaction mixture was allowed to stir at room temperature for 12 h. The reaction mixture was concentrated and diluted with ice cold water (100 mL) with constant stirring and the solid residue was filtered and dried to obtain the title compound. MS (M+1): 259.9. Reaction mixture The reaction mixture was concentrated diluted with ice cold water (100 mL) with constant stirring the solid residue was filtered dried

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 3-chloro-2-iodoaniline (143-3; 1.1 g, 0.0043 mol), AIBN (0.282 g, 0.0017 mol), tributyl tinhydride (1.8 g, 0.0064 mol) in dimethyl sulphoxide (10 mL) was added ethylacrylate (1.7 g, 0.173 mol) portion wise at 0° C. Reaction mixture was allowed to stir at 120° C. for 12 h. The reaction mixture was diluted with ice cold water (150 mL) and extracted with ethyl acetate (4×100 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to obtain the title compound. 1H NMR (400 MHz, CDCl3) δ 7.159-7.119 (t, J=7.6 Hz, 1H), 7.021-7.002 (d, J=7.6 Hz, 1H), 6.819-6.800 (d, J=7.6 Hz, 1H), 2.941-2.651 (t, J=8 Hz, 4H). MS (M+1): 181.8. Reaction mixture extracted with ethyl acetate (4×100 mL) The combined organic layer was washed with saturated aqueous sodium chloride solution dried over sodium sulphate concentrated under vacuum

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In the same manner as in Reference Example 1, 60% sodium hydride in oil was added portionwise to a solution of 5-chloro-3,4-dihydrocarbostyril in DMF, the resultant mixture was stirred for 30 minutes, 1-bromo-3-chloropropane was then added, and the resultant mixture was further stirred at 80°-90° C. for 8 hours. The DMF was distilled off under reduced pressure, and the residue was extracted with chloroform. The extract was washed with water and dried (anhydrous magnesium sulfate), the chloroform was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 5-chloro-1-(3-chloropropyl)-3,4-dihydrocarbostyril as a pale yellow oil. The DMF was distilled off under reduced pressure the residue was extracted with chloroform The extract was washed with water dried (anhydrous magnesium sulfate) the chloroform was distilled off under reduced pressure the residue was purified by silica gel column chromatography