N-butylpiperidine-4-carboxamide

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

Procedure: Cyanoacetic acid (0.9 g., 0.01 mole) was dissolved in 11 ml. of dioxane and 4 ml. of water. N-butyl isonipecotamide (1.84 g., 0.01 mole) was added with stirring in portions to keep the temperature below 30° C. In 2 minutes 37% aqueous formaldehyde (1.66 g., 0.02 mole) was added and the temperatures maintained at 25°-28° C. Carbon dioxide evolution was evident. After 4 hours, the reaction appeared complete as determined by thin layer chromatography on silica gel developed with chloroform-methyl alcohol (95:5). The solvents were removed by stripping at 35° C./15 mm. and the residue taken up in 100 ml. methylene chloride. The organic phase was washed with water, dried and stripped to yield 1.7 g. of product, analytically pure. the temperature below 30° C the temperatures maintained at 25°-28° C The solvents were removed by stripping at 35° C. The organic phase was washed with water dried to yield 1.7 g

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

Procedure: Cyanoacetic acid (0.9 g., 0.01 mole) was dissolved in 11 ml. of dioxane and 4 ml. of water. N-Butyl isonipecotamide (1.84 g., 0.01 mole) was added with stirring in portions to keep the temperature below 30° C. In 2 minutes 37% aqueous formaldehyde (1.66 g., 0.02 mole) was added and the temperature maintained at 25°-28° C. Carbon dioxide evolution was evident. After 4 hours, the reaction appeared complete as determined by thin layer chromatography on silica gel developed with chloroform-methyl alcohol (95:5). The solvents were removed by stripping at 35° C./15 mm. and the residue taken up in 100 ml. methylene chloride. The organic phase was washed with water, dried and stripped to yield 1.7 g. of product, analytically pure. the temperature below 30° C the temperature maintained at 25°-28° C The solvents were removed by stripping at 35° C. The organic phase was washed with water dried to yield 1.7 g

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

Procedure: Cyanoacetic acid (0.9 g., 0.01 mole) was dissolved in 11 ml. of dioxane and 4 ml. of water. N-butyl isonipecotamide (1.84 g., 0.01 mole) was added with stirring in portions to keep the temperature below 30° C. In 2 minutes 37% aqueous formaldehyde (1.66 g., 0.02 mole) was added and the temperatures maintained at 25°-28° C. Carbon dioxide evolution was evident. After 4 hours, the reaction appeared complete as determined by thin layer chromatography on silica gel developed with chloroform-methyl alcohol (95:5). The solvents were removed by stripping at 35° C./15 mm. and the residue taken up in 100 ml. methylene chloride. The organic phase was washed with water, dried and stripped to yield 1.7 g. of product, analytically pure. the temperature below 30° C the temperatures maintained at 25°-28° C The solvents were removed by stripping at 35° C. The organic phase was washed with water dried to yield 1.7 g

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

Procedure: Cyanoacetic acid (0.9 g., 0.01 mole) was dissolved in 11 ml. of dioxane and 4 ml. of water. N-butyl isonipecotamide (1.84 g., 0.01 mole) was added with stirring in portions to keep the temperature below 30° C. In 2 minutes 37% aqueous formaldehyde (1.66 g., 0.02 mole) was added and the temperatures maintained at 25°-28° C. Carbon dioxide evolution was evident. After 4 hours, the reaction appeared complete as determined by thin layer chromatography on silica gel developed with chloroform-methyl alcohol (95:5). The solvents were removed by stripping at 35° C./15 mm. and the residue taken up in 100 ml. methylene chloride. The organic phase was washed with water, dried and stripped to yield 1.7 g. of product, analytically pure. the temperature below 30° C the temperatures maintained at 25°-28° C The solvents were removed by stripping at 35° C. The organic phase was washed with water dried to yield 1.7 g

