(1S)-3-methyl-1-(2-piperidin-1-ylphenyl)butan-1-amine

Conditions: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a round bottom flask fitted with a dean stark condenser, 3-Ethoxy-4-ethoxycarbonyl phenyl acetic acid (10.26 g, 0.0426 mol) was dissolved in toluene (100 ml) followed by slow addition of phenylboronic acid (0.494 g, 0.0040 mol) and (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine (10 g, 0.0406 mol). The reaction mixture was refluxed for 16-18 hours. The resulting mass was cooled at 25-30° C. followed by filtration. The toluene layer was washed with water and 1% sodium bicarbonate solution followed by complete distillation of toluene. Hexane (50 ml) was added to the resulting residue after complete removal of toluene in order to precipitate the solid, with stirring for 1 hour. The resulting solid was filtered and washed with hexane (10 ml). The wet material was further dried at 50-55° C. under vacuum for 4-6 hours to produce Ethyl (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]benzoate (Yield=89.6%; HPLC Purity: 99.66%). In a round bottom flask fitted with a dean stark condenser The reaction mixture was refluxed for 16-18 hours followed by filtration The toluene layer was washed with water and 1% sodium bicarbonate solution followed by complete distillation of toluene Hexane (50 ml) was added to the resulting residue after complete removal of toluene in order to precipitate the solid The resulting solid was filtered washed with hexane (10 ml) The wet material was further dried at 50-55° C. under vacuum for 4-6 hours

Conditions: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a round bottom flask fitted with a dean stark condenser, (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine (10 g, 0.0406 mol) was dissolved in toluene (100 ml), followed by the addition of 3-ethoxy-4-ethoxycarbonyl phenyl acetic acid (10.26 g, 0.0407 mol) and boric acid (0.26 g, 0.0042 mol). The reaction mixture was refluxed for 16-18 hours. The resulting mass was then cooled to 25-30° C. followed by filtration. The filtrate was washed with water and 1.0% sodium bicarbonate solution followed by complete distillation of toluene and the resulting residue was stirred with hexane (50 ml) for 1 hour. The precipitated solid was filtered and washed with hexane (10 ml). The wet product was dried at 50-55° C. under vacuum for 4-6 hours to produce Ethyl (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonyl methyl]-benzoate (Yield=73.3%; HPLC Purity: 99.50%). In a round bottom flask fitted with a dean stark condenser The reaction mixture was refluxed for 16-18 hours followed by filtration The filtrate was washed with water and 1.0% sodium bicarbonate solution followed by complete distillation of toluene The precipitated solid was filtered washed with hexane (10 ml) The wet product was dried at 50-55° C. under vacuum for 4-6 hours

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

Procedure: 2.77 g (11 mMol) of 3-ethoxy-4-ethoxycarbonylphenylacetic acid are added at ambient temperature to a solution of 2.71 g (11 mMol) of anhydrous (S)-3-methyl-1-(2-piperidino-phenyl)-1-butylamine (ee=98.5%) in 30 ml of absolute toluene and the mixture is stirred until dissolved. Then 2.38 g (11.55 mMol) of N,N'-dicyclohexyl-carbodiimide are added and the mixture is stirred at ambient temperature. After 24 hours a further 0.54 g (2.14 mMol) of 3-ethoxy-4-ethoxycarbonylphenylacetic acid and 0.48 g (2.33 mMol) of N,N'-dicyclohexylcarbodiimide are added and the mixture is stirred overnight. It is then cooled to an internal temperature of +5° C. and suction filtered to separate the precipitate, which is washed once with 5 ml of toluene. The combined toluene filtrates are evaporated down in vacuo to a volume of about 10 ml. The resulting solution is heated over the stem bath and petroleum ether is added in batches thereto (total of 55 ml) until the turbidity remains. It is cooled in ice, whereupon crystallisation takes place. It is suction filtered and dried at 75° C/4 torr. The product obtained (4.57 g; melting point 111°-112° C; ee=98.9%) is suspended in 50 ml of petroleum ether. The mixture is heated over the steam bath and sufficient toluene is added in batches (8 ml in total) until a solution is obtained. This is then cooled in ice and suction filtered to separate the crystals, which are dried at 75° C./4 torr. until dissolved the mixture is stirred at ambient temperature the mixture is stirred overnight It is then cooled to an internal temperature of +5° C. and suction filtered to separate the precipitate, which is washed once with 5 ml of toluene The combined toluene filtrates are evaporated down in vacuo to a volume of about 10 ml The resulting solution is heated over the stem bath and petroleum ether is added in batches It is cooled in ice, whereupon crystallisation filtered dried at 75° C/4 torr The product obtained (4.57 g; melting point 111°-112° C; ee=98.9%) is added in batches (8 ml in total) until a solution is obtained This is then cooled in ice suction filtered to separate the crystals, which are dried at 75° C./4 torr

