2-(2-chlorophenyl)-4-piperidin-1-ylbutanenitrile

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

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

Procedure: The synthesis outlined in Scheme II comprises (a) reacting commercially available 2-chlorobenzeneacetonitrile with 1-(2-chloroethyl)piperidine in the presence of a base, such as sodium hydroxide, and methyltributylammonium chloride to give (±)-α-(2-chlorophenyl)-1-piperidinebutanenitrile; (b) alkylating the resulting piperidinebutanenitrile with bromoacetaldehyde dimethyl acetal in dimethylsulfoxide (DMSO) in the presence of potassium hydroxide to produce (±)-α-(2-chlorophenyl)-α-(2,2-dimethoxyethyl)-1-piperidinebutanenitrile; (c) hydrolyzing the resulting piperidinebutanenitrile in a solvent such as toluene with hydrochloric acid to produce (±)-α-(2-chlorophenyl)-α-(2-oxoethyl)-1-piperidinebutanenitrile; (d) reacting the resulting piperidinebutanenitrile with isopropylamine in a solvent such as toluene in the presence of potassium carbonate to form an imine substituted piperidinebutanenitrile; (e) reducing the resulting imine substituted piperidinebutanenitrile with sodium borohydride and ethanol to form an amino substituted piperidinebutanenitrile; (f) acetylating the resulting amino substituted piperidinebutanenitrile with acetic anhydride in a solvent such as toluene to produce an acetylated amino substituted piperidinebutanenitrile; (g) hydrolyzing the resulting acetylated amino substituted piperidinebutanenitrile with sulfuric acid to produce an acetylated amino substituted-1-piperidinebutanamide; and (h) isolating the resulting 1-piperidinebutanamide.

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

Procedure: The present invention relates to a novel process for the preparation of N-heterocyclealkanamide derivatives having the following formula: ##STR1## which comprises reacting 1-(2-chloroethyl)piperidine with 2-chlorobenzeneacetonitrile to give (±)-α-(2-chlorophenyl)-1-piperidinebutanenitrile; alkylating the piperidenebutanenitrile to give (±)-α-(2-chlorophenyl)-α-(2,2-dimethoxyethyl)piperidine-1-butanenitrile; hydrolyzing the resulting alkylated piperidinebutanenitrile to give (±)-α-(2-chlorophenyl)-α-(2-oxoethyl)piperidine-1-butanenitrile; reacting the resulting piperidinebutanenitrile with isopropylamine to form (±)-α-(2-chlorophenyl)-α-[2-[(1-methylethyl)imino]ethyl]piperidine-1-butanenitrile; reducing the resulting imine to form (±)-α-(2-chlorophenyl)-α-[2-[(1-methylethyl)amino]ethyl]-piperidine-1-butanenitrile; acetylating the resulting amine to form (±)-N-[3-(2-chlorophenyl)-3-cyano-5-(1-piperidinyl)pentyl]-N-(1-methylethyl)acetamide; hydrolyzing the resulting acetylated amino substituted piperidine butanenitrile to form (±)-α-[2-[acetyl(1-methylethyl)amino]ethyl]-α-(2-chlorophenyl)-1-piperidinebutanamide; and isolating the resulting piperidinebutanamide. The present invention relates to a novel process for the preparation of N-heterocyclealkanamide derivatives

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

Procedure: The synthesis outlined in Scheme II comprises (a) reacting commercially available 2-chlorobenzeneacetonitrile with 1-(2-chloroethyl)piperidine in the presence of a base, such as sodium hydroxide, and methyltributylammonium chloride to give (±)-α-(2-chlorophenyl)-1-piperidinebutanenitrile; (b) alkylating the resulting piperidinebutanenitrile with bromoacetaldehyde dimethyl acetal in dimethylsulfoxide (DMSO) in the presence of potassium hydroxide to produce (±)-α-(2-chlorophenyl)-α-(2,2-dimethoxyethyl)-1-piperidinebutanenitrile; (c) hydrolyzing the resulting piperidinebutanenitrile in a solvent such as toluene with hydrochloric acid to produce (±)-α-(2-chlorophenyl)-α-(2-oxoethyl)-1-piperidinebutanenitrile; (d) reacting the resulting piperidinebutanenitrile with isopropylamine in a solvent such as toluene in the presence of potassium carbonate to form an imine substituted piperidinebutanenitrile; (e) reducing the resulting imine substituted piperidinebutanenitrile with sodium borohydride and ethanol to form an amino substituted piperidinebutanenitrile; (f) acetylating the resulting amino substituted piperidinebutanenitrile with acetic anhydride in a solvent such as toluene to produce an acetylated amino substituted piperidinebutanenitrile; (g) hydrolyzing the resulting acetylated amino substituted piperidinebutanenitrile with sulfuric acid to produce an acetylated amino substituted-1-piperidinebutanamide; and (h) isolating the resulting 1-piperidinebutanamide.

