2-chloro-N-(5-fluoro-2-methylphenyl)acetamide

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

Procedure: A mixture of 6.6 parts of 2-chloro-N-(5-fluoro-2-methylphenyl)acetamide, 5 parts of hexahydro-3,3-dimethyl-3H-oxazolo[3,4-a]pyrazine, 6.1 parts of N,N-diethylethanamine and 67.5 parts of N,N-dimethylformamide was stirred and heated for 8 hours at about 70° C. After cooling overnight to room temperature, the reaction mixture was evaporated. The residue was dissolved in trichloromethane. The solution was washed with water, dried, filtered and evaporated, yielding 8.5 parts of N-(5-fluoro-2-methylphenyl)-tetrahydro-3,3-dimethyl-3H-oxazolo[3,4-a]pyrazine-7(8H)-acetamide as an oily residue (intermediate 121). After cooling overnight to room temperature the reaction mixture was evaporated The residue was dissolved in trichloromethane The solution was washed with water dried filtered evaporated

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 5.04 parts of 4-[5,5-bis(4-fluorophenyl)pentyl]-2-piperazinecarboxamide, 2.9 parts of 2-chloro-N-(5-fluoro-2-methylphenyl) acetamide, 2.1 parts of sodium carbonate, 0.1 parts of potassium iodide and 120 parts of 4-methyl-2-pentanone was stirred and refluxed for 18 hours. After cooling, the reaction mixture was washed with water. The organic layer was 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 acetonitrile and 2-propanol. The precipitate was filtered off and the filtrate was evaporated. The residue was dried at 80° C., yielding 5.48 parts (71%) of 2-(aminocarbonyl)-4-[5,5-bis(4-fluorophenyl)pentyl]-N-(5-fluoro-2-methylphenyl)-1-piperazineacetamide monohydrochloride; mp. 148.2° C. (compound 9). refluxed for 18 hours After cooling the reaction mixture was washed with water The organic layer was 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 precipitate was filtered off the filtrate was evaporated The residue was dried at 80° C.

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

Procedure: A mixture of 5.04 parts of 4-[5,5-bis(4-fluorophenyl)pentyl]-2-piperazinecarboxamide, 2.9 parts of 2-chloro-N-(5-fluoro-2-methylphenyl) acetamide, 2.1 parts of sodium carbonate, 0.1 parts of potassium iodide and 120 parts of 4-methyl-2-pentanone was stirred and refluxed for 18 hours. After cooling, the reaction mixture was washed with water. The organic layer was 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 acetonitrile and 2-propanol. The precipitate was filtered off and the filtrate was evaporated. The residue was dried at 80° C., yielding 5.48 parts (71%) of 2-(aminocarbonyl)-4-[5,5-bis(4-fluorophenyl)pentyl]-N-(5-fluoro-2-methylphenyl)-1-piperazineacetamide monohydrochloride; mp. 148.2° C. (compound 9). refluxed for 18 hours After cooling the reaction mixture was washed with water The organic layer was 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 precipitate was filtered off the filtrate was evaporated The residue was dried at 80° C.

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

Procedure: A mixture of 6.6 parts of 2-chloro-N-(5-fluoro-2-methylphenyl)acetamide, 5 parts of hexahydro-3,3-dimethyl-3H-oxazolo[3,4-a]pyrazine, 6.1 parts of N,N-diethylethanamine and 67.5 parts of N,N-dimethylformamide was stirred and heated for 8 hours at about 70° C. After cooling overnight to room temperature, the reaction mixture was evaporated. The residue was dissolved in trichloromethane. The solution was washed with water, dried, filtered and evaporated, yielding 8.5 parts of N-(5-fluoro-2-methylphenyl)-tetrahydro-3,3-dimethyl-3H-oxazolo[3,4-a]pyrazine-7(8H)-acetamide as an oily residue (intermediate 121). After cooling overnight to room temperature the reaction mixture was evaporated The residue was dissolved in trichloromethane The solution was washed with water dried filtered evaporated

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 6.6 parts of 2-chloro-N-(5-fluoro-2-methylphenyl)acetamide, 5 parts of hexahydro-3,3-dimethyl-3H-oxazolo[3,4-a]pyrazine, 6.1 parts of N,N-diethylethanamine and 67.5 parts of N,N-dimethylformamide was stirred and heated for 8 hours at about 70° C. After cooling overnight to room temperature, the reaction mixture was evaporated. The residue was dissolved in trichloromethane. The solution was washed with water, dried, filtered and evaporated, yielding 8.5 parts of N-(5-fluoro-2-methylphenyl)-tetrahydro-3,3-dimethyl-3H-oxazolo[3,4-a]pyrazine-7(8H)-acetamide as an oily residue (intermediate 121). After cooling overnight to room temperature the reaction mixture was evaporated The residue was dissolved in trichloromethane The solution was washed with water dried filtered evaporated

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

Procedure: A mixture of 5.04 parts of 4-[5,5-bis(4-fluorophenyl)pentyl]-2-piperazinecarboxamide, 2.9 parts of 2-chloro-N-(5-fluoro-2-methylphenyl)acetamide, 2.1 parts of sodium carbonate, 0.1 parts of potassium iodide and 120 parts of 4-methyl-2-pentanone was stirred and refluxed for 18 hours. After cooling, the reaction mixture was washed with water. The organic layer was 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 acetonitrile and 2-propanol. The precipitate was filtered off and the filtrate was evaporated. The residue was dried at 80° C., yielding 5.48 parts (71%) of 2-(aminocarbonyl)-4-[5,5-bis(4-fluorophenyl)pentyl]-N-(5-fluoro-2-methylphenyl)-1-piperazineacetamide monohydrochloride; mp. 148.2° C. (compound 9). refluxed for 18 hours After cooling the reaction mixture was washed with water The organic layer was 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 precipitate was filtered off the filtrate was evaporated The residue was dried at 80° C.

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

Procedure: A mixture of 5.04 parts of 4-[5,5-bis(4-fluorophenyl)pentyl]-2-piperazinecarboxamide, 2.9 parts of 2-chloro-N-(5-fluoro-2-methylphenyl) acetamide, 2.1 parts of sodium carbonate, 0.1 parts of potassium iodide and 120 parts of 4-methyl-2-pentanone was stirred and refluxed for 18 hours. After cooling, the reaction mixture was washed with water. The organic layer was 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 acetonitrile and 2-propanol. The precipitate was filtered off and the filtrate was evaporated. The residue was dried at 80° C., yielding 5.48 parts (71%) of 2-(aminocarbonyl)-4-[5,5-bis(4-fluorophenyl)pentyl]-N-(5-fluoro-2-methylphenyl)-1-piperazineacetamide monohydrochloride; mp. 148.2° C. (compound 9). refluxed for 18 hours After cooling the reaction mixture was washed with water The organic layer was 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 precipitate was filtered off the filtrate was evaporated The residue was dried at 80° C.