N-ETHYL-4-CHLOROANILINE

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: To a solution of N-ethyl-4-chloroaniline (650 mg, 4.18 mmol) in anhydrous toluene at 10° C. was slowly added a 2M solution of trimethylaluminium in hexanes (2.1 mL, 4.18 mmol). The reaction mixture was stirred at room temperature until gas evolution stopped. A second round bottom flask was charged with cis-2-methyl-1-(pyridine-4-carbonyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid methyl ester (370 mg, 1.19 mmol) and the preformed aluminum amide was added. The resulting reaction mixture was refluxed for 20 hours. The reaction was concentrated, quenched with 1M aqueous hydrochloric acid at 0° C. (exothermic!), basified with 1M aqueous sodium hydroxide, and extracted with ethyl acetate. The resulting organic layer was separated, washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to afford an orange oil which was purified via flash chromatography (1% methanol/methylene chloride) followed by HPLC to provide (±)-trans-2-methyl-1-(pyridine-4-carbonyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide (11%). 1H-NMR (CDCl3) δ: 1.02-1.18 (m, 6H), 1.60-1.70 (m, 1H), 2.45-2.55 (m, 1H), 3.60-3.70 (m, 1H), 3.80 (q, 2H), 4.98-5.10 (m, 1H), 6.40 (d, 1H), 6.90 (m, 2H), 7.00 (t, 1H), 7.30 (m, 2H), 7.50 (d, 2H), 7.60 (d, 2H), 8.55 (d, 2H). MS m/z: 434/436 (M+1). The resulting reaction mixture was refluxed for 20 hours The reaction was concentrated quenched with 1M aqueous hydrochloric acid at 0° C. (exothermic!) extracted with ethyl acetate The resulting organic layer was separated washed with brine dried over magnesium sulfate filtered The filtrate was concentrated in vacuo to afford an orange oil which was purified via flash chromatography (1% methanol/methylene chloride)

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

Procedure: To a solution of N-ethyl-4-chloroaniline (650 mg, 4.18 mmol) in anhydrous toluene at 10° C. was slowly added a 2M solution of trimethylaluminium in hexanes (2.1 mL, 4.18 mmol). The reaction mixture was stirred at room temperature until gas evolution stopped. A second round bottom flask was charged with cis-2-methyl-1-(pyridine-4-carbonyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid methyl ester (370 mg, 1.19 mmol) and the preformed aluminum amide was added. The resulting reaction mixture was refluxed for 20 hours. The reaction was concentrated, quenched with 1M aqueous hydrochloric acid at 0° C. (exothermic!), basified with 1M aqueous sodium hydroxide, and extracted with ethyl acetate. The resulting organic layer was separated, washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to afford an orange oil which was purified via flash chromatography (1% methanol/methylene chloride) followed by HPLC to provide (±)-trans-2-methyl-1-(pyridine-4-carbonyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide (11%). 1H-NMR (CDCl3) δ: 1.02-1.18 (m, 6H), 1.60-1.70 (m, 1H), 2.45-2.55 (m, 1H), 3.60-3.70 (m, 1H), 3.80 (q, 2H), 4.98-5.10 (m, 1H), 6.40 (d, 1H), 6.90 (m, 2H), 7.00 (t, 1H), 7.30 (m, 2H), 7.50 (d, 2H), 7.60 (d, 2H), 8.55 (d, 2H). MS m/z: 434/436 (M+1). The resulting reaction mixture was refluxed for 20 hours The reaction was concentrated quenched with 1M aqueous hydrochloric acid at 0° C. (exothermic!) extracted with ethyl acetate The resulting organic layer was separated washed with brine dried over magnesium sulfate filtered The filtrate was concentrated in vacuo to afford an orange oil which was purified via flash chromatography (1% methanol/methylene chloride)

