piperazine-2-carboxamide

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

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

Procedure: To a solution of 4-benzyloxycarbonyl-1-(4-[5-fluoro-1-(2-trimethylsilylethane-sulfonyl)indol-3-yl]piperidine-1-sulfonyl)piperazine-2-(RS)-carboxylic acid(288 mg, 0.40 mmol), [prepared as described in Step 6 above] in methylene chloride (5 ml) at 0° C. were added a few drops of DMF and oxalyl chloride (89 ml, 1.0 mmol). The reaction mixture was warmed to RT over 1 h, and stirring was continued for an additional 14 h. The reaction mixture was concentrated in vacua, redissolved in methylene chloride (5 ml) and cooled to 0° C. N,O-bis-trithylsilyl hydroxylamine (0.304 ml, 1.42 mmol) added, the reaction was warmed to RT, stred for 3 h, and then recooled to 0° C. After adding methanol (3 ml), the mixture was stirred for an additional 30 min., and then concentrated in vacuo. The residue was partitioned between methylene chloride (50 ml) and aqueous 2.4 M HCl (10 ml), the organic layer was separated and washed with saturated aqueous sodium bicarbonate, dried over MgSO4, and concentrated in vacuo to afford N-hydroxy-4-benzyloxycarbonyl-1-j4-[5-fluoro-1-2-trmethylsilylethanesulfonyl)-indol-3-yl]-piperidine-1-sulfonyl ) piperazine-2-(RS)-carboxamide as a yellow foam (250 mg, 86%). The residue was used without further purification. The reaction mixture was concentrated in vacua redissolved in methylene chloride (5 ml) cooled to 0° C the reaction was warmed to RT stred for 3 h recooled to 0° C the mixture was stirred for an additional 30 min. concentrated in vacuo The residue was partitioned between methylene chloride (50 ml) and aqueous 2.4 M HCl (10 ml) the organic layer was separated washed with saturated aqueous sodium bicarbonate dried over MgSO4 concentrated in vacuo

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: A mixture of 17.7 parts of N-(4-chlorobutyl)-4-fluoro-N-(4-fluorophenyl)benzenamine. 23.3 parts of 2-piperazinecarboxamide, 17.6 parts of N,N-diethylethanamine and 300 parts of 2-methoxyethanol was stirred for 48 hours at 70° C. The reaction mixture was evaporated and the residue was taken up in water and a small amount of methanol. The product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fraction was collected and the eluent was evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and acetonitrile (80:20 by volume). The product was filtered off and dried, yielding 12.82 parts (55.0%) of 4-[4-[bis-(4-fluorophenyl)amino]butyl]-2-piperazinecarboxamide; mp. 67.4° C. (int. 28). The reaction mixture was evaporated The product was extracted twice with dichloromethane The combined extracts were washed with water dried filtered evaporated The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol The pure fraction was collected the eluent was evaporated The residue was crystallized from a mixture of 2,2'-oxybispropane and acetonitrile (80:20 by volume) The product was filtered off dried

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

Procedure: A mixture of 17.7 parts of N-(4-chlorobutyl)-4-fluoro-N-(4-fluorophenyl)benzenamine. 23.3 parts of 2-piperazinecarboxamide, 17.6 parts of N,N-diethylethanamine and 300 parts of 2-methoxyethanol was stirred for 48 hours at 70° C. The reaction mixture was evaporated and the residue was taken up in water and a small amount of methanol. The product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fraction was collected and the eluent was evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and acetonitrile (80:20 by volume). The product was filtered off and dried, yielding 12.82 parts (55.0%) of 4-[4-[bis-(4-fluorophenyl)amino]butyl]-2-piperazinecarboxamide; mp. 67.4° C. (int. 28). The reaction mixture was evaporated The product was extracted twice with dichloromethane The combined extracts were washed with water dried filtered evaporated The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol The pure fraction was collected the eluent was evaporated The residue was crystallized from a mixture of 2,2'-oxybispropane and acetonitrile (80:20 by volume) The product was filtered off dried

