2-(morpholin-4-ylmethyl)prop-2-enoic acid

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

Procedure: A tetrahydrofuran solution of 2.06 g (0.012 moles) of 2-Morpholin-4-ylmethyl-acrylic acid in 25 mL of tetrahydrofuran was cooled in an ice bath, and 1.56 mL (1.64 g; 0.012 mole) of isobutylchloroformate was added, giving a precipitate. This was followed by 1.32 mL (1.22 g; 0.012 mole) of N-methylmorpholine. After 2 minutes, 3.15 g (0.01 mole) of N-(3-bromophenyl)-4,6-quinazolindiamine in 25 mL of pyridine was added. Cooling and stirring were continued for 1 ½ hours. Then the reaction was poured onto ice and 25 mL of ethyl acetate. The resulting mixture was extracted with 3 portions of ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over sodium sulfate, and taken to an oil in vacuo. This was washed with water and chromatographed on silica gel. The column was eluted with a gradient ranging from 1:1 ethyl acetate hexanes to 1:19 methanol ethyl acetate. The fifth fraction contained 0.733 g (15%) of the desired product Mass Spectrum (m/e) M+H 235.5. giving a precipitate Cooling were continued for 1 ½ hours The resulting mixture was extracted with 3 portions of ethyl acetate The combined ethyl acetate extracts were washed with brine dried over sodium sulfate This was washed with water chromatographed on silica gel The column was eluted with a gradient

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

Procedure: A tetrahydrofuran solution of 2.06 g (0.012 moles) of 2-Morpholin-4-ylmethyl-acrylic acid in 25 mL of tetrahydrofuran was cooled in an ice bath, and 1.56 mL (1.64 g; 0.012 mole) of isobutylchloroformate was added, giving a precipitate. This was followed by 1.32 mL (1.22 g; 0.012 mole) of N-methylmorpholine. After 2 minutes, 3.15 g (0.01 mole) of N-(3-bromophenyl)-4,6-quinazolindiamine in 25 mL of pyridine was added. Cooling and stirring were continued for 1 ½ hours. Then the reaction was poured onto ice and 25 mL of ethyl acetate. The resulting mixture was extracted with 3 portions of ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over sodium sulfate, and taken to an oil in vacuo. This was washed with water and chromatographed on silica gel. The column was eluted with a gradient ranging from 1:1 ethyl acetate hexanes to 1:19 methanol ethyl acetate. The fifth fraction contained 0.733 g (15%) of the desired product Mass Spectrum (m/e) M+H 235.5. giving a precipitate Cooling were continued for 1 ½ hours The resulting mixture was extracted with 3 portions of ethyl acetate The combined ethyl acetate extracts were washed with brine dried over sodium sulfate This was washed with water chromatographed on silica gel The column was eluted with a gradient

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

Procedure: In a manner described by Krawczyk [Henryk Krawczyk, Synthetic Communications, 25 641-650, (1995)] an 8.8 mL (8.8 g; 0.1 mole) portion of morpholine was added to 6.6 g (0.22 eq) of paraformaldehyde and 10.4 g (0.1 mole) of malonic acid in 100 mL of dioxane. After heating in an oil bath at 70 deg for 1 {fraction (1/12)} hours, the solvents were removed in vacuo. The residue was dissolved in acetone, some insoluble material being filtered. The filtrate was taken to an oil in vacuo. This oil was chromatographed on silica gel. Elution of the product with 1:19 methanol methylene chloride gave 5.51 g (32%) of the product, which melted at 121-125° C. the solvents were removed in vacuo The residue was dissolved in acetone some insoluble material being filtered This oil was chromatographed on silica gel Elution of the product with 1:19 methanol methylene chloride

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

Procedure: In a manner described by Krawczyk [Henryk Krawczyk, Synthetic Communications, 25 641-650, (1995)] an 8.8 mL (8.8 g; 0.1 mole) portion of morpholine was added to 6.6 g (0.22 eq) of paraformaldehyde and 10.4 g (0.1 mole) of malonic acid in 100 mL of dioxane. After heating in an oil bath at 70 deg for 1 {fraction (1/12)} hours, the solvents were removed in vacuo. The residue was dissolved in acetone, some insoluble material being filtered. The filtrate was taken to an oil in vacuo. This oil was chromatographed on silica gel. Elution of the product with 1:19 methanol methylene chloride gave 5.51 g (32%) of the product, which melted at 121-125° C. the solvents were removed in vacuo The residue was dissolved in acetone some insoluble material being filtered This oil was chromatographed on silica gel Elution of the product with 1:19 methanol methylene chloride

