2-(1-benzylpiperidin-4-yl)acetonitrile

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

Procedure: To a solution of 25 parts of 1-(phenylmethyl)-4-piperidineacetonitrile in 178 parts of tetrahydrofuran were added dropwise 37.97 parts of ethyl chloroformate at room temperature. The reaction mixture was stirred for 15 hours at room temperature and was then evaporated. The residue was taken up in 90 parts of ethyl acetate and the whole was washed successively with HCl 3N, NaHCO3 and NaCl (sat.). The solvent was evaporated and the residue was distilled (100°-110° C./6.7 Pa), yielding 18.7 parts (81.4%) of ethyl 4-(cyanomethyl)-1-piperidinecarboxylate (interm. 24). was then evaporated the whole was washed successively with HCl 3N, NaHCO3 and NaCl (sat.) The solvent was evaporated the residue was distilled (100°-110° C./6.7 Pa)

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium metal (0.8 g, 34.78 mmol) was dissolved in dry methanol (10 mL) at 0-10° C. and this solution was added slowly into a suspension of hydroxylamine hydrochloride (2.43 g, 34.96 mmol) in methanol (10 mL) at room temperature. The reaction mixture was stirred for 10 min until a clear solution was obtained, 2-(1-Benzylpiperidin-4-yl)acetonitrile (compound of Example 27; 3 g, 13.99 mmol) in dry methanol (20 mL) was added into the resulting reaction mixture and heated at 75° C. for 13 h. The solvent was evaporated at 50° C. to 55° C. and the crude product obtained was purified by column chromatography (silica gel, chloroform-methanol) to afford the title compound. was obtained The solvent was evaporated at 50° C. to 55° C. the crude product obtained was purified by column chromatography (silica gel, chloroform-methanol)

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

Procedure: To a solution of benzylpiperidin-4-ylideneacetonitrile (compound of Example 26; 1 g, 4.7 mmol) in methanol (50 mL), magnesium turnings (4.58 g, 188.3 mmol) was added at 0° C. The reaction mixture was stirred at 5° C. to 10° C. for 4 h. The magnesium salts were dissolved by addition of concentrated hydrochloric acid, and the mixture was basified with 10N sodium hydroxide solution. The precipitate was filtered and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water (2×15 mL) followed by brine (10 mL). The organic phase obtained was dried over anhydrous sodium sulphate and evaporated to afford the title compound. The precipitate was filtered extracted with ethyl acetate (2×20 mL) The combined organic layers were washed with water (2×15 mL) The organic phase obtained was dried over anhydrous sodium sulphate evaporated

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

Procedure: To a solution of benzylpiperidin-4-ylideneacetonitrile (compound of Example 26; 1 g, 4.7 mmol) in methanol (50 mL), magnesium turnings (4.58 g, 188.3 mmol) was added at 0° C. The reaction mixture was stirred at 5° C. to 10° C. for 4 h. The magnesium salts were dissolved by addition of concentrated hydrochloric acid, and the mixture was basified with 10N sodium hydroxide solution. The precipitate was filtered and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water (2×15 mL) followed by brine (10 mL). The organic phase obtained was dried over anhydrous sodium sulphate and evaporated to afford the title compound. The precipitate was filtered extracted with ethyl acetate (2×20 mL) The combined organic layers were washed with water (2×15 mL) The organic phase obtained was dried over anhydrous sodium sulphate evaporated

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

Procedure: To a solution of 25 parts of 1-(phenylmethyl)-4-piperidineacetonitrile in 178 parts of tetrahydrofuran were added dropwise 37.97 parts of ethyl chloroformate at room temperature. The reaction mixture was stirred for 15 hours at room temperature and was then evaporated. The residue was taken up in 90 parts of ethyl acetate and the whole was washed successively with HCl 3N, NaHCO3 and NaCl (sat.). The solvent was evaporated and the residue was distilled (100°-110° C./6.7 Pa), yielding 18.7 parts (81.4%) of ethyl 4-(cyanomethyl)-1-piperidinecarboxylate (interm. 24). was then evaporated the whole was washed successively with HCl 3N, NaHCO3 and NaCl (sat.) The solvent was evaporated the residue was distilled (100°-110° C./6.7 Pa)