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

Procedure: The present invention relates to a novel process for the preparation of N-heterocyclealkanamide derivatives having the following formula: ##STR1## which comprises reacting 1-(2-chloroethyl)piperidine with 2-chlorobenzeneacetonitrile to give (±)-α-(2-chlorophenyl)-1-piperidinebutanenitrile; alkylating the piperidenebutanenitrile to give (±)-α-(2-chlorophenyl)-α-(2,2-dimethoxyethyl)piperidine-1-butanenitrile; hydrolyzing the resulting alkylated piperidinebutanenitrile to give (±)-α-(2-chlorophenyl)-α-(2-oxoethyl)piperidine-1-butanenitrile; reacting the resulting piperidinebutanenitrile with isopropylamine to form (±)-α-(2-chlorophenyl)-α-[2-[(1-methylethyl)imino]ethyl]piperidine-1-butanenitrile; reducing the resulting imine to form (±)-α-(2-chlorophenyl)-α-[2-[(1-methylethyl)amino]ethyl]-piperidine-1-butanenitrile; acetylating the resulting amine to form (±)-N-[3-(2-chlorophenyl)-3-cyano-5-(1-piperidinyl)pentyl]-N-(1-methylethyl)acetamide; hydrolyzing the resulting acetylated amino substituted piperidine butanenitrile to form (±)-α-[2-[acetyl(1-methylethyl)amino]ethyl]-α-(2-chlorophenyl)-1-piperidinebutanamide; and isolating the resulting piperidinebutanamide. The present invention relates to a novel process for the preparation of N-heterocyclealkanamide derivatives

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

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

Procedure: alkylating α-(2-chlorophenyl)-1-piperidinebutanenitrile with N-(2-chloroethyl)-N-(1-methylethyl)benzenemethanamine, monohydrochloride in the presence of base and dimethyl sulfoxide to give α-(2-chlorophenyl)-α-[2-[(1-methylethyl) (phenylmethyl)amino]ethyl]-1-piperidine butanenitrile;

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a reaction vessel under a nitrogen atmosphere was charged 35.0 kg of pulverized potassium hydroxide (90%) and 34.0 L of dimethyl sulfoxide. A solution of 29.5 kg of α-(2-chlorophenyl)-1-piperidinebutanenitrile (product of Example 3) in 23 L of dimethyl sulfoxide was added while maintaining the temperature below 25° C. A solution of 30.7 kg of N-(2-chloroethyl)-N-(1-methylethyl)benzenemethanamine, monohydrochloride in 112 L of dimethyl sulfoxide was added while maintaining the temperature below 20° C. The mixture was stirred at 25° C. until the reaction was complete as indicated by gas chromatographic analysis (GC Method C). The mixture was cooled and diluted with 122 L of heptane and 200 L of water. The layers were separated, and the organic phase was filtered through a layer of diatomaceous earth. The filter cake was washed with 40 L of heptane. The combined organic phase was washed twice with 70 L of water and dried by azeotropic distillation. The solvent was removed by distillation under reduced pressure to give 49.4 kg (100.0%) of the title product α-(2-chlorophenyl)-α-[2-[(1-methylethyl)(phenylmethyl)amino]ethyl]-1-piperidinebutanenitrile as an oil. Analysis calcd for C27H36ClN3 : C,74.03; H,8.28; Cl,8.09; N,9.59. Found: C,73.35; H,8.36; Cl,7.27; N,9.15. The crude product (oil) was carried forward to the next step without purification. The purity of the title compound was estimated to be >85% based on GC Method C. while maintaining the temperature below 25° C while maintaining the temperature below 20° C The mixture was cooled The layers were separated the organic phase was filtered through a layer of diatomaceous earth The filter cake was washed with 40 L of heptane The combined organic phase was washed twice with 70 L of water dried by azeotropic distillation The solvent was removed by distillation under reduced pressure