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

Procedure: Partially dissolved 1.26 g (7.37 mmol) 2-morpholin-4-ylmethyl-2-propenoic acid in 40 ml THF and chilled to 0° C. under N2. Added 810 μl (7.37 mmol) N-methylmorpholine and 950 μl (7.37 mmol) isobutyl chloroformate. After stirring 10 minutes, added a solution of 1.00 g (2.95 mmol) 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 2.5 ml DMF and 20 ml THF. Stripped solvent at 2 hours, slurried residue with water, collected solids, and dried in vacuo. Recrystallized from ethyl acetate and dried in vacuo, giving 334 mg of yellow-orange solid: mass spectrum (electrospray m/e): M+H=492, 494.3. Stripped solvent at 2 hours collected solids dried in vacuo Recrystallized from ethyl acetate dried in vacuo

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

Procedure: Partially dissolved 1.26 g (7.37 mmol) 2-morpholin-4-ylmethyl-2-propenoic acid in 40 ml THF and chilled to 0° C. under N2. Added 810 μl (7.37 mmol) N-methylmorpholine and 950 μl (7.37 mmol) isobutyl chloroformate. After stirring 10 minutes, added a solution of 1.00 g (2.95 mmol) 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 2.5 ml DMF and 20 ml THF. Stripped solvent at 2 hours, slurried residue with water, collected solids, and dried in vacuo. Recrystallized from ethyl acetate and dried in vacuo, giving 334 mg of yellow-orange solid: mass spectrum (electrospray m/e): M+H=492, 494.3. Stripped solvent at 2 hours collected solids dried in vacuo Recrystallized from ethyl acetate dried in vacuo

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

Procedure: Partially dissolved 1.37 g (8.00 mmol) 2-morpholin-4ylmethyl-2-propenoic acid in 50 ml ThF and chilled to 0° C. under N2. Added 1.06 ml (9.6 mmol) N-methylmorpholine and 833 μl (6.4 mmol) isobutyl chloroformate. Stirred at 0° C. for 1 hour and added a solution of 1.00 g (3.20 mmol) 6-amino-4-[(3-chloro-4-fluorophenyl)-amino]-3-quinolinecarbonitrile in 5 ml pyridine. Stirred overnight at 25° C. Poured onto a mixture of ice and saturated sodium bicarbonate, extracted with ethyl acetate, dried organic layer with brine and sodium sulfate, and stripped solvent to a small volume. Loaded onto a column of silica gel, eluted with 1% methanol/ethyl acetate, stripped solvent from desired fractions and dried under vacuum, giving 139 mg of yellow-orange solid: mass spectrum (electrospray m/e): M+H=465.8, 468.0. Stirred overnight at 25° C extracted with ethyl acetate, dried organic layer with brine and sodium sulfate eluted with 1% methanol/ethyl acetate dried under vacuum

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

Procedure: Partially dissolved 1.37 g (8.00 mmol) 2-morpholin-4ylmethyl-2-propenoic acid in 50 ml ThF and chilled to 0° C. under N2. Added 1.06 ml (9.6 mmol) N-methylmorpholine and 833 μl (6.4 mmol) isobutyl chloroformate. Stirred at 0° C. for 1 hour and added a solution of 1.00 g (3.20 mmol) 6-amino-4-[(3-chloro-4-fluorophenyl)-amino]-3-quinolinecarbonitrile in 5 ml pyridine. Stirred overnight at 25° C. Poured onto a mixture of ice and saturated sodium bicarbonate, extracted with ethyl acetate, dried organic layer with brine and sodium sulfate, and stripped solvent to a small volume. Loaded onto a column of silica gel, eluted with 1% methanol/ethyl acetate, stripped solvent from desired fractions and dried under vacuum, giving 139 mg of yellow-orange solid: mass spectrum (electrospray m/e): M+H=465.8, 468.0. Stirred overnight at 25° C extracted with ethyl acetate, dried organic layer with brine and sodium sulfate eluted with 1% methanol/ethyl acetate dried under vacuum