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

Procedure: To a solution of 25 parts of 1-(phenylmethyl)-4-piperidineacetonitrile in 178 parts of tetrahydrofuran were added dropwise 37.97 parts of ethyl chloroformate at room temperature. The reaction mixture was stirred for 15 hours at room temperature and was then evaporated. The residue was taken up in 90 parts of ethyl acetate and the whole was washed successively with HCl 3N, NaHCO3 and NaCl (sat.). The solvent was evaporated and the residue was distilled (100°-110° C./6.7 Pa), yielding 18.7 parts (81.4%) of ethyl 4-(cyanomethyl)-1-piperidinecarboxylate (interm. 24). was then evaporated the whole was washed successively with HCl 3N, NaHCO3 and NaCl (sat.) The solvent was evaporated the residue was distilled (100°-110° C./6.7 Pa)

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

Procedure: To a stirred and refluxing Grignard-complex, previously prepared starting from 3.65 parts of magnesium, 26 parts of 1-bromo-3-methylbenzene and 70 parts of 1,1'-oxybisethane, is added dropwise a solution of 21.4 parts of 1-(phenylmethyl)-4-piperidineacetonitrile in 70 parts of 1,1'-oxybisethane. Upon completion, stirring is continued for 4 hours at reflux temperature. The reaction mixture is cooled in and ice-bath and decomposed by the addition of a saturated ammonium chloride solution. The layers are separated and the aqueous phase is extracted twice with 1,1'-oxybisethane. The combined organic phases are dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is stirred in 2,2'-oxybispropane with activated charcoal. The latter is filtered off till a clear filtrate is obtained. The filtrate is acidified with 2 -propanol saturated with hydrogen chloride. The whole is evaporated and the residue is crystallized from warm 4-methyl-2-pentanone, yielding 24.5 parts (71%) of 1-(3-methylphenyl)-2-[1-(phenylmethyl)-4-piperidinyl]ethanone hydrochloride; mp. 165.8° C. refluxing Grignard-complex previously prepared Upon completion, stirring at reflux temperature The reaction mixture is cooled in and ice-bath The layers are separated the aqueous phase is extracted twice with 1,1'-oxybisethane The combined organic phases are dried filtered evaporated The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent The pure fractions are collected the eluent is evaporated The oily residue is stirred in 2,2'-oxybispropane with activated charcoal The latter is filtered off till a clear filtrate is obtained The whole is evaporated the residue is crystallized from warm 4-methyl-2-pentanone

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

Procedure: A mixture of 58 parts of ethyl α-cyano-1-(phenylmethyl)-4-piperidineacetate and 125 parts of sodium hydroxide solution 2 N is stirred for 3 hours at room temperature. The mixture is neutralized with concentrated hydrochloric acid while cooling and the solvent is evaporated. The residue is stirred for 4 hours at 150° C. in 180 parts of N,N-dimethylacetamide. The reaction mixture is cooled, filtered and the filtrate is evaporated. The residue is taken up in water and extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is distilled, yielding 35 parts (82%) of 1-(phenylmethyl)-4-piperidineacetonitrile; bp. 135°-140° C. at 0.2-0.3 mm. pressure. while cooling the solvent is evaporated The residue is stirred for 4 hours at 150° C. in 180 parts of N,N-dimethylacetamide The reaction mixture is cooled filtered the filtrate is evaporated extracted with methylbenzene The extract is dried filtered evaporated The residue is distilled

