2-chloro-4-methoxyaniline

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

Procedure: To cyanuric chloride (36.911 g, 200.0 mmol) dissolved in acetone (250 mL) stirring at approximately 0–5° C. (ice-water bath), was added a solution of 3-chloro-p-anisidine (31.528 g, 200.0 mmol) in acetone (150 mL) followed by the addition of NaOH solution (80 mL, 2.5 N, 200.0 mmol). The reaction mixture was allowed to stir at approximately 0–5° C. (ice-water bath) for about 1 hour. The reaction mixture was then poured over crushed ice and neutralized with 10% HCl (aq). The resulting solid was washed with water and dried overnight under vacuum to afford 101 (58.3 g, 96%), mp 165° C.; HPLC: YMC Pack Pro C18, 40:30:30 [KH2PO4 (0.01M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt 24.3 min, 97.8% purity); MS (ESI): in/z 305 (M+H, 100), 283 (26.3), 271 (26.9), 269 (75.2), 139 (16.2). The reaction mixture was then poured over crushed ice The resulting solid was washed with water dried overnight under vacuum

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

Procedure: To cyanuric chloride (36.911 g, 200.0 mmol) dissolved in acetone (250 mL) stirring at approximately 0-5° C. (ice-water bath), was added a solution of 3-chloro-p-anisidine (31.528 g, 200.0 mmol) in acetone (150 mL) followed by the addition of NaOH solution (80 mL, 2.5 N, 200.0 mmol). The reaction mixture was allowed to stir at approximately 0-5° C. (ice-water bath) for about 1 hour. The reaction mixture was then poured over crushed ice and neutralized with 10% HCl (aq). The resulting solid was washed with water and dried overnight under vacuum to afford 101 (58.3 g, 96%), mp 165° C.; HPLC: YMC Pack Pro C18, 40:30:30 [KH2PO4 (0.01 M, pH 3.2): CH3OH:CH3CN], 264 nm, Rt 24.3 min, 97.8% purity); MS (ESI): m/z 305 (M+H, 100), 283 (26.3), 271 (26.9), 269 (75.2), 139 (16.2). The reaction mixture was then poured over crushed ice The resulting solid was washed with water dried overnight under vacuum

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

Procedure: To cyanuric chloride (36.911 g, 200.0 mmol) dissolved in acetone (250 mL) stirring at approximately 0-5° C. (ice-water bath), was added a solution of 3-chloro-p-anisidine (31.528 g, 200.0 mmol) in acetone (150 mL) followed by the addition of NaOH solution (80 mL, 2.5 N, 200.0 mmol). The reaction mixture was allowed to stir at approximately 0-5° C. (ice-water bath) for about 1 hour. The reaction mixture was then poured over crushed ice and neutralized with 10% HCl (aq). The resulting solid was washed with water and dried overnight under vacuum to afford 101 (58.3 g, 96%), mp 165° C.; HPLC: YMC Pack Pro C18, 40:30:30 [KH2PO4 (0.01M, pH 3.2):CH3OH:CH3CN], 264 nm, Rt 24.3 min, 97.8% purity); MS (ESI): m/z 305 (M+H, 100), 283 (26.3), 271 (26.9), 269 (75.2), 139 (16.2). The reaction mixture was then poured over crushed ice The resulting solid was washed with water dried overnight under vacuum

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-chloro-4-anisidine (Aldrich; 0.633 g), bis(2-chloroethyl)amine hydrochloride (Aldrich; 0.860 g), potassium carbonate (1.11 g), and N,N-dimethylacetamide (6 mL) is stirred at 100° C. for 17.5 h, at which time the mixture is cooled and partioned between dichloromethane and water/sodium bicarbonate. The organic layers are dried over sodium sulfate, concentrated, and the residue is chromatographed on silica gel using methanol/dichloromethane (8/92) to give 0.297 g of 1-(3-chloro-4-methoxyphenyl)piperazine. 1H NMR (CDCl3) δ 3.05, 3.86, 6.80, 6.87, 6.99. is cooled The organic layers are dried over sodium sulfate concentrated the residue is chromatographed on silica gel

