trimethylsilyl 4-bromobut-2-enoate

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

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

Procedure: 4-Bromobut-2-enoyl chloride was generated by the reaction of 4-bromobut-2-enoic acid, trimethylsilyl ester (0.63 mL) with oxalyl chloride (0.33 mL) in methylene chloride (6 mL) with one drop of N,N-dimethyl formamide for one hour. The reaction was stripped of solvent and redissolved in 8 mL of anhydrous tetrahydrofuran. An aliquot of 4 mL of this reagent was added to a solution of 500 mg of 6-amino-4-(3-bromo-phenylamino)-[1.7]naphthyridine-3-carbonitrile in 15 mL of tetrahydrofuran containing 315 uL of Hunig's base at 0° C. After 2 hours, an additional 2 mL of acid chloride/tetrahydrofuran was added. After an additional hour, saturated aqueous sodium bicarbonate and chloroform was added and the chloroform phase dried and stripped to give a crude product that was purified by flash chromatography with a gradient of ethyl acetate/chloroform, then methanol/chloroform to give 360 mg of a one-to-one mixture of 4-bromo-but-2-enoic acid, [4-(3-bromo-phenylamino)-3-cyano-[1.7]naphthyridin-6-yl]-amide, and 4-chloro-but-2-enoic acid, [4-(3-bromo-phenylamino)-3-cyano-[1.7]naphthyridin-6-yl]-amide. This material was dissolved in 10 mL of tetrahydrofuran containing 1 mL of N,N-dimethyl formamide and reacted with 200 mg of NaBr for three days. An aliquot of 2 mL of 1 M dimethyl amine in tetrahydrofuran was then added at 0° C. The reaction was diluted with saturated aqueous sodium bicarbonate, ice, and chloroform. The organic phase was dried with sodium sulfate, evaporated, and purified by flash chromatography with a gradient of 5-10% methanol/chloroform to give 190 mg of 4-dimethylamino-but-2-enoic acid, [4-(3-bromo-phenylamino)-3-cyano-[1.7]naphthyridin-6-yl]-amide as an amorphous yellow solid: melting point 180-185° C. (decomposed); mass spectrum (mri/e): M+H 450.9, 452.9. After an additional hour the chloroform phase dried to give a crude product that was purified by flash chromatography with a gradient of ethyl acetate/chloroform methanol/chloroform to give The organic phase was dried with sodium sulfate evaporated purified by flash chromatography with a gradient of 5-10% methanol/chloroform

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

Procedure: 4-Bromobut-2-enoyl chloride was generated by the reaction of 4-bromobut-2-enoic acid, trimethylsilyl ester (0.63 mL) with oxalyl chloride (0.33 mL) in methylene chloride (6 mL) with one drop of N,N-dimethyl formamide for one hour. The reaction was stripped of solvent and redissolved in 8 mL of anhydrous tetrahydrofuran. An aliquot of 4 mL of this reagent was added to a solution of 500 mg of 6-amino-4-(3-bromo-phenylamino)-[1.7]naphthyridine-3-carbonitrile in 15 mL of tetrahydrofuran containing 315 uL of Hunig's base at 0° C. After 2 hours, an additional 2 mL of acid chloride/tetrahydrofuran was added. After an additional hour, saturated aqueous sodium bicarbonate and chloroform was added and the chloroform phase dried and stripped to give a crude product that was purified by flash chromatography with a gradient of ethyl acetate/chloroform, then methanol/chloroform to give 360 mg of a one-to-one mixture of 4-bromo-but-2-enoic acid, [4-(3-bromo-phenylamino)-3-cyano-[1.7]naphthyridin-6-yl]-amide, and 4-chloro-but-2-enoic acid, [4-(3-bromo-phenylamino)-3-cyano-[1.7]naphthyridin-6-yl]-amide. This material was dissolved in 10 mL of tetrahydrofuran containing 1 mL of N,N-dimethyl formamide and reacted with 200 mg of NaBr for three days. An aliquot of 2 mL of 1 M dimethyl amine in tetrahydrofuran was then added at 0° C. The reaction was diluted with saturated aqueous sodium bicarbonate, ice, and chloroform. The organic phase was dried with sodium sulfate, evaporated, and purified by flash chromatography with a gradient of 5-10% methanol/chloroform to give 190 mg of 4-dimethylamino-but-2-enoic acid, [4-(3-bromo-phenylamino)-3-cyano-[1.7]naphthyridin-6-yl]-amide as an amorphous yellow solid: melting point 180-185° C. (decomposed); mass spectrum (mri/e): M+H 450.9, 452.9. After an additional hour the chloroform phase dried to give a crude product that was purified by flash chromatography with a gradient of ethyl acetate/chloroform methanol/chloroform to give The organic phase was dried with sodium sulfate evaporated purified by flash chromatography with a gradient of 5-10% methanol/chloroform