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

Procedure: To a solution of 4-benzyloxycarbonyl-1-(4-[5-fluoro-1-(2-trimethylsilylethane-sulfonyl)indol-3-yl]piperidine-1-sulfonyl)piperazine-2-(RS)-carboxylic acid(288 mg, 0.40 mmol), [prepared as described in Step 6 above] in methylene chloride (5 ml) at 0° C. were added a few drops of DMF and oxalyl chloride (89 ml, 1.0 mmol). The reaction mixture was warmed to RT over 1 h, and stirring was continued for an additional 14 h. The reaction mixture was concentrated in vacua, redissolved in methylene chloride (5 ml) and cooled to 0° C. N,O-bis-trithylsilyl hydroxylamine (0.304 ml, 1.42 mmol) added, the reaction was warmed to RT, stred for 3 h, and then recooled to 0° C. After adding methanol (3 ml), the mixture was stirred for an additional 30 min., and then concentrated in vacuo. The residue was partitioned between methylene chloride (50 ml) and aqueous 2.4 M HCl (10 ml), the organic layer was separated and washed with saturated aqueous sodium bicarbonate, dried over MgSO4, and concentrated in vacuo to afford N-hydroxy-4-benzyloxycarbonyl-1-j4-[5-fluoro-1-2-trmethylsilylethanesulfonyl)-indol-3-yl]-piperidine-1-sulfonyl ) piperazine-2-(RS)-carboxamide as a yellow foam (250 mg, 86%). The residue was used without further purification. The reaction mixture was concentrated in vacua redissolved in methylene chloride (5 ml) cooled to 0° C the reaction was warmed to RT stred for 3 h recooled to 0° C the mixture was stirred for an additional 30 min. concentrated in vacuo The residue was partitioned between methylene chloride (50 ml) and aqueous 2.4 M HCl (10 ml) the organic layer was separated washed with saturated aqueous sodium bicarbonate dried over MgSO4 concentrated in vacuo

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

Procedure: To a stirred and warm solution of 3 parts of 2-piperazinecarboxamide in 16 parts of 2-methoxyethanol were added 51.2 parts of 2-propanone. The whole was stirred and refluxed for 20 hours. The reaction mixture was evaporated. The solid residue was crystallized from acetonitrile, yielding 2.5 parts (64%) of hexahydro-3,3-dimethylimidazo[1,5-a]pyrazin-1(5H)-one; mp. 174.2° C. (intermediate 83). The whole was stirred refluxed for 20 hours The reaction mixture was evaporated The solid residue was crystallized from acetonitrile

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

Procedure: To 1 part of a solution of 2 parts of thiophene in 40 parts of ethanol were added 2.2 parts of benzaldehyde, 2.6 parts of 2-piperazinecarboxamide and 120 parts of methanol. The whole was hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The solid residue was boiled in 64 parts of acetonitrile. The mixture was filtered and the filtrate was allowed to crystallize at room temperature. The product was filtered off and dried, yielding 2.4 parts (55%) of 4-(phenylmethyl)-2-piperazinecarboxamide; mp. 168.3° C. (intermediate 36). the catalyst was filtered off the filtrate was evaporated The mixture was filtered to crystallize at room temperature The product was filtered off dried

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

Procedure: To a stirred and warm solution of 3 parts of 2-piperazinecarboxamide in 16 parts of 2-methoxyethanol were added 51.2 parts of 2-propanone. The whole was stirred and refluxed for 20 hours. The reaction mixture was evaporated. The solid residue was crystallized from acetonitrile, yielding 2.5 parts (64%) of hexahydro-3,3-dimethylimidazo[1,5-a]pyrazin-1(5H)-one; mp. 174.2° C. (intermediate 83). The whole was stirred refluxed for 20 hours The reaction mixture was evaporated The solid residue was crystallized from acetonitrile

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

Procedure: To 1 part of a solution of 2 parts of thiophene in 40 parts of ethanol were added 2.2 parts of benzaldehyde, 2.6 parts of 2-piperazinecarboxamide and 120 parts of methanol. The whole was hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The solid residue was boiled in 64 parts of acetonitrile. The mixture was filtered and the filtrate was allowed to crystallize at room temperature. The product was filtered off and dried, yielding 2.4 parts (55%) of 4-(phenylmethyl)-2-piperazinecarboxamide; mp. 168.3° C. (intermediate 36). the catalyst was filtered off the filtrate was evaporated The mixture was filtered to crystallize at room temperature The product was filtered off dried

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

Procedure: 4-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]piperazine-2-carboxamide was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and piperazine-2-carboxylic acid amide following General Procedure C.