2-amino-N-propylbenzamide

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

Procedure: To 32.6 g of isatoic anhydride in 150 ml of isopropyl alcohol was added 25 ml of n-propylamine portionwise as the reaction was exothermic. Evaporation of the solution gave 30 g of 2-amino-N-propylbenzamide as colorless crystals, mp 100°-102° C. To a stirred solution of 25.0 g of 2-amino-N-propylbenzamide in 300 ml of tetrahydrofuran was added 22.9 g of benzoylisothiocyanate over 10 minutes. After 2 hours the mixture was diluted with 100 ml of ether and was filtered to give 30.7 g of 2-[[benzoylamino)thioxomethyl]amino]-N-propylbenzamide, mp 172°-174° C. Then, to a solution of 10.2 g of 2-[[benzoylamino)thioxomethyl]amino]-N-propylbenzamide in 100 ml of dichloromethane was added 30 ml of 1N sodium hydroxide to form a two-phase mixture, and to this was added 20 ml of iodomethane and then 4 drops of benzyltrimethylammonium hydroxide solution. After stirring for 3 hours, the organic phase was separated and dried over anhydrous sodium sulfate. Filtration and evaporation of the filtrate gave 9.4 g of N-benzoyl-N'-(2-propylaminocarbonylphenyl)carbamimidothioic acid, methyl ester, mp 86°-89° C. To a solution of 7.10 g of this compound in 300 ml of anhydrous dioxane was added 1.45 g of 60% sodium hydride in mineral oil suspension and the mixture was refluxed for 5 hours. The reaction mixture was then poured into 1.5 liter of water and made acidic with hydrochloric acid. The crystals that formed were collected and recrystallized from ethyl acetate-hexane to give N-(3,4-dihydro-3-propyl-4oxo-2-quinazolinyl)benzamide as colorless crystals, mp 133°-135° C. was filtered

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

Procedure: To 32.6 g of isatoic anhydride in 150 ml of isopropyl alcohol was added 25 ml of n-propylamine portionwise as the reaction was exothermic. Evaporation of the solution gave 30 g of 2-amino-N-propylbenzamide as colorless crystals, mp 100°-102° C. To a stirred solution of 25.0 g of 2-amino-N-propylbenzamide in 300 ml of tetrahydrofuran was added 22.9 g of benzoylisothiocyanate over 10 minutes. After 2 hours the mixture was diluted with 100 ml of ether and was filtered to give 30.7 g of 2-[[benzoylamino)thioxomethyl]amino]-N-propylbenzamide, mp 172°-174° C. Then, to a solution of 10.2 g of 2-[[benzoylamino)thioxomethyl]amino]-N-propylbenzamide in 100 ml of dichloromethane was added 30 ml of 1N sodium hydroxide to form a two-phase mixture, and to this was added 20 ml of iodomethane and then 4 drops of benzyltrimethylammonium hydroxide solution. After stirring for 3 hours, the organic phase was separated and dried over anhydrous sodium sulfate. Filtration and evaporation of the filtrate gave 9.4 g of N-benzoyl-N'-(2-propylaminocarbonylphenyl)carbamimidothioic acid, methyl ester, mp 86°-89° C. To a solution of 7.10 g of this compound in 300 ml of anhydrous dioxane was added 1.45 g of 60% sodium hydride in mineral oil suspension and the mixture was refluxed for 5 hours. The reaction mixture was then poured into 1.5 liter of water and made acidic with hydrochloric acid. The crystals that formed were collected and recrystallized from ethyl acetate-hexane to give N-(3,4-dihydro-3-propyl-4oxo-2-quinazolinyl)benzamide as colorless crystals, mp 133°-135° C. Evaporation of the solution

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Amino-N-propyl-benzamide (0.360 g, 0.00202 mol), 2,4,5-Trichloro-pyrimidine (0.370 g, 0.00202 mol) and Potassium carbonate (0.837 g, 0.00606 mol) were dissolved in N,N-Dimethylformamide (10.0 mL, 0.129 mol) and the reaction was heated at 90° C. and was allowed to stir overnight. The reaction mixture was then cooled was poured over saturated ammonium chloride, and organics were extracted with ethyl acetate/dichloromethane. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo. The crude mixture was purified by Isco flash column chromatography (Hexane/Ethyl Acetate). Combined fractions were reduced en vacuo to afford 420 mg (64%) of 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-propyl-benzamide. LC/MS (ESI): 325.12. 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-butyl-benzamide was made in an analogous fashion replacing 1-aminopropane with 1-aminobutane. The reaction mixture was then cooled organics were extracted with ethyl acetate/dichloromethane Combined organics were dried over sodium sulfate filtered The crude mixture was purified by Isco flash column chromatography (Hexane/Ethyl Acetate)