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Made 2.07 mmol of 5-bromo-but-2-enoyl chloride by mixing 363 μl (2.07 mmol) trimethylsilyl 4-bromo-but-2-enoate, 8 ml methylene chloride, 270 μl (3.10 mmol) oxalyl chloride and 2 drops of DMF. Removed solvent when bubbling subsided and dissolved in 10 ml THF. The acid chloride solution was added to a mixture of 800 mg A (2.07 mmol) 6-amino-4-[(3-bromo-4-fluorophenyl)amino]-7-methoxy-3-quinolinecarbonitrile, 50 ml THF, and 721 μl (4.14 mmol) N,N-diisopropylethylamine chilled to 0° C. under N2. At 1.5 hours added this mixture to a solution of 900 g (10.4 mmol) morpholine in 4.3 ml THF at 0° C. Warmed to 25° C. after complete addition, and at 2 hours added 900 μl more morpholine. At 3 hours, poured onto a mixture of ice and saturated sodium bicarbonate, extracted with ethyl acetate, dried with sodium sulfate, and reduced solvent to a small volume. Loaded compound onto a column of silica gel, eluted with 12% methanol/ethyl acetate, stripped solvent from desired fractions, and dried in vacuo, giving 287 mg of orange-brown solid: mass spectrum (electrospray m/e): M+H=539.9, 541.9. Removed solvent when bubbling dissolved in 10 ml THF Warmed to 25° C. after complete addition extracted with ethyl acetate dried with sodium sulfate eluted with 12% methanol/ethyl acetate dried in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Made 2.07 mmol of 5-bromo-but-2-enoyl chloride by mixing 363 μl (2.07 mmol) trimethylsilyl 4-bromo-but-2-enoate, 8 ml methylene chloride, 270 μl (3.10 mmol) oxalyl chloride and 2 drops of DMF. Removed solvent when bubbling subsided and dissolved in 10 ml THF. The acid chloride solution was added to a mixture of 800 mg A (2.07 mmol) 6-amino-4-[(3-bromo-4-fluorophenyl)amino]-7-methoxy-3-quinolinecarbonitrile, 50 ml THF, and 721 μl (4.14 mmol) N,N-diisopropylethylamine chilled to 0° C. under N2. At 1.5 hours added this mixture to a solution of 900 g (10.4 mmol) morpholine in 4.3 ml THF at 0° C. Warmed to 25° C. after complete addition, and at 2 hours added 900 μl more morpholine. At 3 hours, poured onto a mixture of ice and saturated sodium bicarbonate, extracted with ethyl acetate, dried with sodium sulfate, and reduced solvent to a small volume. Loaded compound onto a column of silica gel, eluted with 12% methanol/ethyl acetate, stripped solvent from desired fractions, and dried in vacuo, giving 287 mg of orange-brown solid: mass spectrum (electrospray m/e): M+H=539.9, 541.9. Removed solvent when bubbling dissolved in 10 ml THF Warmed to 25° C. after complete addition extracted with ethyl acetate dried with sodium sulfate eluted with 12% methanol/ethyl acetate dried in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Made 2.25 mmol of 5-bromo-but-2-enoyl chloride by mixing 386 μl (2.25 mmol) trimethylsilyl 4-bromo-but-2-enoate, 10 ml methylene chloride, 294 μl (3.38 mmol) oxalyl chloride, and 2 drops of DMF. After bubbling had subsided, removed solvent and dissolved in 10 ml THF. This solution was added to a mixture of 800 mg (2.25 mmol) 6-amino-4-[(3-bromo-4-fluorophenyl)amino]-3-quinolinecarbonitrile, 50 ml THF, and 392 μl (2.25 mmol) N,N-diisopropylethylamine chilled to 0° C. under N2. At 1 hour, added the mixture dropwise to a solution of 1 ml (11.2 mmol) morpholine in 4.5 ml THF chilled to 0° C. After complete addition, removed the ice bath, and at 2 hours poured onto a mixture of ice and saturated sodium bicarbonate. Extracted with ethyl acetate, dried organic layer with sodium sulfate and reduced solvent to a small volume. Loaded onto a column of silica gel, eluted with 12% methanol/ethyl acetate, stripped solvent from desired fractions and dried in vacuo, giving 369 mg of yellow solid: mass spectrum (electrospray m/e): M+H=509.9, 511.9. After bubbling removed solvent dissolved in 10 ml THF chilled to 0° C After complete addition removed the ice bath at 2 hours poured onto a mixture of ice and saturated sodium bicarbonate Extracted with ethyl acetate, dried organic layer with sodium sulfate eluted with 12% methanol/ethyl acetate dried in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Made 