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

Procedure: Cyanoacetic acid (0.9 g., 0.01 mole) was dissolved in 11 ml. of dioxane and 4 ml. of water. N-Butyl isonipecotamide (1.84 g., 0.01 mole) was added with stirring in portions to keep the temperature below 30° C. In 2 minutes 37% aqueous formaldehyde (1.66 g., 0.02 mole) was added and the temperature maintained at 25°-28° C. Carbon dioxide evolution was evident. After 4 hours, the reaction appeared complete as determined by thin layer chromatography on silica gel developed with chloroform-methyl alcohol (95:5). The solvents were removed by stripping at 35° C./15 mm. and the residue taken up in 100 ml. methylene chloride. The organic phase was washed with water, dried and stripped to yield 1.7 g. of product, analytically pure. the temperature below 30° C the temperature maintained at 25°-28° C The solvents were removed by stripping at 35° C. The organic phase was washed with water dried to yield 1.7 g

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

Procedure: Cyanoacetic acid (0.9 g., 0.01 mole) was dissolved in 11 ml. of dioxane and 4 ml. of water. N-butyl isonipecotamide (1.84 g., 0.01 mole) was added with stirring in portions to keep the temperature below 30° C. In 2 minutes 37% aqueous formaldehyde (1.66 g., 0.02 mole) was added and the temperatures maintained at 25°-28° C. Carbon dioxide evolution was evident. After 4 hours, the reaction appeared complete as determined by thin layer chromatography on silica gel developed with chloroform-methyl alcohol (95:5). The solvents were removed by stripping at 35° C./15 mm. and the residue taken up in 100 ml. methylene chloride. The organic phase was washed with water, dried and stripped to yield 1.7 g. of product, analytically pure. the temperature below 30° C the temperatures maintained at 25°-28° C The solvents were removed by stripping at 35° C. The organic phase was washed with water dried to yield 1.7 g

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

Procedure: Cyanoacetic acid (0.9 g., 0.01 mole) was dissolved in 11 ml. of dioxane and 4 ml. of water. N-butyl isonipecotamide (1.84 g., 0.01 mole) was added with stirring in portions to keep the temperature below 30° C. In 2 minutes 37% aqueous formaldehyde (1.66 g., 0.02 mole) was added and the temperatures maintained at 25°-28° C. Carbon dioxide evolution was evident. After 4 hours, the reaction appeared complete as determined by thin layer chromatography on silica gel developed with chloroform-methyl alcohol (95:5). The solvents were removed by stripping at 35° C./15 mm. and the residue taken up in 100 ml. methylene chloride. The organic phase was washed with water, dried and stripped to yield 1.7 g. of product, analytically pure. the temperature below 30° C the temperatures maintained at 25°-28° C The solvents were removed by stripping at 35° C. The organic phase was washed with water dried to yield 1.7 g

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

Procedure: Cyanoacetic acid (0.9 g., 0.01 mole) was dissolved in 11 ml. of dioxane and 4 ml. of water. N-butyl isonipecotamide (1.84 g., 0.01 mole) was added with stirring in portions to keep the temperature below 30° C. In 2 minutes 37% aqueous formaldehyde (1.66 g., 0.02 mole) was added and the temperatures maintained at 25°-28° C. Carbon dioxide evolution was evident. After 4 hours, the reaction appeared complete as determined by thin layer chromatography on silica gel developed with chloroform-methyl alcohol (95:5). The solvents were removed by stripping at 35° C./15 mm. and the residue taken up in 100 ml. methylene chloride. The organic phase was washed with water, dried and stripped to yield 1.7 g. of product, analytically pure. the temperature below 30° C the temperatures maintained at 25°-28° C The solvents were removed by stripping at 35° C. The organic phase was washed with water dried to yield 1.7 g

