2-(2,6-dichlorophenyl)ethanamine

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

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

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

Procedure: 0.38 ml of 4-tert-butylbenzaldehyde (2.25 mmol) and 288 mg 2-(2,6-dichloro-phenyl)-ethylamine (1.5 mmol) were dissolved in 4.5 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2 h. After cooling down to rt, 85 mg (2.25 mmol) sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was then refluxed for 3 h. After cooling down to rt, the reaction mixture was treated with 4 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:2) to give 533 mg colorless viscous oil (95%). MS (ISP) 336.2 (M+H)+. were refluxed for 2 h After cooling down to rt after stirring for 5 min at rt the reaction mixture was then refluxed for 3 h After cooling down to rt concentrated in vacuo The residue was diluted with water/EtOAc After separation of the organic phase the aqueous phase was extracted with EtOAc the combined organic phases were washed with brine dried with magnesium sulfate filtered off concentrated in vacuo The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:2)

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

Procedure: 0.38 ml of 4-tert-butylbenzaldehyde (2.25 mmol) and 288 mg 2-(2,6-dichloro-phenyl)-ethylamine (1.5 mmol) were dissolved in 4.5 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2 h. After cooling down to rt, 85 mg (2.25 mmol) sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was then refluxed for 3 h. After cooling down to rt, the reaction mixture was treated with 4 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:2) to give 533 mg colorless viscous oil (95%). MS (ISP) 336.2 (M+H)+. were refluxed for 2 h After cooling down to rt after stirring for 5 min at rt the reaction mixture was then refluxed for 3 h After cooling down to rt concentrated in vacuo The residue was diluted with water/EtOAc After separation of the organic phase the aqueous phase was extracted with EtOAc the combined organic phases were washed with brine dried with magnesium sulfate filtered off concentrated in vacuo The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:2)

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

Procedure: (4-Formylphenyl)-acetic acid ethyl ester (Example 16, step a, 0.44 g) was added to a solution of acetic acid (0.14 mL), trimethylorthoformate (2.53 g) and 2-(2,6-dichlorophenyl)ethylamine (0.54 mL) in dimethylformamide (10 mL) and stirred at room temperature, under nitrogen. After 1 hour, sodium triacetoxyborohydride (0.79 g) was added and the resulting mixture stirred for 18 hours, then concentrated. The residue was dissolved in methanol (5 mL) and loaded onto conditioned Tosic-65A resin (5 g, Argonaut). The resin was washed with methanol (3×20 mL) and then eluted with 3M methanolic ammonia solution (2×15 mL). The combined elution fractions were evaporated. The residue was dissolved in dichloromethane (10 mL) and di-tert-butyl dicarbonate (0.42 g) was added. The mixture was stirred at room temperature, under nitrogen, for 18 hours. Purification on silica, eluting with a gradient of iso-hexane/ethyl acetate [1:0 to 9:1] to give a clear oil. The oil was dissolved in tetrahydrofuran (4 mL) and a solution of lithium hydroxide (21 mg) in water (2 mL) was added and stirred for 18 hours, under nitrogen. The pH was adjusted to pH˜4 with acetic acid and the mixture concentrated to ˜2 mL. The aqueous residue was extracted with ethyl acetate (3×10 mL), the organics combined, washed with brine (10 mL), dried (magnesium sulfate) and evaporated, to give the subtitle compound as a gum (350 mg). the resulting mixture stirred for 18 hours concentrated The residue was dissolved in methanol (5 mL) The resin was washed with methanol (3×20 mL) eluted with 3M methanolic ammonia solution (2×15 mL) The combined elution fractions were evaporated The residue was dissolved in dichloromethane (10 mL) di-tert-butyl dicarbonate (0.42 g) was added The mixture was stirred at room temperature, under nitrogen, for 18 hours Purification on silica eluting with a gradient of iso-hexane/ethyl acetate [1:0 to 9:1] to give a clear oil stirred for 18 hours, under nitrogen the mixture concentrated to ˜2 mL The aqueous residue was extracted with ethyl acetate (3×10 mL) washed with brine (10 mL) dried (magnesium sulfate) evaporated

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

Procedure: (4-Formylphenyl)-acetic acid ethyl ester (Example 16, step a, 0.44 g) was added to a solution of acetic acid (0.14 mL), trimethylorthoformate (2.53 g) and 2-(2,6-dichlorophenyl)ethylamine (0.54 mL) in dimethylformamide (10 mL) and stirred at room temperature, under nitrogen. After 1 hour, sodium triacetoxyborohydride (0.79 g) was added and the resulting mixture stirred for 18 hours, then concentrated. The residue was dissolved in methanol (5 mL) and loaded onto conditioned Tosic-65A resin (5 g, Argonaut). The resin was washed with methanol (3×20 mL) and then eluted with 3M methanolic ammonia solution (2×15 mL). The combined elution fractions were evaporated. The residue was dissolved in dichloromethane (10 mL) and di-tert-butyl dicarbonate (0.42 g) was added. The mixture was stirred at room temperature, under nitrogen, for 18 hours. Purification on silica, eluting with a gradient of iso-hexane/ethyl acetate [1:0 to 9:1] to give a clear oil. The oil was dissolved in tetrahydrofuran (4 mL) and a solution of lithium hydroxide (21 mg) in water (2 mL) was added and stirred for 18 hours, under nitrogen. The pH was adjusted to pH˜4 with acetic acid and the mixture concentrated to ˜2 mL. The aqueous residue was extracted with ethyl acetate (3×10 mL), the organics combined, washed with brine (10 mL), dried (magnesium sulfate) and evaporated, to give the subtitle compound as a gum (350 mg). the resulting mixture stirred for 18 hours concentrated The residue was dissolved in methanol (5 mL) The resin was washed with methanol (3×20 mL) eluted with 3M methanolic ammonia solution (2×15 mL) The combined elution fractions were evaporated The residue was dissolved in dichloromethane (10 mL) di-tert-butyl dicarbonate (0.42 g) was added The mixture was stirred at room temperature, under nitrogen, for 18 hours Purification on silica eluting with a gradient of iso-hexane/ethyl acetate [1:0 to 9:1] to give a clear oil stirred for 18 hours, under nitrogen the mixture concentrated to ˜2 mL The aqueous residue was extracted with ethyl acetate (3×10 mL) washed with brine (10 mL) dried (magnesium sulfate) evaporated