2.25 mmol of 5-bromo-but-2-enoyl chloride by mixing 386 μl (2.25 mmol) trimethylsilyl 4-bromo-but-2-enoate, 10 ml methylene chloride, 294 μl (3.38 mmol) oxalyl chloride, and 2 drops of DMF. After bubbling had subsided, removed solvent and dissolved in 10 ml THF. This solution was added to a mixture of 800 mg (2.25 mmol) 6-amino-4-[(3-bromo-4-fluorophenyl)amino]-3-quinolinecarbonitrile, 50 ml THF, 3 ml DMF (failed to dissolve amine) and 392 μl (2.25 mmol) N,N-diisopropylethylamine chilled to 0° C. under N2. Removed ice bath at 20 minutes. At 1 hour added dropwise to a solution of 1.2 ml (11.2 mmol) diethylamine in 4.4 ml THF chilled to -78° C. Removed dry ice bath after complete addition and stirred for 3 hours. Poured into a mixture of ice and saturated sodium bicarbonate, extracted with ethyl acetate, dried organic layer with sodium sulfate and reduced solvent to a small volume. Loaded compound onto a column of silica gel, eluted with 30% methanol/ethyl acetate, stripped solvent from desired fractions and dried in vacuo, giving 321 mg of yellow-brown solid: mass spectrum (electrospray m/e): M+H=496.0, 497.9. After bubbling removed solvent dissolved in 10 ml THF chilled to -78° C Removed dry ice bath after complete addition extracted with ethyl acetate, dried organic layer with sodium sulfate eluted with 30% methanol/ethyl acetate dried in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Made 2.25 mmol of 5-bromo-but-2-enoyl chloride by mixing 386 μl (2.25 mmol) trimethylsilyl 4-bromo-but-2-enoate, 10 ml methylene chloride, 294 μl (3.38 mmol) oxalyl chloride, and 2 drops of DMF. After bubbling had subsided, removed solvent and dissolved in 10 ml THF. This solution was added to a mixture of 800 mg (2.25 mmol) 6-amino-4-[(3-bromo-4-fluorophenyl)amino]-3-quinolinecarbonitrile, 50 ml THF, 3 ml DMF (failed to dissolve amine) and 392 μl (2.25 mmol) N,N-diisopropylethylamine chilled to 0° C. under N2. Removed ice bath at 20 minutes. At 1 hour added dropwise to a solution of 1.2 ml (11.2 mmol) diethylamine in 4.4 ml THF chilled to -78° C. Removed dry ice bath after complete addition and stirred for 3 hours. Poured into a mixture of ice and saturated sodium bicarbonate, extracted with ethyl acetate, dried organic layer with sodium sulfate and reduced solvent to a small volume. Loaded compound onto a column of silica gel, eluted with 30% methanol/ethyl acetate, stripped solvent from desired fractions and dried in vacuo, giving 321 mg of yellow-brown solid: mass spectrum (electrospray m/e): M+H=496.0, 497.9. After bubbling removed solvent dissolved in 10 ml THF chilled to -78° C Removed dry ice bath after complete addition extracted with ethyl acetate, dried organic layer with sodium sulfate eluted with 30% methanol/ethyl acetate dried in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Made 2.25 mmol of 5-bromo-but-2-enoyl chloride by mixing 386 μl (2.25 mmol) trimethylsilyl 4-bromo-but-2-enoate, 10 ml methylene chloride, 294 μl (3.38 mmol) oxalyl chloride, and 2 drops of DMF. After bubbling had subsided, removed solvent and dissolved in 10 ml THF. This solution was added to a mixture of 800 mg (2.25 mmol) 6-amino-4-[(3-bromo-4-fluorophenyl)amino]-3-quinolinecarbonitrile, 50 ml THF, and 392 μl (2.25 mmol) N,N-diisopropylethylamine chilled to 0° C. under N2. At 1 hour, added dropwise to a solution of 5.62 ml of 2.0M dimethyl amine in THF (11.2 mmol) at -78° C. Removed dry ice bath after complete addition. After 2 hours, poured into a cold solution of sodium bicarbonate, extracted with ethyl acetate, dried organic layer with sodium sulfate and reduced solvent to a small volume. Loaded onto a column of silica gel and eluted with 50% methanol/ethyl acetate. Stripped solvent of desired fractions and dried in vacuo, giving 386 mg of yellow solid: mass spectrum (electrospray m/e): M+H=467.9, 469.9. After bubbling removed solvent dissolved in 10 ml THF Removed dry ice bath after complete addition After 2 hours extracted with ethyl acetate, dried organic layer with sodium sulfate eluted with 50% methanol/ethyl acetate dried in vacuo

