4-chloro-3-methylaniline

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Synthesized according to General Procedure 1. 4-chloro-3-methylaniline (5 g, 35.3 mmol) in water (15 mL) and conc. HCl (9.5 mL, 116.5 mmol) at −5° C. was added a freshly prepared aqueous solution of sodium nitrite (3.2 g, 45.9 mmol) in water (8 mL) slowly over 10 minutes. After stirring for 15 minutes at −5° C. a freshly prepared aqueous solution of sodium tetrafluoroborate (5.4 g, 49.4 mmol) in water (14 mL) was added in one portion causing the formation of a precipitate. The solid was filtered and washed with cold (5° C.) diethyl ether (10 mL). The solid was dissolved in acetone (15 mL) and filtered. To the filtrate was added diethyl ether (15 mL) causing the precipitation of the arenediazonium tetrafluoroborate. The solid was filtered, washed with cold (5° C.) diethyl ether (5 mL) and then air dried overnight to provide 4-chloro-3-methylbenzenediazonium tetrafluoroborate (8.07 g, 33.6 mmol, 95% yield) as a tan solid. 1H-NMR (400 MHz, DMSO-d6) δ 8.68 (d, J=2.2 Hz, 1H), 8.56 (dd, J=2.4, 8.8 Hz, 1H), 8.10 (d, J=8.8 Hz, 1H) and 3.47 (s, 3H) ppm. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA), m/z: M+1 obs=125.0; tR=0.24 min. Synthesized was added in one portion The solid was filtered washed with cold (5° C.) diethyl ether (10 mL) The solid was dissolved in acetone (15 mL) filtered To the filtrate was added diethyl ether (15 mL) the precipitation of the arenediazonium tetrafluoroborate The solid was filtered washed with cold (5° C.) diethyl ether (5 mL) air dried overnight

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

Procedure: 1-Benzyloxycarbonylpiperidine-4-carboxylic acid (1.00 g, 3.80 mmol) and 4-chloro-3-methyl-aniline (0.592 g, 4.18 mmol) in CH2Cl2 (5 mL) were treated with HOBT (0.582, 3.80 mmol) and EDC (1.46 g, 7.60 mmol), and stirred at rt for 16 h. The mixture was directly purified on SiO2 (50 to 100% EtOAc, hexanes) to afford the title compound. HPLC/MS: 387.2/389.1 (M+1); Rt=1.22 min (LC2). The mixture was directly purified on SiO2 (50 to 100% EtOAc, hexanes)

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

Procedure: To 4-chloro-3-methylaniline (3.33 g, 19.98 mmole) in dichloromethane (100 mL) and pyridine (20 mL) was added cinnamoyl chloride (2.83 g, 19.98 mmole) at 0° C. The mixture was stirred at room temperature for 2 h. Solvent and pyridine were removed by rotary evaporator under reduced pressure. The residue was diluted with ethyl acetate and washed 1N HCl (2×100 mL), water (2×100 mL), sodium bicarbonate solution (2×100 mL) and dried over sodium sulfate. After removing solvent a white solid was recovered (5.38 g, 99% yield). The product was used for the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ 7.76-7.24 (m, 10H), 6.58 (d, 1H), 2.55 (s, 3H); MS (ESI) m/z: Calculated for C16H14ClNO: 271.1. found: 272 (M+H)+. Solvent and pyridine were removed by rotary evaporator under reduced pressure The residue was diluted with ethyl acetate washed 1N HCl (2×100 mL), water (2×100 mL), sodium bicarbonate solution (2×100 mL) dried over sodium sulfate After removing solvent a white solid was recovered (5.38 g, 99% yield) The product was used for the next step without further purification

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

Procedure: Alternatively, to a solution of 4-chloro-3-methyl aniline (20.0 g, 0.141 mol) in MeOH (400 mL) was added drop-wise dimethyl acetylenedicarboxylate (21.07 g, 0.148 mol). The reaction mixture was stirred at ambient temperature for 30 minutes. The solvent was removed by evaporation and the residue was added to stirred diphenyl ether (300 mL), which has been preheated to 250° C. After 30 minutes, the mixture was cooled to ambient temperature and the resulting precipitate was collected and washed with 1 L of hot petroleum ether to give a mixture (29.0 g) of 2-methoxycarbonyl-6-chloro-7-methyl-4-oxoquinoline and 2-methoxycarbonyl-6-chloro-5-methyl-4-oxoquinoline as a gray solid. The mixture was dissolved in boiling methanol (1 L) and filtered hot. The collected solids were boiled in 1.2 L of methanol and filtered hot to afford (6.45 g, 16%) of 2-methoxycarbonyl-6-chloro-7-methyl-4-oxoquinoline: 1H NMR (DMSO-d6) 2.41 (s, 3), 3.92 (s, 3), 6.58 (s, 1), 7.86 (s, 1), 7.96 (s, 1) ppm. The solvent was removed by evaporation the residue was added to stirred diphenyl ether (300 mL), which has been preheated to 250° C After 30 minutes the mixture was cooled to ambient temperature the resulting precipitate was collected washed with 1 L of hot petroleum ether