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

Procedure: 2-(2,6-Dichlorophenyl)ethylamine (1.0 g) and 3-iodobenzaldehyde (1.2 g) were combined in dichloromethane (50 mL). After 1 hour, sodium triacetoxyborohydride (2.2 g) was added. After 3.5 hours, the reaction mixture was poured onto 1M aqueous sodium hydroxide (200 mL) and extracted twice with dichloromethane. The organics were combined, dried (sodium sulfate) and evaporated to give the subtitle product, as an oil (2.0 g). After 3.5 hours extracted twice with dichloromethane dried (sodium sulfate) evaporated

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

Procedure: 2-(2,6-Dichlorophenyl)ethylamine (1 ml, 0.00663 mol) and TEA (1.4 ml, 1.5 eq) were dissolved in THF (20 ml) and cooled in an ice-water bath. Ethyl chloroformate (0.95 ml, 1.5 eq) was added slowly and the mixture stirred at rt for 2 h. NH4Cl (sat) was added and the mixture extracted with EtOAc, the combined extracts were washed with NH4Cl (sat), and dried (MgSO4). The organic solvent was removed and the residue dissolved in Et2O (5 ml). This solution was slowly added to a slurry of LiAlH4 (530 mg, 2 eq) in Et2O (15 ml) at −78° C. The mixture was allowed to slowly warm to rt and stirred overnight. The mixture was cooled in an ice-water bath and water (0.53 ml), 15% NaOH (0.53 ml), and water (1.5 ml) added sequentially. The mixture was stirred vigorously for 30 min and the resulting slurry filtered. The filtrate was concentrated under reduced pressure to give 1.2 g of [2-(2,6-dichlorophenyl)ethyl]methylamine. cooled in an ice-water bath the mixture extracted with EtOAc the combined extracts were washed with NH4Cl (sat) dried (MgSO4) The organic solvent was removed the residue dissolved in Et2O (5 ml) to slowly warm to rt stirred overnight The mixture was cooled in an ice-water bath The mixture was stirred vigorously for 30 min the resulting slurry filtered The filtrate was concentrated under reduced pressure

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

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

Procedure: 2-(2,6-Dichlorophenyl)ethylamine (1 ml, 0.00663 mol) and TEA (1.4 ml, 1.5 eq) were dissolved in THF (20 ml) and cooled in an ice-water bath. Ethyl chloroformate (0.95 ml, 1.5 eq) was added slowly and the mixture stirred at rt for 2 h. NH4Cl (sat) was added and the mixture extracted with EtOAc, the combined extracts were washed with NH4Cl (sat), and dried (MgSO4). The organic solvent was removed and the residue dissolved in Et2O (5 ml). This solution was slowly added to a slurry of LiAlH4 (530 mg, 2 eq) in Et2O (15 ml) at −78° C. The mixture was allowed to slowly warm to rt and stirred overnight. The mixture was cooled in an ice-water bath and water (0.53 ml), 15% NaOH (0.53 ml), and water (1.5 ml) added sequentially. The mixture was stirred vigorously for 30 min and the resulting slurry filtered. The filtrate was concentrated under reduced pressure to give 1.2 g of [2-(2,6-dichlorophenyl)ethyl]methylamine. cooled in an ice-water bath the mixture extracted with EtOAc the combined extracts were washed with NH4Cl (sat) dried (MgSO4) The organic solvent was removed the residue dissolved in Et2O (5 ml) to slowly warm to rt stirred overnight The mixture was cooled in an ice-water bath The mixture was stirred vigorously for 30 min the resulting slurry filtered The filtrate was concentrated under reduced pressure

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

Procedure: Followed the same procedure described for the synthesis of 1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro -pyrido[1,2-a]pyrimidin-6-one, the sulfoxide (0.1 g, 0.27 mmol) was displaced with 2-(2,6-dichlorophenyl)ethylamine (0.16 g, 0.82 mmol) to give the title compound as a yellow solid. MS m/e 492 (M+H)+.

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

Procedure: The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acid ethyl ester (EXAMPLE 49, step 2) and 2-(2,6-dichloro-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C23H27Cl2NO5 [M−H]−: 466, [M+H]−: 468. to produce a colorless oil