2-N-(1-benzylpiperidin-4-yl)benzene-1,2-diamine

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

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 200 mg of N-(1-benzyl-piperidin-4-yl)-benzene-1,2-diamine (from Step A) in 6 mL of trimethyl orthoformate was added 0.2 mL concentrated HCl. After stirring at 80° C. for 16 hours, the reaction mixture was diluted with 30 ml of EtOAc. The organic phase was washed with 15 mL saturated NaHCO3 aqueous solution. After separating layers, the aqueous phase was extracted with 2×20 mL EtOAc. The combined organic phases were washed with 10 mL of brine, dried over MgSO4 and concentrated under reduced pressure to give 198 mg yellow solid. 1H NMR (400 MHz, CDCl3): δ2.11-2.22 (m, 6H), 3.06 (m, 2H), 3.58(s, 2H), 4.20 (s, 1H), 7.24-7.34(m, 7H),7.42(m, 1H), 7.81 (m, 1H), 8.04(s, 1H). ESI-MS 292 (M+H); HPLC A: 1.80 min. The organic phase was washed with 15 mL saturated NaHCO3 aqueous solution After separating layers the aqueous phase was extracted with 2×20 mL EtOAc The combined organic phases were washed with 10 mL of brine dried over MgSO4 concentrated under reduced pressure

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

Procedure: To a solution of 1.0 g 1-benzyl4-piperidone and 1.14 g of 1,2-phenylenediamine in 15 mL of THF was added two spatula tips of molecular sieves 4Å. After stirring at room temperature for 10 minutes, 1.34 g of sodium triacetoxyborohydride was added and the reaction was stirred at room temperature for 18 hours. The reaction was quenched with 50 mL of CH3OH and diluted with EtOAc. After filtering molecular sieves, the filtrate was concentrated under reduced pressure. The residue was partitioned between 50 mL of EtOAc and 30 ml saturated NaHCO3 aqueous solution. After separating layers, the aqueous phase was extracted with 2×50 mL EtOAc. The combined organic phases were washed with 15 mL of brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 100% EtOAc, then 90% EtOAc in CH3OH to give 666 mg of the title compound as a solid. 1H NMR (400 MHz, CDCl3): δ1.56 (m, 2H), 2.07 (m, 2H), 2.18(m, 2H), 2.87 (d, J=11.6 Hz, 2H), 3.29(m, 1H), 3.56(s, 2H), 6.69 (m, 3H), 6.72(m, 1H), 7.25-7.61(m, 5H). ESI-MS 282 (M+H); HPLC A: 1.92 min. the reaction was stirred at room temperature for 18 hours The reaction was quenched with 50 mL of CH3OH diluted with EtOAc After filtering molecular sieves the filtrate was concentrated under reduced pressure The residue was partitioned between 50 mL of EtOAc and 30 ml saturated NaHCO3 aqueous solution After separating layers the aqueous phase was extracted with 2×50 mL EtOAc The combined organic phases were washed with 15 mL of brine dried over MgSO4 concentrated under reduced pressure The residue was purified by flash chromatography eluting with 100% EtOAc

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

Procedure: A mixture of 5 parts of N-[1-(phenylmethyl)-4-piperidinyl]-1,2-benzenediamine, 2.35 parts of methyl (iminomethoxymethyl)carbamate, 5 parts of acetic acid and 75 parts of trichloromethane is stirred and refluxed for 48 hours. The reaction mixture is evaporated and the residue is taken up in water. The solution is neutralized with ammonium hydroxide solution. The precipitated product 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, yielding 1.75 parts of methyl {1,3-dihydro-1-[1-(phenylmethyl)-4-piperidinyl]-2H-benzimidazol-2-ylidene}carbamate; mp. 169.7° C. refluxed for 48 hours The reaction mixture is evaporated The precipitated product 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

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

Procedure: A solution of 31 parts of N-(2-nitrophenyl)-1-(phenylmethyl)-4-piperidinamine in 160 parts of tetrahydrofuran is hydrogenated at normal pressure and at a temperature of 40° C, with 20 parts of Raney nickel catalyst. After the calculated amount of hydrogen is taken up (3 moles) hydrogenation is stopped. The catalyst is filtered off and from the filtrate the solvent is evaporated. The solid residue is washed with 160 parts of 2,2'-oxybispropane, to yield 22 parts of N-[1-(phenylmethyl)-4-piperidinyl]-1,2-benzenediamine; mp. 112°-113° C. On concentrating the filtrate to about one quarter of its volume a second crop of 2.5 parts of N-[1-(phenylmethyl)-4-piperidinyl]-1,2-benzenediamine is obtained; mp. 108°-109° C. The catalyst is filtered off and from the filtrate the solvent is evaporated The solid residue is washed with 160 parts of 2,2'-oxybispropane