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

Procedure: Alternatively, to a solution of 4-chloro-3-methyl aniline (20.0 g, 0.141 mol) in MeOH (400 mL) was added drop-wise dimethyl acetylenedicarboxylate (21.07 g, 0.148 mol). The reaction mixture was stirred at ambient temperature for 30 minutes. The solvent was removed by evaporation and the residue was added to stirred diphenyl ether (300 mL), which has been preheated to 250° C. After 30 minutes, the mixture was cooled to ambient temperature and the resulting precipitate was collected and washed with 1 L of hot petroleum ether to give a mixture (29.0 g) of 2-methoxycarbonyl-6-chloro-7-methyl-4-oxoquinoline and 2-methoxycarbonyl-6-chloro-5-methyl-4-oxoquinoline as a gray solid. The mixture was dissolved in boiling methanol (1 L) and filtered hot. The collected solids were boiled in 1.2 L of methanol and filtered hot to afford (6.45 g, 16%) of 2-methoxycarbonyl-6-chloro-7-methyl-4-oxoquinoline: 1H NMR (DMSO-d6) 2.41 (s, 3), 3.92 (s, 3), 6.58 (s, 1), 7.86 (s, 1), 7.96 (s, 1) ppm. The solvent was removed by evaporation the residue was added to stirred diphenyl ether (300 mL), which has been preheated to 250° C After 30 minutes the mixture was cooled to ambient temperature the resulting precipitate was collected washed with 1 L of hot petroleum ether

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Synthesized according to General Procedure 1. 4-chloro-3-methylaniline (5 g, 35.3 mmol) in water (15 mL) and conc. HCl (9.5 mL, 116.5 mmol) at −5° C. was added a freshly prepared aqueous solution of sodium nitrite (3.2 g, 45.9 mmol) in water (8 mL) slowly over 10 minutes. After stirring for 15 minutes at −5° C. a freshly prepared aqueous solution of sodium tetrafluoroborate (5.4 g, 49.4 mmol) in water (14 mL) was added in one portion causing the formation of a precipitate. The solid was filtered and washed with cold (5° C.) diethyl ether (10 mL). The solid was dissolved in acetone (15 mL) and filtered. To the filtrate was added diethyl ether (15 mL) causing the precipitation of the arenediazonium tetrafluoroborate. The solid was filtered, washed with cold (5° C.) diethyl ether (5 mL) and then air dried overnight to provide 4-chloro-3-methylbenzenediazonium tetrafluoroborate (8.07 g, 33.6 mmol, 95% yield) as a tan solid. 1H-NMR (400 MHz, DMSO-d6) δ 8.68 (d, J=2.2 Hz, 1H), 8.56 (dd, J=2.4, 8.8 Hz, 1H), 8.10 (d, J=8.8 Hz, 1H) and 3.47 (s, 3H) ppm. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA), m/z: M+1 obs=125.0; tR=0.24 min. Synthesized was added in one portion The solid was filtered washed with cold (5° C.) diethyl ether (10 mL) The solid was dissolved in acetone (15 mL) filtered To the filtrate was added diethyl ether (15 mL) the precipitation of the arenediazonium tetrafluoroborate The solid was filtered washed with cold (5° C.) diethyl ether (5 mL) air dried overnight

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

Procedure: Synthesized according to General Procedure 1. 4-chloro-3-methylaniline (5 g, 35.3 mmol) in water (15 mL) and conc. HCl (9.5 mL, 116.5 mmol) at −5° C. was added a freshly prepared aqueous solution of sodium nitrite (3.2 g, 45.9 mmol) in water (8 mL) slowly over 10 minutes. After stirring for 15 minutes at −5° C. a freshly prepared aqueous solution of sodium tetrafluoroborate (5.4 g, 49.4 mmol) in water (14 mL) was added in one portion causing the formation of a precipitate. The solid was filtered and washed with cold (5° C.) diethyl ether (10 mL). The solid was dissolved in acetone (15 mL) and filtered. To the filtrate was added diethyl ether (15 mL) causing the precipitation of the arenediazonium tetrafluoroborate. The solid was filtered, washed with cold (5° C.) diethyl ether (5 mL) and then air dried overnight to provide 4-chloro-3-methylbenzenediazonium tetrafluoroborate (8.07 g, 33.6 mmol, 95% yield) as a tan solid. 1H-NMR (400 MHz, DMSO-d6) δ 8.68 (d, J=2.2 Hz, 1H), 8.56 (dd, J=2.4, 8.8 Hz, 1H), 8.10 (d, J=8.8 Hz, 1H) and 3.47 (s, 3H) ppm. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA), m/z: M+1 obs=125.0; tR=0.24 min. Synthesized was added in one portion The solid was filtered washed with cold (5° C.) diethyl ether (10 mL) The solid was dissolved in acetone (15 mL) filtered To the filtrate was added diethyl ether (15 mL) the precipitation of the arenediazonium tetrafluoroborate The solid was filtered washed with cold (5° C.) diethyl ether (5 mL) air dried overnight

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

Procedure: In a manner similar to that employed in Referential Example 242, the title compound was prepared from 4-chloro-3-methylaniline and methyl chlorooxoacetate.