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

Procedure: Isonicotinoyl chloride (100.0 g) was added over 1 hour to a solution of n-butylamine (51.6 g) in toluene (600 ml) at 0°. The mixture was allowed to stand overnight, heated on a steam bath for 1/2 hour, then water was added. The aqueous layer was separated, basified to about pH 12 (NaOH), and extracted with ethyl acetate (2 times). The combined organic extracts were dried (MgSO4), evaporated and the resulting residue (36.0 g) dissolved in acetic acid (400 ml) and hydrogenated at 50 p.s.i./30° in the presence of platinum oxide. The catalyst was removed by filtration, the solution evaporated to dryness, the residue basified to about pH 12 (Na2CO3), and extracted with chloroform. The chloroform extracts were dried (Na2SO4) and evaporated to give 4-(N-n-butylcarbamoyl)piperidine, (18.7 g), m.p. 75°-79°. The oxalate salt was prepared in isopropanol from the free base and oxalic acid and was recrystallised from isopropanol/ethyl acetate, m.p. 143°-144° . heated on a steam bath for 1/2 hour The aqueous layer was separated extracted with ethyl acetate (2 times) The combined organic extracts were dried (MgSO4) evaporated the resulting residue (36.0 g) dissolved in acetic acid (400 ml) 30° The catalyst was removed by filtration the solution evaporated to dryness extracted with chloroform The chloroform extracts were dried (Na2SO4) evaporated

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

Procedure: 4-Amino-2-chloro-6,7-dimethoxyquinazoline (1.2 g), 4-(N-n-butylcarbamoyl)piperidine (1.01 g) and triethylamine (2.52 g) in n-butanol (105 ml) were heated under reflux for 24 hours. The mixture was then cooled, the solvent evaporated in vacuo, and the resultant solid shaken with chloroform and water. The solid product was collected by filtration, and recrystallised twice from ethanol to give 4-amino-6,7-dimethoxy-2-[4-(N-n-butylcarbamoyl)piperidino]quinazoline hydrochloride (0.57 g), m.p. 263°-264°. under reflux for 24 hours The mixture was then cooled the solvent evaporated in vacuo The solid product was collected by filtration recrystallised twice from ethanol

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

Procedure: Cyanoacetic acid (0.9 g., 0.01 mole) was dissolved in 11 ml. of dioxane and 4 ml. of water. N-butyl isonipecotamide (1.84 g., 0.01 mole) was added with stirring in portions to keep the temperature below 30° C. In 2 minutes 37% aqueous formaldehyde (1.66 g., 0.02 mole) was added and the temperatures maintained at 25°-28° C. Carbon dioxide evolution was evident. After 4 hours, the reaction appeared complete as determined by thin layer chromatography on silica gel developed with chloroform-methyl alcohol (95:5). The solvents were removed by stripping at 35° C./15 mm. and the residue taken up in 100 ml. methylene chloride. The organic phase was washed with water, dried and stripped to yield 1.7 g. of product, analytically pure. the temperature below 30° C the temperatures maintained at 25°-28° C The solvents were removed by stripping at 35° C. The organic phase was washed with water dried to yield 1.7 g

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

Procedure: Cyanoacetic acid (0.9 g., 0.01 mole) was dissolved in 11 ml. of dioxane and 4 ml. of water. N-Butyl isonipecotamide (1.84 g., 0.01 mole) was added with stirring in portions to keep the temperature below 30° C. In 2 minutes 37% aqueous formaldehyde (1.66 g., 0.02 mole) was added and the temperature maintained at 25°-28° C. Carbon dioxide evolution was evident. After 4 hours, the reaction appeared complete as determined by thin layer chromatography on silica gel developed with chloroform-methyl alcohol (95:5). The solvents were removed by stripping at 35° C./15 mm. and the residue taken up in 100 ml. methylene chloride. The organic phase was washed with water, dried and stripped to yield 1.7 g. of product, analytically pure. the temperature below 30° C the temperature maintained at 25°-28° C The solvents were removed by stripping at 35° C. The organic phase was washed with water dried to yield 1.7 g