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A reaction vessel under a nitrogen atmosphere containing 74.0 kg of 1-(2-chloroethyl)piperidine, monohydrochloride at 10° C. was charged with 255.4 kg of sodium hydroxide solution (50% w/w). The reaction was warmed to 30° to 35° C. and 67.0 kg of 2-chlorobenzeneacetonitrile and 1.4 kg of methyltributylammonium chloride (75% w/w in water) were added. The reaction was stirred at 40° C. for 6 h and then heated to 60° C. for at least 6 h. When the reaction was completed as indicated by gas chromatographic analysis, the reaction mixture was cooled to 25° C. The reaction mixture was diluted with 335 L of water and 134 L of toluene and stirred for 30 min. After separation of the layers, the organic phase was extracted with 275 L of hydrochloric acid (2N). The acidic extract was washed twice with 50 L of toluene, basified with 30 L of sodium hydroxide solution (50% w/w) to a pH>12 and extracted twice with a total of 368 L of heptane. The combined organic phase was washed with 50 L of water and filtered through a layer of diatomaceous earth. The filtrate was dried by azeotropic distillation. The solvent was removed by distillation under reduced pressure to give 104.5 kg (90.0%) of the title product α-(2-chlorophenyl)-1-piperidinebutanenitrile as an oil. Analysis calcd for C15H19ClN2 : C,68.56; H,7.29; Cl,13.49; N,10.66. Found: C,69.64; H,7.53; Cl,12.45; N,9.75. The crude product (oil) was carried forward to the next step without purification. The purity of the title compound was estimated to be 98% based on GC Method B. The reaction was warmed to 30° to 35° C. heated to 60° C. for at least 6 h the reaction mixture was cooled to 25° C stirred for 30 min After separation of the layers the organic phase was extracted with 275 L of hydrochloric acid (2N) The acidic extract was washed twice with 50 L of toluene extracted twice with a total of 368 L of heptane The combined organic phase was washed with 50 L of water filtered through a layer of diatomaceous earth The filtrate was dried by azeotropic distillation The solvent was removed by distillation under reduced pressure

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

Procedure: alkylating α-(2-chlorophenyl)-1-piperidine butanenitrile with N-(2-chloroethyl)-N-(1-methylethyl)benzenemethanamine, monohydrochloride in the presence of base and dimethyl sulfoxide to give α-(2-chlorophenyl)-α-[2-[(1-methylethyl) (phenylmethyl)amino]ethyl]-1-piperidinebutane nitrile;

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

Procedure: The synthesis outlined in Scheme II comprises (a) reacting commercially available 2-chlorobenzeneacetonitrile with 1-(2-chloroethyl)piperidine in the presence of a base, such as sodium hydroxide, and methyltributylammonium chloride to give (±)-α-(2-chlorophenyl)-1-piperidinebutanenitrile; (b) alkylating the resulting piperidinebutanenitrile with bromoacetaldehyde dimethyl acetal in dimethylsulfoxide (DMSO) in the presence of potassium hydroxide to produce (±)-α-(2-chlorophenyl)-α-(2,2-dimethoxyethyl)-1-piperidinebutanenitrile; (c) hydrolyzing the resulting piperidinebutanenitrile in a solvent such as toluene with hydrochloric acid to produce (±)-α-(2-chlorophenyl)-α-(2-oxoethyl)-1-piperidinebutanenitrile; (d) reacting the resulting piperidinebutanenitrile with isopropylamine in a solvent such as toluene in the presence of potassium carbonate to form an imine substituted piperidinebutanenitrile; (e) reducing the resulting imine substituted piperidinebutanenitrile with sodium borohydride and ethanol to form an amino substituted piperidinebutanenitrile; (f) acetylating the resulting amino substituted piperidinebutanenitrile with acetic anhydride in a solvent such as toluene to produce an acetylated amino substituted piperidinebutanenitrile; (g) hydrolyzing the resulting acetylated amino substituted piperidinebutanenitrile with sulfuric acid to produce an acetylated amino substituted-1-piperidinebutanamide; and (h) isolating the resulting 1-piperidinebutanamide.

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

Procedure: The present invention relates to a novel process for the preparation of N-heterocyclealkanamide derivatives having the following formula: ##STR1## which comprises reacting 1-(2-chloroethyl)piperidine with 2-chlorobenzeneacetonitrile to give (±)-α-(2-chlorophenyl)-1-piperidinebutanenitrile; alkylating the piperidenebutanenitrile to give (±)-α-(2-chlorophenyl)-α-(2,2-dimethoxyethyl)piperidine-1-butanenitrile; hydrolyzing the resulting alkylated piperidinebutanenitrile to give (±)-α-(2-chlorophenyl)-α-(2-oxoethyl)piperidine-1-butanenitrile; reacting the resulting piperidinebutanenitrile with isopropylamine to form (±)-α-(2-chlorophenyl)-α-[2-[(1-methylethyl)imino]ethyl]piperidine-1-butanenitrile; reducing the resulting imine to form (±)-α-(2-chlorophenyl)-α-[2-[(1-methylethyl)amino]ethyl]-piperidine-1-butanenitrile; acetylating the resulting amine to form (±)-N-[3-(2-chlorophenyl)-3-cyano-5-(1-piperidinyl)pentyl]-N-(1-methylethyl)acetamide; hydrolyzing the resulting acetylated amino substituted piperidine butanenitrile to form (±)-α-[2-[acetyl(1-methylethyl)amino]ethyl]-α-(2-chlorophenyl)-1-piperidinebutanamide; and isolating the resulting piperidinebutanamide. The present invention relates to a novel process for the preparation of N-heterocyclealkanamide derivatives