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

Procedure: Partially dissolved 1.26 g (7.37 mmol) 2-morpholin-4-ylmethyl-2-propenoic acid in 40 ml THF and chilled to 0° C. under N2. Added 810 μl (7.37 mmol) N-methylmorpholine and 950 μl (7.37 mmol) isobutyl chloroformate. After stirring 10 minutes, added a solution of 1.00 g (2.95 mmol) 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 2.5 ml DMF and 20 ml THF. Stripped solvent at 2 hours, slurried residue with water, collected solids, and dried in vacuo. Recrystallized from ethyl acetate and dried in vacuo, giving 334 mg of yellow-orange solid: mass spectrum (electrospray m/e): M+H=492, 494.3. Stripped solvent at 2 hours collected solids dried in vacuo Recrystallized from ethyl acetate dried in vacuo

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

Procedure: Partially dissolved 1.37 g (8.00 mmol) 2-morpholin-4-ylmethyl-2-propenoic acid in 50 ml THF and chilled to 0° C. under N2. Added 1.06 ml (9.6 mmol) N-methylmorpholine and 833 μl (6.4 mmol) isobutyl chloroformate. Stirred at 0° C. for 1 hour and added a solution of 1.00 g (3.20 mmol) 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-3-quinolinecarbonitrile in 5 ml pyridine. Stirred overnight at 25° C. Poured onto a mixture of ice and saturated sodium bicarbonate, extracted with ethyl acetate, dried organic layer with brine and sodium sulfate, and stripped solvent to a small volume. Loaded onto a column of silica gel, eluted with 1% methanol/ethyl acetate, stripped solvent from desired fractions and dried under vacuum, giving 139 mg of yellow-orange solid: mass spectrum (electrospray m/e): M+H=465.8, 468.0. Stirred overnight at 25° C extracted with ethyl acetate, dried organic layer with brine and sodium sulfate eluted with 1% methanol/ethyl acetate dried under vacuum

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

Procedure: A tetrahydrofuran solution of 2.06 g (0.012 moles) of 2-Morpholin-4-ylmethyl-acrylic acid in 25 mL of tetrahydrofuran was cooled in an ice bath, and 1.56 mL (1.64 g; 0.012 mole) of isobutylchloroformate was added, giving a precipitate. This was followed by 1.32 mL (1.22 g; 0.012 mole) of N-methylmorpholine. After 2 minutes, 3.15 g (0.01 mole) of N-(3-bromophenyl)-4,6-quinazolindiamine in 25 mL of pyridine was added. Cooling and stirring were continued for 1 ½ hours. Then the reaction was poured onto ice and 25 mL of ethyl acetate. The resulting mixture was extracted with 3 portions of ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over sodium sulfate, and taken to an oil in vacuo. This was washed with water and chromatographed on silica gel. The column was eluted with a gradient ranging from 1:1 ethyl acetate hexanes to 1:19 methanol ethyl acetate. The fifth fraction contained 0.733 g (15%) of the desired product Mass Spectrum (m/e) M+H 235.5. giving a precipitate Cooling were continued for 1 ½ hours The resulting mixture was extracted with 3 portions of ethyl acetate The combined ethyl acetate extracts were washed with brine dried over sodium sulfate This was washed with water chromatographed on silica gel The column was eluted with a gradient

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

Procedure: In a manner described by Krawczyk [Henryk Krawczyk, Synthetic Communications, 25 641-650, (1995)] an 8.8 mL (8.8 g; 0.1 mole) portion of morpholine was added to 6.6 g (0.22 eq) of paraformaldehyde and 10.4 g (0.1 mole) of malonic acid in 100 mL of dioxane. After heating in an oil bath at 70 deg for 1 {fraction (1/12)} hours, the solvents were removed in vacuo. The residue was dissolved in acetone, some insoluble material being filtered. The filtrate was taken to an oil in vacuo. This oil was chromatographed on silica gel. Elution of the product with 1:19 methanol methylene chloride gave 5.51 g (32%) of the product, which melted at 121-125° C. the solvents were removed in vacuo The residue was dissolved in acetone some insoluble material being filtered This oil was chromatographed on silica gel Elution of the product with 1:19 methanol methylene chloride