2-chloro-N-(2,6-dichlorophenyl)acetamide

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4.05 parts of 2-chloro-N-(2,6-dichlorophenyl)acetamide, 5.6 parts of 1-[4,4-bis(4-fluorophenyl)butyl]-2-piperazinecarboxamide, 2.94 parts of N,N-diethylethanamine and 63 parts of N,N-dimethylformamide was stirred for 5 hours at 70° C. The reaction mixture was poured onto ice-water. The precipitated product was filtered off and dissolved in dichloromethane. The solution was washed with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanone and 2-propanol. The salt was filtered off and stirred for 30 minutes in 1,1'-oxybisethane, yielding 4.54 parts of 3-(aminocarbonyl)-4-[4,4-bis(4-fluorophenyl)butyl]-N-(2,6-dichlorophenyl)-1-piperazineacetamide dihydrochloride monohydrate; mp. 182.7° C. (compound 72). The reaction mixture was poured onto ice-water The precipitated product was filtered off dissolved in dichloromethane The solution was washed with water dried filtered evaporated The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent The pure fractions were collected the eluent was evaporated The salt was filtered off stirred for 30 minutes in 1,1'-oxybisethane

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

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

Procedure: In a manner similar to Preparation 12, react 2-chloro-N-(2,6-dichlorophenyl)acetamide with 3,4-dimethoxybenzenemethanamine to obtain the title compound. In a manner similar to Preparation 12

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4.05 parts of 2-chloro-N-(2,6-dichlorophenyl)acetamide, 5.6 parts of 1-[4,4-bis(4-fluorophenyl)butyl]-2-piperazinecarboxamide, 2.94 parts of N,N-diethylethanamine and 63 parts of N,N-dimethylformamide was stirred for 5 hours at 70° C. The reaction mixture was poured onto ice-water. The precipitated product was filtered off and dissolved in dichloromethane. The solution was washed with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanone and 2-propanol. The salt was filtered off and stirred for 30 minutes in 1,1'-oxybisethane, yielding 4.54 parts of 3-(aminocarbonyl)-4-[4,4-bis(4-fluorophenyl)butyl]-N-(2,6-dichlorophenyl)-1-piperazineacetamide dihydrochloride monohydrate; mp. 182.7° C. (compound 72). The reaction mixture was poured onto ice-water The precipitated product was filtered off dissolved in dichloromethane The solution was washed with water dried filtered evaporated The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent The pure fractions were collected the eluent was evaporated The salt was filtered off stirred for 30 minutes in 1,1'-oxybisethane

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

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4.05 parts of 2-chloro-N-(2,6-dichlorophenyl)acetamide, 5.6 parts of 1-[4,4-bis(4-fluorophenyl)butyl]-2-piperazinecarboxamide, 2.94 parts of N,N-diethylethanamine and 63 parts of N,N-dimethylformamide was stirred for 5 hours at 70° C. The reaction mixture was poured onto ice-water. The precipitated product was filtered off and dissolved in dichloromethane. The solution was washed with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanone and 2-propanol. The salt was filtered off and stirred for 30 minutes in 1,1'-oxybisethane, yielding 4.54 parts of 3-(aminocarbonyl)-4-[4,4-bis(4-fluorophenyl)butyl]-N-(2,6-dichlorophenyl)-1-piperazineacetamide dihydrochloride monohydrate; mp. 182.7° C. (compound 72). The reaction mixture was poured onto ice-water The precipitated product was filtered off dissolved in dichloromethane The solution was washed with water dried filtered evaporated The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent The pure fractions were collected the eluent was evaporated The salt was filtered off stirred for 30 minutes in 1,1'-oxybisethane

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-[4-(4-fluorophenyl)-4-(3-pyridinyl)butyl]-2-piperazinecarboxamide (6.75 g), 2-chloro-N-(2,6-dichlorophenyl)acetamide (5.24 g), sodium carbonate (3.16 g) and DMF (143 ml) was stirred for 4 hours at 70° C. The reaction mixture was evaporated and water was added to the residue. After extraction with DCM, the combined organic layers were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel (eluent:CHCl3/CH3OH 95/5). The desired fractions were collected and the solvent was evaporated. The residue was dissolved in 2-propanol and DIPE and converted into the hydrochloride salt. The salt was filtered off and dried, yielding 2.23 g of 3-(amino-carbonyl)-N-(2,6-dichloro-phenyl)-4-[4-(4-fluorophenyl)-4-(3-pyridinyl)-butyl]-1-piperazineacetamide dihydrochloride.monohydrate (compound 14, mp. 226.3° C.). The reaction mixture was evaporated water was added to the residue After extraction with DCM the combined organic layers were washed with water dried filtered evaporated The residue was purified by column chromatography over silica gel (eluent:CHCl3/CH3OH 95/5) The desired fractions were collected the solvent was evaporated The residue was dissolved in 2-propanol The salt was filtered off dried

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

Procedure: In a manner similar to Preparation 12, react 2-chloro-N-(2,6-dichlorophenyl)acetamide with 3,4-dimethoxybenzenemethanamine to obtain the title compound. In a manner similar to Preparation 12

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

Procedure: In a manner similar to Preparation 12, react 2-chloro-N-(2,6-dichlorophenyl)acetamide with 3,4-dimethoxybenzenemethanamine to obtain the title compound. In a manner similar to Preparation 12