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

Procedure: A solution of 31 parts of N-(2-nitrophenyl)-1-(phenylmethyl)-4-piperidinamine in 160 parts of tetrahydrofuran is hydrogenated at normal pressure and at a temperature of 40° C, with 20 parts of Raney nickel catalyst. After the calculated amount of hydrogen is taken up (3 moles) hydrogenation is stopped. The catalyst is filtered off and from the filtrate the solvent is evaporated. The solid residue is washed with 160 parts of 2,2'-oxybispropane, to yield 22 parts of N-[1-(phenylmethyl)-4-piperidinyl]-1,2-benzenediamine; mp. 112°-113° C. On concentrating the filtrate to about one quarter of its volume a second crop of 2.5 parts of N-[1-(phenylmethyl)-4-piperidinyl]-1,2-benzenediamine is obtained; mp. 108°-109° C. The catalyst is filtered off and from the filtrate the solvent is evaporated The solid residue is washed with 160 parts of 2,2'-oxybispropane

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

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 200 mg of N-(1-benzyl-piperidin-4-yl)-benzene-1,2-diamine (from Step A) in 6 mL of trimethyl orthoformate was added 0.2 mL concentrated HCl. After stirring at 80° C. for 16 hours, the reaction mixture was diluted with 30 ml of EtOAc. The organic phase was washed with 15 mL saturated NaHCO3 aqueous solution. After separating layers, the aqueous phase was extracted with 2×20 mL EtOAc. The combined organic phases were washed with 10 mL of brine, dried over MgSO4 and concentrated under reduced pressure to give 198 mg yellow solid. 1H NMR (400 MHz, CDCl3): δ2.11-2.22 (m, 6H), 3.06 (m, 2H), 3.58(s, 2H), 4.20 (s, 1H), 7.24-7.34(m, 7H),7.42(m, 1H), 7.81 (m, 1H), 8.04(s, 1H). ESI-MS 292 (M+H); HPLC A: 1.80 min. The organic phase was washed with 15 mL saturated NaHCO3 aqueous solution After separating layers the aqueous phase was extracted with 2×20 mL EtOAc The combined organic phases were washed with 10 mL of brine dried over MgSO4 concentrated under reduced pressure

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

Procedure: To a solution of 1.0 g 1-benzyl4-piperidone and 1.14 g of 1,2-phenylenediamine in 15 mL of THF was added two spatula tips of molecular sieves 4Å. After stirring at room temperature for 10 minutes, 1.34 g of sodium triacetoxyborohydride was added and the reaction was stirred at room temperature for 18 hours. The reaction was quenched with 50 mL of CH3OH and diluted with EtOAc. After filtering molecular sieves, the filtrate was concentrated under reduced pressure. The residue was partitioned between 50 mL of EtOAc and 30 ml saturated NaHCO3 aqueous solution. After separating layers, the aqueous phase was extracted with 2×50 mL EtOAc. The combined organic phases were washed with 15 mL of brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 100% EtOAc, then 90% EtOAc in CH3OH to give 666 mg of the title compound as a solid. 1H NMR (400 MHz, CDCl3): δ1.56 (m, 2H), 2.07 (m, 2H), 2.18(m, 2H), 2.87 (d, J=11.6 Hz, 2H), 3.29(m, 1H), 3.56(s, 2H), 6.69 (m, 3H), 6.72(m, 1H), 7.25-7.61(m, 5H). ESI-MS 282 (M+H); HPLC A: 1.92 min. the reaction was stirred at room temperature for 18 hours The reaction was quenched with 50 mL of CH3OH diluted with EtOAc After filtering molecular sieves the filtrate was concentrated under reduced pressure The residue was partitioned between 50 mL of EtOAc and 30 ml saturated NaHCO3 aqueous solution After separating layers the aqueous phase was extracted with 2×50 mL EtOAc The combined organic phases were washed with 15 mL of brine dried over MgSO4 concentrated under reduced pressure The residue was purified by flash chromatography eluting with 100% EtOAc

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

Procedure: A mixture of 5 parts of N-[1-(phenylmethyl)-4-piperidinyl]-1,2-benzenediamine, 2.35 parts of methyl (iminomethoxymethyl)carbamate, 5 parts of acetic acid and 75 parts of trichloromethane is stirred and refluxed for 48 hours. The reaction mixture is evaporated and the residue is taken up in water. The solution is neutralized with ammonium hydroxide solution. The precipitated product 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, yielding 1.75 parts of methyl {1,3-dihydro-1-[1-(phenylmethyl)-4-piperidinyl]-2H-benzimidazol-2-ylidene}carbamate; mp. 169.7° C. refluxed for 48 hours The reaction mixture is evaporated The precipitated product 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

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

Procedure: A solution of 31 parts of N-(2-nitrophenyl)-1-(phenylmethyl)-4-piperidinamine in 160 parts of tetrahydrofuran is hydrogenated at normal pressure and at a temperature of 40° C, with 20 parts of Raney nickel catalyst. After the calculated amount of hydrogen is taken up (3 moles) hydrogenation is stopped. The catalyst is filtered off and from the filtrate the solvent is evaporated. The solid residue is washed with 160 parts of 2,2'-oxybispropane, to yield 22 parts of N-[1-(phenylmethyl)-4-piperidinyl]-1,2-benzenediamine; mp. 112°-113° C. On concentrating the filtrate to about one quarter of its volume a second crop of 2.5 parts of N-[1-(phenylmethyl)-4-piperidinyl]-1,2-benzenediamine is obtained; mp. 108°-109° C. The catalyst is filtered off and from the filtrate the solvent is evaporated The solid residue is washed with 160 parts of 2,2'-oxybispropane