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

Procedure: (2-Propylcarbamoyl-phenyl)-carbamic acid tert-butyl ester (0.570 g, 0.00205 mol) was dissolved in Methylene chloride (5.0 mL, 0.078 mol) and Trifluoroacetic Acid (3.0 mL, 0.039 mol) was added to the mixture. The reaction was allowed to stir overnight at room temperature. The reaction mixture was reduced under nitrogen and the crude product (360 mg, 99%) was used in subsequent chemistry without further purification. The excess TFA will be neutralized in the next synthetic step. LC/MS (ESI): 179.24. the crude product (360 mg, 99%) was used in subsequent chemistry without further purification

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

Procedure: 2-Amino-N-propylbenzamide (prepared from propylamine and isatoic anhydride, using, the methods described in Example 17) and CMI were reacted using conditions described in the general procedure for CMI coupling to give 2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino]-N-propylbenzamide, isolated as the hydrochloride salt. were reacted

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Amino-N-propyl-benzamide (0.360 g, 0.00202 mol), 2,4,5-Trichloro-pyrimidine (0.370 g, 0.00202 mol) and Potassium carbonate (0.837 g, 0.00606 mol) were dissolved in N,N-Dimethylformamide (10.0 mL, 0.129 mol) and the reaction was heated at 90° C. and was allowed to stir overnight. The reaction mixture was then cooled was poured over saturated ammonium chloride, and organics were extracted with ethyl acetate/dichloromethane. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo. The crude mixture was purified by Isco flash column chromatography (Hexane/Ethyl Acetate). Combined fractions were reduced en vacuo to afford 420 mg (64%) of 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-propyl-benzamide. LC/MS (ESI): 325.12. 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-butyl-benzamide was made in an analogous fashion replacing 1-aminopropane with 1-aminobutane. The reaction mixture was then cooled organics were extracted with ethyl acetate/dichloromethane Combined organics were dried over sodium sulfate filtered The crude mixture was purified by Isco flash column chromatography (Hexane/Ethyl Acetate)

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

Procedure: (2-Propylcarbamoyl-phenyl)-carbamic acid tert-butyl ester (0.570 g, 0.00205 mol) was dissolved in Methylene chloride (5.0 mL, 0.078 mol) and Trifluoroacetic Acid (3.0 mL, 0.039 mol) was added to the mixture. The reaction was allowed to stir overnight at room temperature. The reaction mixture was reduced under nitrogen and the crude product (360 mg, 99%) was used in subsequent chemistry without further purification. The excess TFA will be neutralized in the next synthetic step. LC/MS (ESI): 179.24. the crude product (360 mg, 99%) was used in subsequent chemistry without further purification

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

Procedure: To 32.6 g of isatoic anhydride in 150 ml of isopropyl alcohol was added 25 ml of n-propylamine portionwise as the reaction was exothermic. Evaporation of the solution gave 30 g of 2-amino-N-propylbenzamide as colorless crystals, mp 100°-102° C. To a stirred solution of 25.0 g of 2-amino-N-propylbenzamide in 300 ml of tetrahydrofuran was added 22.9 g of benzoylisothiocyanate over 10 minutes. After 2 hours the mixture was diluted with 100 ml of ether and was filtered to give 30.7 g of 2-[[benzoylamino)thioxomethyl]amino]-N-propylbenzamide, mp 172°-174° C. Then, to a solution of 10.2 g of 2-[[benzoylamino)thioxomethyl]amino]-N-propylbenzamide in 100 ml of dichloromethane was added 30 ml of 1N sodium hydroxide to form a two-phase mixture, and to this was added 20 ml of iodomethane and then 4 drops of benzyltrimethylammonium hydroxide solution. After stirring for 3 hours, the organic phase was separated and dried over anhydrous sodium sulfate. Filtration and evaporation of the filtrate gave 9.4 g of N-benzoyl-N'-(2-propylaminocarbonylphenyl)carbamimidothioic acid, methyl ester, mp 86°-89° C. To a solution of 7.10 g of this compound in 300 ml of anhydrous dioxane was added 1.45 g of 60% sodium hydride in mineral oil suspension and the mixture was refluxed for 5 hours. The reaction mixture was then poured into 1.5 liter of water and made acidic with hydrochloric acid. The crystals that formed were collected and recrystallized from ethyl acetate-hexane to give N-(3,4-dihydro-3-propyl-4oxo-2-quinazolinyl)benzamide as colorless crystals, mp 133°-135° C. was filtered