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

Procedure: To cyanuric chloride (36.911 g, 200.0 mmol) dissolved in acetone (250 mL) stirring at approximately 0–5° C. (ice-water bath), was added a solution of 3-chloro-p-anisidine (31.528 g, 200.0 mmol) in acetone (150 mL) followed by the addition of NaOH solution (80 mL, 2.5 N, 200.0 mmol). The reaction mixture was allowed to stir at approximately 0–5° C. (ice-water bath) for about 1 hour. The reaction mixture was then poured over crushed ice and neutralized with 10% HCl (aq). The resulting solid was washed with water and dried overnight under vacuum to afford 101 (58.3 g, 96%), mp 165° C.; HPLC: YMC Pack Pro C18, 40:30:30 [KH2PO4 (0.01M, pH 3.2):CH3OH:CH3CN], 264 nm, Rt 24.3 min, 97.8% purity); MS (ESI): m/z 305 (M+H, 100), 283 (26.3), 271 (26.9), 269 (75.2), 139 (16.2). The reaction mixture was then poured over crushed ice The resulting solid was washed with water dried overnight under vacuum

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

Procedure: To cyanuric chloride (36.911 g, 200.0 mmol) dissolved in acetone (250 mL) stirring at approximately 0–5° C. (ice-water bath), was added a solution of 3-chloro-p-anisidine (31.528 g, 200.0 mmol) in acetone (150 mL) followed by the addition of NaOH solution (80 mL, 2.5 N, 200.0 mmol). The reaction mixture was allowed to stir at approximately 0–5° C. (ice-water bath) for about 1 hour. The reaction mixture was then poured over crushed ice and neutralized with 10% HCl (aq). The resulting solid was washed with water and dried overnight under vacuum to afford 101 (58.3 g, 96%), mp 165° C.; HPLC: YMC Pack Pro C18, 40:30:30 [KH2PO4 (0.01M, pH 3.2):CH3OH:CH3CN], 264 nm, Rt 24.3 min, 97.8% purity); MS (ESI): m/z 305 (M+H, 100), 283 (26.3), 271 (26.9), 269 (75.2), 139 (16.2). The reaction mixture was then poured over crushed ice The resulting solid was washed with water dried overnight under vacuum

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

Procedure: A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.158 g of 3-chloro-p-anisidine, 20 mg of pyridine hydrochloride, and 10 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 30 minutes. The mixture was cooled and added to 40 ml of water. To this mixture was added sodium carbonate and concentrated hydrogen chloride to adjust pH to 7. The product was collected, washed with water, and dried to give 0.324 g of 4-(3-chloro-4-methoxy-phenylamino)-6,7-dimethoxy-quinoline-3-carbonitrile as a solid, mp 278-280° C.; mass spectrum (EI, m/e): M 369.0860. at reflux temperature for 30 minutes The mixture was cooled The product was collected washed with water dried

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

Procedure: A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.158 g of 3-chloro-p-anisidine, 20 mg of pyridine hydrochloride, and 10 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 30 minutes. The mixture was cooled and added to 40 ml of water. To this mixture was added sodium carbonate and concentrated hydrogen chloride to adjust pH to 7. The product was collected, washed with water, and dried to give 0.324 g of 4-(3-chloro-4-methoxy-phenylamino)-6,7-dimethoxy-quinoline-3-carbonitrile as a solid, mp 278-280° C.; mass spectrum (EI, m/e): M 369.0860. at reflux temperature for 30 minutes The mixture was cooled The product was collected washed with water dried

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-4-methoxyaniline (2.719 g, 14 mmol) was added to 8.0M aqueous hydrochloric acid (15 ml) and the suspension cooled to −5° C. Sodium nitrite (1.063 g, 15.4 mmol) was added as a solution in water (3 ml). After addition the pH was brought to pH 4-5 by addition of sodium acetate. In a separate flask, ethyl-α-ethyl acetoacetate (2.18 ml, 15.4 mmol) in ethanol (15 ml) at −5° C. was treated with potassium hydroxide (864 mg, 15.4 mmol) in water (3 ml) followed by ice (4 g). The diazonium salt prepared initially was then added rapidly to the second solution and stirred at −5° C. for 4 hours then allowed to warm to ambient temperature overnight. The mixture was extracted with ethyl acetate (3×100 ml) and the organic solutions dried (MgSO4), filtered and solvent removed in vacuo to give an orange oil. This oil was dissolved in ethanol (35 ml) and the flask fitted with a reflux condenser. Concentrated sulphuric acid (35 ml) was then added dropwise, this caused the reaction to reflux with no external heating. The solution was stirred for 1 hour then the solvent removed by evaporation. The residue was taken up in water then extracted with ethyl acetate (3×100 ml). The organic solution was washed with brine, dried (MgSO4), filtered and evaporated to give a brown oil. The crude oil was purified by silica column chromatography, eluting with dichloromethane to give ethyl 7-chloro-5-methoxyindole-2-carboxylate (125 mg, 4%). After addition the pH was then added rapidly to the second solution to warm to ambient temperature overnight The mixture was extracted with ethyl acetate (3×100 ml) the organic solutions dried (MgSO4) filtered solvent removed in vacuo to give an orange oil the flask fitted with a reflux condenser the reaction to reflux with no external heating The solution was stirred for 1 hour the solvent removed by evaporation then extracted with ethyl acetate (3×100 ml) The organic solution was washed with brine dried (MgSO4) filtered evaporated to give a brown oil The crude oil was purified by silica column chromatography eluting with dichloromethane