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

Procedure: 4-Bromobut-2-enoyl chloride was generated by the reaction of 4-bromobut-2-enoic acid, trimethylsilyl ester (0.63 mL) with oxalyl chloride (0.33 mL) in methylene chloride (6 mL) with one drop of N,N-dimethyl formamide for one hour. The reaction was stripped of solvent and redissolved in 8 mL of anhydrous tetrahydrofuran. An aliquot of 4 mL of this reagent was added to a solution of 500 mg of 6-amino-4-(3-bromo-phenylamino)-[1.7]naphthyridine-3-carbonitrile in 15 mL of tetrahydrofuran containing 315 uL of Hunig's base at 0° C. After 2 hours, an additional 2 mL of acid chloride/tetrahydrofuran was added. After an additional hour, saturated aqueous sodium bicarbonate and chloroform was added and the chloroform phase dried and stripped to give a crude product that was purified by flash chromatography with a gradient of ethyl acetate/chloroform, then methanol/chloroform to give 360 mg of a one-to-one mixture of 4-bromo-but-2-enoic acid, [4-(3-bromo-phenylamino)-3-cyano-[1.7]naphthyridin-6-yl]-amide, and 4-chloro-but-2-enoic acid, [4-(3-bromo-phenylamino)-3-cyano-[1.7]naphthyridin-6-yl]-amide. This material was dissolved in 10 mL of tetrahydrofuran containing 1 mL of N,N-dimethyl formamide and reacted with 200 mg of NaBr for three days. An aliquot of 2 mL of 1 M dimethyl amine in tetrahydrofuran was then added at 0° C. The reaction was diluted with saturated aqueous sodium bicarbonate, ice, and chloroform. The organic phase was dried with sodium sulfate, evaporated, and purified by flash chromatography with a gradient of 5-10% methanol/chloroform to give 190 mg of 4-dimethylamino-but-2-enoic acid, [4-(3-bromo-phenylamino)-3-cyano-[1.7]naphthyridin-6-yl]-amide as an amorphous yellow solid: melting point 180-185° C. (decomposed); mass spectrum (mri/e): M+H 450.9, 452.9. After an additional hour the chloroform phase dried to give a crude product that was purified by flash chromatography with a gradient of ethyl acetate/chloroform methanol/chloroform to give The organic phase was dried with sodium sulfate evaporated purified by flash chromatography with a gradient of 5-10% methanol/chloroform

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Made 2.07 mmol of 5-bromo-but-2-enoyl chloride by mixing 363 μl (2.07 mmol) trimethylsilyl 4-bromo-but-2-enoate, 8 ml methylene chloride, 270 μl (3.10 mmol) oxalyl chloride and 2 drops of DMF. Removed solvent when bubbling subsided and dissolved in 10 ml THF. The acid chloride solution was added to a mixture of 800 mg (2.07 mmol) 6-amino-4-[(3-bromo-4-fluorophenyl)amino]-7-methoxy-3-quinolinecarbonitrile, 50 ml THF, and 721 μl (4.14 mmol) N,N-diisopropylethylamine chilled to 0° C. under N2. At 1.5 hours added this mixture to a solution of 900 μl (10.4 mmol) morpholine in 4.3 ml THF at 0° C. Warmed to 25° C. after complete addition, and at 2 hours added 900 μl more morpholine. At 3 hours, poured onto a mixture of ice and saturated sodium bicarbonate, extracted with ethyl acetate, dried with sodium sulfate, and reduced solvent to a small volume. Loaded compound onto a column of silica gel, eluted with 12% methanol/ethyl acetate, stripped solvent from desired fractions, and dried in vacuo, giving 287 mg of orange-brown solid: mass spectrum (electrospray m/e): M+H=539.9, 541.9. Removed solvent when bubbling dissolved in 10 ml THF Warmed to 25° C. after complete addition extracted with ethyl acetate dried with sodium sulfate eluted with 12% methanol/ethyl acetate dried in vacuo