N-[(2,4-difluorophenyl)methyl]propan-1-amine

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

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

Procedure: 3-(4-Hydroxyphenyl)propionic acid (245 mg, 1.474 mmol) in DMF (5 ml) was cooled in an ice-bath. N-(2,4-Difluorobenzyl)-N-propylamine (300.4 mg, 1.622 mmol) was added and then TBTU (521 mg, 1.622 mmol) followed by DIPEA (400 mg, 3.096 mmol). The mixture was stirred at room temperature overnight. Sodium hydrogencarbonate aqueous solution (sat.) was added. The mixture was extracted with ethyl acetate (×2). The extracts were combined and dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 5 g/25 ml) using DCM/heptane (50:50), DCM and then MeOH/DCM (1:99, then 2:98) as eluant gave 336 mg the desired product, yield 68%. The mixture was extracted with ethyl acetate (×2) dried (magnesium sulphate) evaporated

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

Procedure: 3-(4-Hydroxyphenyl)propionic acid (245 mg, 1.474 mmol) in DMF (5 ml) was cooled in an ice-bath. N-(2,4-Difluorobenzyl)-N-propylamine (300.4 mg, 1.622 mmol) was added and then TBTU (521 mg, 1.622 mmol) followed by DIPEA (400 mg, 3.096 mmol). The mixture was stirred at room temperature overnight. Sodium hydrogencarbonate aqueous solution (sat.) was added. The mixture was extracted with ethyl acetate (×2). The extracts were combined and dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 5 g/25 ml) using DCM/heptane (50:50), DCM and then MeOH/DCM (1:99, then 2:98) as eluant gave 336 mg the desired product, yield 68%. The mixture was extracted with ethyl acetate (×2) dried (magnesium sulphate) evaporated

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

Procedure: 2,4-Difluorbenzaldehyde (1.003 g, 7.055 mmol) was dissolved in methanol (5 ml). Trimethyl orthoformate (5 ml) was added. Propylamine (401 mg, 6.784 mmol) was then added and followed by acetic acid (0.2 ml). After 1 hour, DCM (5 ml) was added and followed by borohydride polymer-supported (2.5 mmol/g, 5.42 g, 13.55 mmol). The mixture was shaken at room temperature for 4 days and then filtered. The filtrate was evaporated. The residue was dissolved in acetonitrile, then divided into two portions and loaded on two columns (ISOLUTE®PRS, 10 g/70 ml, wetted with acetonitrile). It was eluted with acetonitrile, then methanol and then methanol (NH3 sat.). The product fractions were combined and evaporated. Oil product (892 mg) was obtained, yield 71%. filtered The filtrate was evaporated The residue was dissolved in acetonitrile It was eluted with acetonitrile evaporated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (4-{2-[2-(Methoxycarbonyl)phenoxy]ethyl}phenoxy)acetic acid (0.150 g, 0.454 mmol) was dissolved in DMF (10 ml), N-(2,4-difluorobenzyl)-N-propylamine (0.084 g, 0.454 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.160 g, 0.499 mmol) and N-ethyl-N,N-diisopropylamine (0.123 g, 0.954 mmol) was added. The solution was stirred for two hours at room temperature. EtOAc (20 ml) was added and the organic phase was washed with Na2CO3 (3×20 ml, aq) and HCl (0.5 M, 2×10 ml). The organic layer was dried (MgSO4) and the solvent was removed by evaporation to give 0.220 g of methyl 2-[2-(4-{2-[(2,4-difluorobenzyl)(propyl)amino]-2-oxoethoxy}phenyl)-ethoxy]benzoate (yield 97.4%). the organic phase was washed with Na2CO3 (3×20 ml, aq) and HCl (0.5 M, 2×10 ml) The organic layer was dried (MgSO4) the solvent was removed by evaporation

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (4-{2-[2-(Methoxycarbonyl)phenoxy]ethyl}phenoxy)acetic acid (0.150 g, 0.454 mmol) was dissolved in DMF (10 ml), N-(2,4-difluorobenzyl)-N-propylamine (0.084 g, 0.454 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.160 g, 0.499 mmol) and N-ethyl-N,N-diisopropylamine (0.123 g, 0.954 mmol) was added. The solution was stirred for two hours at room temperature. EtOAc (20 ml) was added and the organic phase was washed with Na2CO3 (3×20 ml, aq) and HCl (0.5 M, 2×10 ml). The organic layer was dried (MgSO4) and the solvent was removed by evaporation to give 0.220 g of methyl 2-[2-(4-{2-[(2,4-difluorobenzyl)(propyl)amino]-2-oxoethoxy}phenyl)-ethoxy]benzoate (yield 97.4%). the organic phase was washed with Na2CO3 (3×20 ml, aq) and HCl (0.5 M, 2×10 ml) The organic layer was dried (MgSO4) the solvent was removed by evaporation

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

Procedure: 3-(4-Hydroxyphenyl)propionic acid (245 mg, 1.474 mmol) in DMF (5 ml) was cooled in an ice-bath. N-(2,4-Difluorobenzyl)-N-propylamine (300.4 mg, 1.622 mmol) was added and then TBTU (521 mg, 1.622 mmol) followed by DIPEA (400 mg, 3.096 mmol). The mixture was stirred at room temperature overnight. Sodium hydrogencarbonate aqueous solution (sat.) was added. The mixture was extracted with ethyl acetate (×2). The extracts were combined and dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 5 g/25 ml) using DCM/heptane (50:50), DCM and then MeOH/DCM (1:99, then 2:98) as eluant gave 336 mg the desired product, yield 68%. The mixture was extracted with ethyl acetate (×2) dried (magnesium sulphate) evaporated

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

Procedure: 2,4-Difluorbenzaldehyde (1.003 g, 7.055 mmol) was dissolved in methanol (5 ml). Trimethyl orthoformate (5 ml) was added. Propylamine (401 mg, 6.784 mmol) was then added and followed by acetic acid (0.2 ml). After 1 hour, DCM (5 ml) was added and followed by borohydride polymer-supported (2.5 mmol/g, 5.42 g, 13.55 mmol). The mixture was shaken at room temperature for 4 days and then filtered. The filtrate was evaporated. The residue was dissolved in acetonitrile, then divided into two portions and loaded on two columns (ISOLUTE®PRS, 10 g/70 ml, wetted with acetonitrile). It was eluted with acetonitrile, then methanol and then methanol (NH3 sat.). The product fractions were combined and evaporated. Oil product (892 mg) was obtained, yield 71%. filtered The filtrate was evaporated The residue was dissolved in acetonitrile It was eluted with acetonitrile evaporated