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

Procedure: 2.77 g (11 mMol) of 3-ethoxy-4-ethoxycarbonylphenylacetic acid are added at ambient temperature to a solution of 2.71 g (11 mMol) of anhydrous (S)-3-methyl-1-(2-piperidino-phenyl)-1-butylamine (ee=98.5%) in 30 ml of absolute toluene and the mixture is stirred until dissolved. Then 2.38 g (11.55 mMol) of N,N'-dicyclohexyl-carbodiimide are added and the mixture is stirred at ambient temperature. After 24 hours a further 0.54 g (2.14 mMol) of 3-ethoxy-4-ethoxycarbonylphenylacetic acid and 0.48 g (2.33 mMol) of N,N'-dicyclohexylcarbodiimide are added and the mixture is stirred overnight. It is then cooled to an internal temperature of +5° C. and suction filtered to separate the precipitate, which is washed once with 5 ml of toluene. The combined toluene filtrates are evaporated down in vacuo to a volume of about 10 ml. The resulting solution is heated over the stem bath and petroleum ether is added in batches thereto (total of 55 ml) until the turbidity remains. It is cooled in ice, whereupon crystallisation takes place. It is suction filtered and dried at 75° C/4 torr. The product obtained (4.57 g; melting point 111°-112° C; ee=98.9%) is suspended in 50 ml of petroleum ether. The mixture is heated over the steam bath and sufficient toluene is added in batches (8 ml in total) until a solution is obtained. This is then cooled in ice and suction filtered to separate the crystals, which are dried at 75° C./4 torr. until dissolved the mixture is stirred at ambient temperature the mixture is stirred overnight It is then cooled to an internal temperature of +5° C. and suction filtered to separate the precipitate, which is washed once with 5 ml of toluene The combined toluene filtrates are evaporated down in vacuo to a volume of about 10 ml The resulting solution is heated over the stem bath and petroleum ether is added in batches It is cooled in ice, whereupon crystallisation filtered dried at 75° C/4 torr The product obtained (4.57 g; melting point 111°-112° C; ee=98.9%) is added in batches (8 ml in total) until a solution is obtained This is then cooled in ice suction filtered to separate the crystals, which are dried at 75° C./4 torr

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

Procedure: Prepared from (S)-3-Methyl-1-(2-piperidino-phenyl)-1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid analogously to Example 1.

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

Procedure: Equimolar quantities of racemic 3-methyl-1-(2-pieridinophenyl)-1-butylamine and of N-acetyl-L-gluatmic acid were refluxed in aceton, whereby methanol was added in such an amount to yield a clear solution. to yield a clear solution

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

Procedure: Equimolar quantities of racemic 3-methyl-1-(2-pieridinophenyl)-1-butylamine and of N-acetyl-L-gluatmic acid were refluxed in aceton, whereby methanol was added in such an amount to yield a clear solution. to yield a clear solution

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Pivaloyl chloride (5.4 g, 45 mmol) was added to a mixture of 3-ethoxy-4-ethoxycarbonyl phenylacetic acid (10.0 g, 40 mmol), toluene (50 ml) and triethylamine (5.0 g, 49 mmol) at −5° C. and stirred for 1 hour. A solution of (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine (9.8 g, 40 mmol) in toluene (20 ml) was then added at below 10° C. The temperature of the reaction mixture was raised to 30° C. and the mixture stirred overnight. It was then washed with water and saturated sodium bicarbonate solution. Toluene was distilled off under reduced pressure to get the crude product. The crude product was dissolved in toluene (35 ml), hexane (200 ml) was added and the mixture cooled at 0° C. The solid product so obtained was filtered and dried to give 14.0 g of the title compound (Yield: 73%, HPLC Purity 99%). the mixture stirred overnight It was then washed with water and saturated sodium bicarbonate solution Toluene was distilled off under reduced pressure to get the crude product the mixture cooled at 0° C The solid product so obtained was filtered dried