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

Procedure: 1-(4-Methoxy-benzoyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (approx. 1.47 mmol) was suspended in methylene chloride (10 mL) to which one drop of dimethylformamide was added. Oxalyl chloride (375 mg, 275 uL, 2.95 mmol) was added. Vigorous bubbling ensued, followed by dissolution of the starting material. After stirring for 4 hours at room temperature, the yellow solution was concentrated and azeotroped with toluene to remove excess oxalyl chloride. The resulting acid chloride solution was dissolved in methylene chloride (10 mL). Diisopropylethylamine (569 mg, 768 uL, 4.41 mmol) was added, followed by 4-chloro-N-ethylaniline (457 mg, 2.93 mmol). The mixture was stirred at room temperature overnight. The reaction was poured into ethyl acetate and washed with water and brine. The combined organics were dried over sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to afford (±)-1-(4-methoxy-benzoyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide (193 mg) as a foam. 1H-NMR (CDCl3) δ: 1.17 (t, 3H), 2.06-2.26 (m, 2H), 3.57-3.70 (m, 2H), 3.73-3.87 (m, 5H), 4.02 (dd, 1H), 6.52 (d, 1H), 6.66-6.74 (m, 2H), 6.84 (ddd, 1H), 6.93-7.06 (m, 2H), 7.17-7.24 (m, 2H), 7.37-7.43 (m, 2H). MS m/z: 449 (M+1). was added Vigorous bubbling followed by dissolution of the starting material the yellow solution was concentrated azeotroped with toluene to remove excess oxalyl chloride The resulting acid chloride solution was dissolved in methylene chloride (10 mL) The mixture was stirred at room temperature overnight washed with water and brine The combined organics were dried over sodium sulfate filtered concentrated The crude residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient)

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

Procedure: 1-(4-Methoxy-benzoyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (approx. 1.47 mmol) was suspended in methylene chloride (10 mL) to which one drop of dimethylformamide was added. Oxalyl chloride (375 mg, 275 uL, 2.95 mmol) was added. Vigorous bubbling ensued, followed by dissolution of the starting material. After stirring for 4 hours at room temperature, the yellow solution was concentrated and azeotroped with toluene to remove excess oxalyl chloride. The resulting acid chloride solution was dissolved in methylene chloride (10 mL). Diisopropylethylamine (569 mg, 768 uL, 4.41 mmol) was added, followed by 4-chloro-N-ethylaniline (457 mg, 2.93 mmol). The mixture was stirred at room temperature overnight. The reaction was poured into ethyl acetate and washed with water and brine. The combined organics were dried over sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to afford (±)-1-(4-methoxy-benzoyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide (193 mg) as a foam. 1H-NMR (CDCl3) δ: 1.17 (t, 3H), 2.06-2.26 (m, 2H), 3.57-3.70 (m, 2H), 3.73-3.87 (m, 5H), 4.02 (dd, 1H), 6.52 (d, 1H), 6.66-6.74 (m, 2H), 6.84 (ddd, 1H), 6.93-7.06 (m, 2H), 7.17-7.24 (m, 2H), 7.37-7.43 (m, 2H). MS m/z: 449 (M+1). was added Vigorous bubbling followed by dissolution of the starting material the yellow solution was concentrated azeotroped with toluene to remove excess oxalyl chloride The resulting acid chloride solution was dissolved in methylene chloride (10 mL) The mixture was stirred at room temperature overnight washed with water and brine The combined organics were dried over sodium sulfate filtered concentrated The crude residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient)

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

Procedure: A round bottom flask with magnetic stirrer was charged with 2-methyl-1-(4-trifluoromethyl-benzoyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (886 mg, 2.44 mmol) in anhydrous pyridine (25.0 mL). To the reaction was added N-ethyl-p-chloroaniline (0.410 mL, 2.95 mmol), followed by EDCI (833 mg, 4.34 mmol). The reaction was stirred at room temperature under an argon atmosphere for 18-20 hours. The reaction was poured into a 1:1 mixture of water/brine (50 mL) and extracted with ethyl acetate (3×35 mL). The combined extractions were washed with brine (1×50 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to afford a brown residue. The residue was purified via silica gel chromatography (hexanes/ethyl acetate) to yield (±)-trans-2-methyl-1-(4-trifluoromethyl-benzoyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide (39%). 1H-NMR (CDCl3) δ: 1.02 (d, 3H), 1.12 (t, 3H), 1.64-1.74 (m, 1H), 2.49-2.58 (m, 1H), 3.59-3.72 (m, 1H), 3.77-3.90 (m, 2H), 5.03-5.14 (m, 1H), 6.35-6.41 (m, 1H), 6.74-6.84 (m, 2H), 6.89-6.95 (m, 1H), 7.17-7.25 (m, 2H), 7.44-7.52 (m, 2H), 7.63-7.69 (m, 2H). MS m/z: 501 (M+1). extracted with ethyl acetate (3×35 mL) The combined extractions were washed with brine (1×50 mL) dried over magnesium sulfate filtered The filtrate was concentrated in vacuo to afford a brown residue The residue was purified via silica gel chromatography (hexanes/ethyl acetate)

