(1-butylpiperidin-4-yl)methanamine

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

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

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

Procedure: 5-Fluoroindole-3-carboxylic acid chloride was reacted with (1-n butyl-4-piperidyl)methylamine (Description 1a) as in the method of Description 1b to afford N-[(1-n butyl-4-piperidyl)methyl] 5-fluoroindole-3-carboxamide as an off-white solid (64%).

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

Procedure: The title compound was prepared according to the procedure of step 1 in example 1 using 6-amino-5-iodo-2-(methyloxy)-3-pyridinecarboxylic acid (step 3) and (1-butyl-4-piperidinyl)methylamine instead of 6-amino-5-chloro-2-(methyloxy)-3-pyridinecarboxylic acid and 1,1-dimethylethyl 4-(aminomethyl)-1-piperidinecarboxylate.

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

Procedure: 5-Chloro-2-methylbenzoxazole-7-carboxylic acid (Ger. Offen. 2,225,544) is converted to its acid chloride by treatment with oxalyl chloride. The acid chloride is treated with N-(1-butyl-4-piperidinyl)methylamine in the presence of triethylamine to afford the title compound.

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

Procedure: 5-Chloro-2-methylbenzoxazole-7-carboxylic acid (Ger. Offen. 2,225,544) is converted to its acid chloride by treatment with oxalyl chloride. The acid chloride is treated with N-(1-butyl-4-piperidinyl)methylamine in the presence of triethylamine to afford the title compound.

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

Procedure: The title compound was prepared according to the procedure described in the step 3 of EXAMPLE 5 from 5-amino-6-chloro-2-ethylimidazo[1,2-a]pyridine-8-carboxylic acid (EXAMPLE 10, Step 2) and 1-(1-butyl-4-piperidinyl)methanamine (EXAMPLE 1, METHOD A, Step 5).

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

Procedure: To a solution of 5-chloro-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (100 mg, 0.376 mmol, step 4) in dichloromethane (1 mL) was added oxalyl chloride (0.10 mL, 1.13 mmol) and a drop of N,N-dimethylformamide at 0° C. The mixture was stirred at room temperature for 1.5 h. The solvent and excess amount of oxalyl chloride was removed in vacuo. The residue was dissolved in dichloromethane (1 mL) and [(1-butylpiperidin-4-yl)methyl]amine (128 mg, 0.753 mmol) in dichloromethane (1 mL) was added at 0° C. and the mixture was stirred at room temperature for 1 h. Then, the mixture was quenched with water (10 mL) and the aqueous layer was extracted with dichloromethane (20 mL×2). The organic layer was dried over sodium sulfate and concentrated in vacuo gave a colorless oil. The resultant oil was dissolved in 10% methanolic hydrogen chloride (5 mL) and stirred for 16 h. The formed precipitate was filtrated and washed with methanol to give 100 mg (59%) of the title compound as a white solid. at 0° C The solvent and excess amount of oxalyl chloride was removed in vacuo The residue was dissolved in dichloromethane (1 mL) the mixture was stirred at room temperature for 1 h Then, the mixture was quenched with water (10 mL) the aqueous layer was extracted with dichloromethane (20 mL×2) The organic layer was dried over sodium sulfate concentrated in vacuo gave a colorless oil stirred for 16 h The formed precipitate was filtrated washed with methanol

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Method A Toluene (85L) was azeotropically dried in an argon purged reactor, cooled to 10° C. and a solution of trimethylaluminum in toluene (18.57 kg, 16.7% w/w, 43 mole) added. To this at 20 to 24° C. was added a solution of 1-n-butyl-4-piperidinylmethylamine (7.39 kg, 99.4% pure, 42.7 mole) in toluene (22 L) over 43 minutes. Methyl 3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxylate (9.65 kg, 98.9% pure, 41.3 mole) was added in one portion and the reaction heated to reflux at 112° C. for 4 hours 10 minutes after which time the reaction was judged to be complete by HPLC analysis. 10% Sodium hydroxide solution (52.2 L), prepared from 32% ww sodium hydroxide (24 L) and water (80 L), was added cautiously over 16 minutes at about 60 to 70° C. The resulting mixture was heated to 70 to 80° C. and the aqueous layer separated. The toluene layer was washed with 10% sodium hydroxide (52.2 L) followed twice by water (29 L each wash). The toluene layer was cooled and diluted with hexane fraction (133 L) to crystallise the product. After cooling to about 2° C. overnight the product was collected by filtration, washed on the filter with hexane (21 L) and dried in vacuo at 40° C. overnight to give SB-207266 batch 207266-HP8 (12.26 kg, 94.5% pure, 75.9%). Method A Toluene (85L) was azeotropically dried in an argon purged reactor the reaction heated to reflux at 112° C. for 4 hours 10 minutes after which time the reaction was added cautiously over 16 minutes at about 60 to 70° C The resulting mixture was heated to 70 to 80° C. the aqueous layer separated The toluene layer was washed with 10% sodium hydroxide (52.2 L) The toluene layer was cooled diluted with hexane fraction (133 L) to crystallise the product After cooling to about 2° C. overnight the product was collected by filtration washed on the filter with hexane (21 L) dried in vacuo at 40° C. overnight

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

Procedure: 2-Chloroindole-3-carboxylic acid (L. Marchetti and A Andreani, Ann. Chim. (Rome), 1973, 63, 681) was converted to its acid chloride and reacted with N-(1-n butyl-4-piperidyl)methylamine (D 1) using the procedure of Description 1b to afford N-[(1-n butyl-4-piperidyl)methyl] 2-chloroindole-3-carboxamide.

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

Procedure: 5-Fluoroindole-3-carboxylic acid chloride was reacted with (1-n butyl-4-piperidyl)methylamine (Description 1a) as in the method of Description 1b to afford N-[(1-n butyl-4-piperidyl)methyl] 5-fluoroindole-3-carboxamide as an off-white solid (64%).

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

Procedure: 5-Chloro-2-methylbenzoxazole-7-carboxylic acid (Ger. Offen. 2,225,544) is converted to its acid chloride by treatment with oxalyl chloride. The acid chloride is treated with N-(1-butyl-4-piperidinyl)methylamine in the presence of triethylamine to afford the title compound.