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Pivaloyl chloride (5.4 g, 45 mmol) was added to a mixture of 3-ethoxy-4-ethoxycarbonyl phenylacetic acid (10.0 g, 40 mmol), toluene (50 ml) and triethylamine (5.0 g, 49 mmol) at −5° C. and stirred for 1 hour. A solution of (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine (9.8 g, 40 mmol) in toluene (20 ml) was then added at below 10° C. The temperature of the reaction mixture was raised to 30° C. and the mixture stirred overnight. It was then washed with water and saturated sodium bicarbonate solution. Toluene was distilled off under reduced pressure to get the crude product. The crude product was dissolved in toluene (35 ml), hexane (200 ml) was added and the mixture cooled at 0° C. The solid product so obtained was filtered and dried to give 14.0 g of the title compound (Yield: 73%, HPLC Purity 99%). the mixture stirred overnight It was then washed with water and saturated sodium bicarbonate solution Toluene was distilled off under reduced pressure to get the crude product the mixture cooled at 0° C The solid product so obtained was filtered dried

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

Procedure: Prepared from (S)-3-Methyl-1-(2-piperidino-phenyl)-1-butylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid analogously to Example 1.

Conditions: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a round bottom flask fitted with a dean stark condenser, 3-Ethoxy-4-ethoxycarbonyl phenyl acetic acid (10.26 g, 0.0426 mol) was dissolved in toluene (100 ml) followed by slow addition of phenylboronic acid (0.494 g, 0.0040 mol) and (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine (10 g, 0.0406 mol). The reaction mixture was refluxed for 16-18 hours. The resulting mass was cooled at 25-30° C. followed by filtration. The toluene layer was washed with water and 1% sodium bicarbonate solution followed by complete distillation of toluene. Hexane (50 ml) was added to the resulting residue after complete removal of toluene in order to precipitate the solid, with stirring for 1 hour. The resulting solid was filtered and washed with hexane (10 ml). The wet material was further dried at 50-55° C. under vacuum for 4-6 hours to produce Ethyl (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]benzoate (Yield=89.6%; HPLC Purity: 99.66%). In a round bottom flask fitted with a dean stark condenser The reaction mixture was refluxed for 16-18 hours followed by filtration The toluene layer was washed with water and 1% sodium bicarbonate solution followed by complete distillation of toluene Hexane (50 ml) was added to the resulting residue after complete removal of toluene in order to precipitate the solid The resulting solid was filtered washed with hexane (10 ml) The wet material was further dried at 50-55° C. under vacuum for 4-6 hours

Conditions: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a round bottom flask fitted with a dean stark condenser, (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine (10 g, 0.0406 mol) was dissolved in toluene (100 ml), followed by the addition of 3-ethoxy-4-ethoxycarbonyl phenyl acetic acid (10.26 g, 0.0407 mol) and boric acid (0.26 g, 0.0042 mol). The reaction mixture was refluxed for 16-18 hours. The resulting mass was then cooled to 25-30° C. followed by filtration. The filtrate was washed with water and 1.0% sodium bicarbonate solution followed by complete distillation of toluene and the resulting residue was stirred with hexane (50 ml) for 1 hour. The precipitated solid was filtered and washed with hexane (10 ml). The wet product was dried at 50-55° C. under vacuum for 4-6 hours to produce Ethyl (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonyl methyl]-benzoate (Yield=73.3%; HPLC Purity: 99.50%). In a round bottom flask fitted with a dean stark condenser The reaction mixture was refluxed for 16-18 hours followed by filtration The filtrate was washed with water and 1.0% sodium bicarbonate solution followed by complete distillation of toluene The precipitated solid was filtered washed with hexane (10 ml) The wet product was dried at 50-55° C. under vacuum for 4-6 hours