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-4-methoxyaniline (2.719 g, 14 mmol) was added to 8.0M aqueous hydrochloric acid (15 ml) and the suspension cooled to −5° C. Sodium nitrite (1.063 g, 15.4 mmol) was added as a solution in water (3 ml). After addition the pH was brought to pH 4-5 by addition of sodium acetate. In a separate flask, ethyl-α-ethyl acetoacetate (2.18 ml, 15.4 mmol) in ethanol (15 ml) at −5° C. was treated with potassium hydroxide (864 mg, 15.4 mmol) in water (3 ml) followed by ice (4 g). The diazonium salt prepared initially was then added rapidly to the second solution and stirred at −5° C. for 4 hours then allowed to warm to ambient temperature overnight. The mixture was extracted with ethyl acetate (3×100 ml) and the organic solutions dried (MgSO4), filtered and solvent removed in vacuo to give an orange oil. This oil was dissolved in ethanol (35 ml) and the flask fitted with a reflux condenser. Concentrated sulphuric acid (35 ml) was then added dropwise, this caused the reaction to reflux with no external heating. The solution was stirred for 1 hour then the solvent removed by evaporation. The residue was taken up in water then extracted with ethyl acetate (3×100 ml). The organic solution was washed with brine, dried (MgSO4), filtered and evaporated to give a brown oil. The crude oil was purified by silica column chromatography, eluting with dichloromethane to give ethyl 7-chloro-5-methoxyindole-2-carboxylate (125 mg, 4%). After addition the pH was then added rapidly to the second solution to warm to ambient temperature overnight The mixture was extracted with ethyl acetate (3×100 ml) the organic solutions dried (MgSO4) filtered solvent removed in vacuo to give an orange oil the flask fitted with a reflux condenser the reaction to reflux with no external heating The solution was stirred for 1 hour the solvent removed by evaporation then extracted with ethyl acetate (3×100 ml) The organic solution was washed with brine dried (MgSO4) filtered evaporated to give a brown oil The crude oil was purified by silica column chromatography eluting with dichloromethane

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

Procedure: To cyanuric chloride (36.911 g, 200.0 mmol) dissolved in acetone (250 mL) stirring at approximately 0–5° C. (ice-water bath), was added a solution of 3-chloro-p-anisidine (31.528 g, 200.0 mmol) in acetone (150 mL) followed by the addition of NaOH solution (80 mL, 2.5 N, 200.0 mmol). The reaction mixture was allowed to stir at approximately 0–5° C. (ice-water bath) for about 1 hour. The reaction mixture was then poured over crushed ice and neutralized with 10% HCl (aq). The resulting solid was washed with water and dried overnight under vacuum to afford 101 (58.3 g, 96%), mp 165° C.; HPLC: YMC Pack Pro C18, 40:30:30 [KH2PO4 (0.01M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt 24.3 min, 97.8% purity); MS (ESI): in/z 305 (M+H, 100), 283 (26.3), 271 (26.9), 269 (75.2), 139 (16.2). The reaction mixture was then poured over crushed ice The resulting solid was washed with water dried overnight under vacuum

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

Procedure: This compound was prepared using 117 mg (0.5 mmol) of 2-[(3-chloro-4-methoxy-phenyl)hydrazono]malononitrile, which was derived from 3-chloro-4-anisidine (157 mg, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. Precipitate formed in the reaction tube immediately after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 93 mg (70%) of the title compound as a yellow solid. This compound was prepared Precipitate formed in the reaction tube The resulting solid was isolated by filtration washed with ethanol dried