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

Procedure: To 32.6 g of isatoic anhydride in 150 ml of isopropyl alcohol was added 25 ml of n-propylamine portionwise as the reaction was exothermic. Evaporation of the solution gave 30 g of 2-amino-N-propylbenzamide as colorless crystals, mp 100°-102° C. To a stirred solution of 25.0 g of 2-amino-N-propylbenzamide in 300 ml of tetrahydrofuran was added 22.9 g of benzoylisothiocyanate over 10 minutes. After 2 hours the mixture was diluted with 100 ml of ether and was filtered to give 30.7 g of 2-[[benzoylamino)thioxomethyl]amino]-N-propylbenzamide, mp 172°-174° C. Then, to a solution of 10.2 g of 2-[[benzoylamino)thioxomethyl]amino]-N-propylbenzamide in 100 ml of dichloromethane was added 30 ml of 1N sodium hydroxide to form a two-phase mixture, and to this was added 20 ml of iodomethane and then 4 drops of benzyltrimethylammonium hydroxide solution. After stirring for 3 hours, the organic phase was separated and dried over anhydrous sodium sulfate. Filtration and evaporation of the filtrate gave 9.4 g of N-benzoyl-N'-(2-propylaminocarbonylphenyl)carbamimidothioic acid, methyl ester, mp 86°-89° C. To a solution of 7.10 g of this compound in 300 ml of anhydrous dioxane was added 1.45 g of 60% sodium hydride in mineral oil suspension and the mixture was refluxed for 5 hours. The reaction mixture was then poured into 1.5 liter of water and made acidic with hydrochloric acid. The crystals that formed were collected and recrystallized from ethyl acetate-hexane to give N-(3,4-dihydro-3-propyl-4oxo-2-quinazolinyl)benzamide as colorless crystals, mp 133°-135° C. Evaporation of the solution

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Amino-N-propyl-benzamide (0.360 g, 0.00202 mol), 2,4,5-Trichloro-pyrimidine (0.370 g, 0.00202 mol) and Potassium carbonate (0.837 g, 0.00606 mol) were dissolved in N,N-Dimethylformamide (10.0 mL, 0.129 mol) and the reaction was heated at 90° C. and was allowed to stir overnight. The reaction mixture was then cooled was poured over saturated ammonium chloride, and organics were extracted with ethyl acetate/dichloromethane. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo. The crude mixture was purified by Isco flash column chromatography (Hexane/Ethyl Acetate). Combined fractions were reduced en vacuo to afford 420 mg (64%) of 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-propyl-benzamide. LC/MS (ESI): 325.12. 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-butyl-benzamide was made in an analogous fashion replacing 1-aminopropane with 1-aminobutane. The reaction mixture was then cooled organics were extracted with ethyl acetate/dichloromethane Combined organics were dried over sodium sulfate filtered The crude mixture was purified by Isco flash column chromatography (Hexane/Ethyl Acetate)

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

Procedure: (2-Propylcarbamoyl-phenyl)-carbamic acid tert-butyl ester (0.570 g, 0.00205 mol) was dissolved in Methylene chloride (5.0 mL, 0.078 mol) and Trifluoroacetic Acid (3.0 mL, 0.039 mol) was added to the mixture. The reaction was allowed to stir overnight at room temperature. The reaction mixture was reduced under nitrogen and the crude product (360 mg, 99%) was used in subsequent chemistry without further purification. The excess TFA will be neutralized in the next synthetic step. LC/MS (ESI): 179.24. the crude product (360 mg, 99%) was used in subsequent chemistry without further purification