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

Procedure: To a stirred and refluxing Grignard-complex, previously prepared starting from 3.65 parts of magnesium, 26 parts of 1-bromo-3-methylbenzene and 70 parts of 1,1'-oxybisethane, is added dropwise a solution of 21.4 parts of 1-(phenylmethyl)-4-piperidineacetonitrile in 70 parts of 1,1'-oxybisethane. Upon completion, stirring is continued for 4 hours at reflux temperature. The reaction mixture is cooled in and ice-bath and decomposed by the addition of a saturated ammonium chloride solution. The layers are separated and the aqueous phase is extracted twice with 1,1'-oxybisethane. The combined organic phases are dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is stirred in 2,2'-oxybispropane with activated charcoal. The latter is filtered off till a clear filtrate is obtained. The filtrate is acidified with 2 -propanol saturated with hydrogen chloride. The whole is evaporated and the residue is crystallized from warm 4-methyl-2-pentanone, yielding 24.5 parts (71%) of 1-(3-methylphenyl)-2-[1-(phenylmethyl)-4-piperidinyl]ethanone hydrochloride; mp. 165.8° C. refluxing Grignard-complex previously prepared Upon completion, stirring at reflux temperature The reaction mixture is cooled in and ice-bath The layers are separated the aqueous phase is extracted twice with 1,1'-oxybisethane The combined organic phases are dried filtered evaporated The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent The pure fractions are collected the eluent is evaporated The oily residue is stirred in 2,2'-oxybispropane with activated charcoal The latter is filtered off till a clear filtrate is obtained The whole is evaporated the residue is crystallized from warm 4-methyl-2-pentanone

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

Procedure: A mixture of 58 parts of ethyl α-cyano-1-(phenylmethyl)-4-piperidineacetate and 125 parts of sodium hydroxide solution 2 N is stirred for 3 hours at room temperature. The mixture is neutralized with concentrated hydrochloric acid while cooling and the solvent is evaporated. The residue is stirred for 4 hours at 150° C. in 180 parts of N,N-dimethylacetamide. The reaction mixture is cooled, filtered and the filtrate is evaporated. The residue is taken up in water and extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is distilled, yielding 35 parts (82%) of 1-(phenylmethyl)-4-piperidineacetonitrile; bp. 135°-140° C. at 0.2-0.3 mm. pressure. while cooling the solvent is evaporated The residue is stirred for 4 hours at 150° C. in 180 parts of N,N-dimethylacetamide The reaction mixture is cooled filtered the filtrate is evaporated extracted with methylbenzene The extract is dried filtered evaporated The residue is distilled

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium metal (0.8 g, 34.78 mmol) was dissolved in dry methanol (10 mL) at 0-10° C. and this solution was added slowly into a suspension of hydroxylamine hydrochloride (2.43 g, 34.96 mmol) in methanol (10 mL) at room temperature. The reaction mixture was stirred for 10 min until a clear solution was obtained, 2-(1-Benzylpiperidin-4-yl)acetonitrile (compound of Example 27; 3 g, 13.99 mmol) in dry methanol (20 mL) was added into the resulting reaction mixture and heated at 75° C. for 13 h. The solvent was evaporated at 50° C. to 55° C. and the crude product obtained was purified by column chromatography (silica gel, chloroform-methanol) to afford the title compound. was obtained The solvent was evaporated at 50° C. to 55° C. the crude product obtained was purified by column chromatography (silica gel, chloroform-methanol)

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

Procedure: To a solution of benzylpiperidin-4-ylideneacetonitrile (compound of Example 26; 1 g, 4.7 mmol) in methanol (50 mL), magnesium turnings (4.58 g, 188.3 mmol) was added at 0° C. The reaction mixture was stirred at 5° C. to 10° C. for 4 h. The magnesium salts were dissolved by addition of concentrated hydrochloric acid, and the mixture was basified with 10N sodium hydroxide solution. The precipitate was filtered and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water (2×15 mL) followed by brine (10 mL). The organic phase obtained was dried over anhydrous sodium sulphate and evaporated to afford the title compound. The precipitate was filtered extracted with ethyl acetate (2×20 mL) The combined organic layers were washed with water (2×15 mL) The organic phase obtained was dried over anhydrous sodium sulphate evaporated