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

Procedure: Solutions of 15.56 g (0.1 mole) of 4-chloro-N-ethylaniline (III) and 11.13 g (0.11 mole) of triethylamine, in each case in 50 ml of tetrahydrofuran, were successively added dropwise to a solution of 21.14 g (0.1 mole) of 2,4,6-trichloropyrimidine-5-carbaldehyde (II) in 100 ml of tetrahydrofuran. The solution was then stirred for three hours at room temperature and the triethylammoniumchloride was filtered off. The filtrate was then evaporated in vacuo and stirred with 150 ml of methanol at 0° C. 23.9 g of colorless crystals were obtained. the triethylammoniumchloride was filtered off The filtrate was then evaporated in vacuo stirred with 150 ml of methanol at 0° C

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and (4-chloro-phenyl)-ethyl-amine. The reaction mixture was stirred for 1 h at room temperature, 2 h at 50° C. and 1 h at 80° C. before subjecting to work-up and purification. MS (ESI): 496.4 (MH+). purification

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

Procedure: To a solution of N-ethyl-4-chloroaniline (650 mg, 4.18 mmol) in anhydrous toluene at 10° C. was slowly added a 2M solution of trimethylaluminium in hexanes (2.1 mL, 4.18 mmol). The reaction mixture was stirred at room temperature until gas evolution stopped. A second round bottom flask was charged with cis-2-methyl-1-(pyridine-4-carbonyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid methyl ester (370 mg, 1.19 mmol) and the preformed aluminum amide was added. The resulting reaction mixture was refluxed for 20 hours. The reaction was concentrated, quenched with 1M aqueous hydrochloric acid at 0° C. (exothermic!), basified with 1M aqueous sodium hydroxide, and extracted with ethyl acetate. The resulting organic layer was separated, washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to afford an orange oil which was purified via flash chromatography (1% methanol/methylene chloride) followed by HPLC to provide (±)-trans-2-methyl-1-(pyridine-4-carbonyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide (11%). 1H-NMR (CDCl3) δ: 1.02-1.18 (m, 6H), 1.60-1.70 (m, 1H), 2.45-2.55 (m, 1H), 3.60-3.70 (m, 1H), 3.80 (q, 2H), 4.98-5.10 (m, 1H), 6.40 (d, 1H), 6.90 (m, 2H), 7.00 (t, 1H), 7.30 (m, 2H), 7.50 (d, 2H), 7.60 (d, 2H), 8.55 (d, 2H). MS m/z: 434/436 (M+1). The resulting reaction mixture was refluxed for 20 hours The reaction was concentrated quenched with 1M aqueous hydrochloric acid at 0° C. (exothermic!) extracted with ethyl acetate The resulting organic layer was separated washed with brine dried over magnesium sulfate filtered The filtrate was concentrated in vacuo to afford an orange oil which was purified via flash chromatography (1% methanol/methylene chloride)

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

Procedure: 1-(4-Methoxy-benzoyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (approx. 1.47 mmol) was suspended in methylene chloride (10 mL) to which one drop of dimethylformamide was added. Oxalyl chloride (375 mg, 275 uL, 2.95 mmol) was added. Vigorous bubbling ensued, followed by dissolution of the starting material. After stirring for 4 hours at room temperature, the yellow solution was concentrated and azeotroped with toluene to remove excess oxalyl chloride. The resulting acid chloride solution was dissolved in methylene chloride (10 mL). Diisopropylethylamine (569 mg, 768 uL, 4.41 mmol) was added, followed by 4-chloro-N-ethylaniline (457 mg, 2.93 mmol). The mixture was stirred at room temperature overnight. The reaction was poured into ethyl acetate and washed with water and brine. The combined organics were dried over sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to afford (±)-1-(4-methoxy-benzoyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide (193 mg) as a foam. 1H-NMR (CDCl3) δ: 1.17 (t, 3H), 2.06-2.26 (m, 2H), 3.57-3.70 (m, 2H), 3.73-3.87 (m, 5H), 4.02 (dd, 1H), 6.52 (d, 1H), 6.66-6.74 (m, 2H), 6.84 (ddd, 1H), 6.93-7.06 (m, 2H), 7.17-7.24 (m, 2H), 7.37-7.43 (m, 2H). MS m/z: 449 (M+1). was added Vigorous bubbling followed by dissolution of the starting material the yellow solution was concentrated azeotroped with toluene to remove excess oxalyl chloride The resulting acid chloride solution was dissolved in methylene chloride (10 mL) The mixture was stirred at room temperature overnight washed with water and brine The combined organics were dried over sodium sulfate filtered concentrated The crude residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient)