(2-aminophenyl)-piperidin-1-ylmethanone

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

Procedure: A mixture of 18.2 g of 1-(2-aminobenzoyl)piperidine and 12.2 g of 2-methyl-4-chloropyridine in 5.0 ml of acetic acid was heated at reflux for six hours and then kept at room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue treated with dilute acid to pH 2 and extracted with methylene dichloride. The aqueous layer was made basic with potassium carbonate and extracted with chloroform. Further work-up of this solution afforded 2.58 g of 1-[2-(2-methyl-4-pyridinylamino)benzoyl]piperidine, m.p. 93°-95° C. when recrystallized from ethyl acetate--ether--hexane. was heated at reflux for six hours The reaction mixture was concentrated in vacuo the residue treated with dilute acid to pH 2 extracted with methylene dichloride extracted with chloroform

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

Procedure: A solution of 2.77 kg 1-(2-aminobenzoyl)piperidine in 16 liters of 2-methoxyethanol was heated until solvent distillation was about to begin (125° C. internal temperature). A solution of 2.1 kg 4-chloropyridine hydrochloride in 21 liters of 2-methoxyethanol was then slowly added over a period of one hour during which 4 liters of distillate was collected. Heating was continued for another hour while 16 liters of distillate was collected. The reaction mixture was concentrated in vacuo, and the thick residue was dissolved in 10 liters of water. Sodium acetate trihydrate (1.85 kg) was added and the solution washed three times with 3 liters of isopropyl acetate and decolorized with activated charcoal. The aqueous solution was made basic (pH>10) by dropwise addition of sodium hydroxide solution. Seeding during the addition generated a precipitate. A small amount of acetic acid was added to lower the pH to 8.5-9, and after 30 minutes of stirring the product was collected, washed with water and air dried to give 2.51 kg of 1-[2-(4-pyridinylamino)benzoyl]piperidine, m.p. 152°-153° C. The latter product was further purified by recrystallization from acetone to give the compound with m.p. 154°-155° C. (125° C. internal temperature) was collected Heating was continued for another hour while 16 liters of distillate was collected The reaction mixture was concentrated in vacuo the thick residue was dissolved in 10 liters of water Sodium acetate trihydrate (1.85 kg) was added the solution washed three times with 3 liters of isopropyl acetate by dropwise addition of sodium hydroxide solution Seeding during the addition A small amount of acetic acid was added was collected washed with water and air dried

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

Procedure: Piperidine (1.63 liter) was added over a period of 30 minutes to a slurry of 2.5 kg isatoic anhydride in 12.5 liters of toluene. The reaction mixture was stirred for 20 minutes and extracted four times with 5 liters of 1.2N hydrochloric acid. The extracts were made basic and the product extracted with 12.5 liters of isopropyl acetate. The organic layer was washed with water and saturated sodium chloride solution and then concentrated to a thick slurry with a volume of 4 liters. The solid product was collected, washed with cold isopropyl acetate and dried overnight in vacuo to give 2.22 kg of 1-(2-aminobenzoyl)piperidine. Concentration of the filtrate afforded a second crop of 0.23 kg. extracted four times with 5 liters of 1.2N hydrochloric acid the product extracted with 12.5 liters of isopropyl acetate The organic layer was washed with water and saturated sodium chloride solution concentrated to a thick slurry with a volume of 4 liters The solid product was collected washed with cold isopropyl acetate dried overnight in vacuo

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

Procedure: A mixture of 18.2 g of 1-(2-aminobenzoyl)piperidine and 12.2 g of 2-methyl-4-chloropyridine in 5.0 ml of acetic acid was heated at reflux for six hours and then kept at room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue treated with dilute acid to pH 2 and extracted with methylene dichloride. The aqueous layer was made basic with potassium carbonate and extracted with chloroform. Further work-up of this solution afforded 2.58 g of 1-[2-(2-methyl-4-pyridinylamino)benzoyl]piperidine, m.p. 93°-95° C. when recrystallized from ethyl acetate--ether--hexane. was heated at reflux for six hours The reaction mixture was concentrated in vacuo the residue treated with dilute acid to pH 2 extracted with methylene dichloride extracted with chloroform

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

Procedure: A solution of 2.77 kg 1-(2-aminobenzoyl)piperidine in 16 liters of 2-methoxyethanol was heated until solvent distillation was about to begin (125° C. internal temperature). A solution of 2.1 kg 4-chloropyridine hydrochloride in 21 liters of 2-methoxyethanol was then slowly added over a period of one hour during which 4 liters of distillate was collected. Heating was continued for another hour while 16 liters of distillate was collected. The reaction mixture was concentrated in vacuo, and the thick residue was dissolved in 10 liters of water. Sodium acetate trihydrate (1.85 kg) was added and the solution washed three times with 3 liters of isopropyl acetate and decolorized with activated charcoal. The aqueous solution was made basic (pH>10) by dropwise addition of sodium hydroxide solution. Seeding during the addition generated a precipitate. A small amount of acetic acid was added to lower the pH to 8.5-9, and after 30 minutes of stirring the product was collected, washed with water and air dried to give 2.51 kg of 1-[2-(4-pyridinylamino)benzoyl]piperidine, m.p. 152°-153° C. The latter product was further purified by recrystallization from acetone to give the compound with m.p. 154°-155° C. (125° C. internal temperature) was collected Heating was continued for another hour while 16 liters of distillate was collected The reaction mixture was concentrated in vacuo the thick residue was dissolved in 10 liters of water Sodium acetate trihydrate (1.85 kg) was added the solution washed three times with 3 liters of isopropyl acetate by dropwise addition of sodium hydroxide solution Seeding during the addition A small amount of acetic acid was added was collected washed with water and air dried

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

Procedure: Piperidine (1.63 liter) was added over a period of 30 minutes to a slurry of 2.5 kg isatoic anhydride in 12.5 liters of toluene. The reaction mixture was stirred for 20 minutes and extracted four times with 5 liters of 1.2N hydrochloric acid. The extracts were made basic and the product extracted with 12.5 liters of isopropyl acetate. The organic layer was washed with water and saturated sodium chloride solution and then concentrated to a thick slurry with a volume of 4 liters. The solid product was collected, washed with cold isopropyl acetate and dried overnight in vacuo to give 2.22 kg of 1-(2-aminobenzoyl)piperidine. Concentration of the filtrate afforded a second crop of 0.23 kg. extracted four times with 5 liters of 1.2N hydrochloric acid the product extracted with 12.5 liters of isopropyl acetate The organic layer was washed with water and saturated sodium chloride solution concentrated to a thick slurry with a volume of 4 liters The solid product was collected washed with cold isopropyl acetate dried overnight in vacuo

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

Procedure: 1-(2-Aminobenzoyl)piperidine (prepared from piperidine 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]phenyl}(1-piperidinyl)methanone. were reacted

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

Procedure: A mixture of 18.2 g of 1-(2-aminobenzoyl)piperidine and 12.2 g of 2-methyl-4-chloropyridine in 5.0 ml of acetic acid was heated at reflux for six hours and then kept at room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue treated with dilute acid to pH 2 and extracted with methylene dichloride. The aqueous layer was made basic with potassium carbonate and extracted with chloroform. Further work-up of this solution afforded 2.58 g of 1-[2-(2-methyl-4-pyridinylamino)benzoyl]piperidine, m.p. 93°-95° C. when recrystallized from ethyl acetate--ether--hexane. was heated at reflux for six hours The reaction mixture was concentrated in vacuo the residue treated with dilute acid to pH 2 extracted with methylene dichloride extracted with chloroform

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

Procedure: A solution of 2.77 kg 1-(2-aminobenzoyl)piperidine in 16 liters of 2-methoxyethanol was heated until solvent distillation was about to begin (125° C. internal temperature). A solution of 2.1 kg 4-chloropyridine hydrochloride in 21 liters of 2-methoxyethanol was then slowly added over a period of one hour during which 4 liters of distillate was collected. Heating was continued for another hour while 16 liters of distillate was collected. The reaction mixture was concentrated in vacuo, and the thick residue was dissolved in 10 liters of water. Sodium acetate trihydrate (1.85 kg) was added and the solution washed three times with 3 liters of isopropyl acetate and decolorized with activated charcoal. The aqueous solution was made basic (pH>10) by dropwise addition of sodium hydroxide solution. Seeding during the addition generated a precipitate. A small amount of acetic acid was added to lower the pH to 8.5-9, and after 30 minutes of stirring the product was collected, washed with water and air dried to give 2.51 kg of 1-[2-(4-pyridinylamino)benzoyl]piperidine, m.p. 152°-153° C. The latter product was further purified by recrystallization from acetone to give the compound with m.p. 154°-155° C. (125° C. internal temperature) was collected Heating was continued for another hour while 16 liters of distillate was collected The reaction mixture was concentrated in vacuo the thick residue was dissolved in 10 liters of water Sodium acetate trihydrate (1.85 kg) was added the solution washed three times with 3 liters of isopropyl acetate by dropwise addition of sodium hydroxide solution Seeding during the addition A small amount of acetic acid was added was collected washed with water and air dried

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

Procedure: Piperidine (1.63 liter) was added over a period of 30 minutes to a slurry of 2.5 kg isatoic anhydride in 12.5 liters of toluene. The reaction mixture was stirred for 20 minutes and extracted four times with 5 liters of 1.2N hydrochloric acid. The extracts were made basic and the product extracted with 12.5 liters of isopropyl acetate. The organic layer was washed with water and saturated sodium chloride solution and then concentrated to a thick slurry with a volume of 4 liters. The solid product was collected, washed with cold isopropyl acetate and dried overnight in vacuo to give 2.22 kg of 1-(2-aminobenzoyl)piperidine. Concentration of the filtrate afforded a second crop of 0.23 kg. extracted four times with 5 liters of 1.2N hydrochloric acid the product extracted with 12.5 liters of isopropyl acetate The organic layer was washed with water and saturated sodium chloride solution concentrated to a thick slurry with a volume of 4 liters The solid product was collected washed with cold isopropyl acetate dried overnight in vacuo