3,3,3-trifluoro-2-methylpropanal

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

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

Procedure: 2-(Trifluoromethyl)propionaldehyde (0.0724 g; 0.574 mmole) was dissolved in tetrahydrofurane (3 ml) and sulfuric acid (4 M; 0.041 ml; 0.164 mmole) was added under stirring, followed by addition of 3-{4-[2-(4-aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid hydro chloride (described in Example 56a) (0.2 g; 0.547 mmole) dissolved in tetrahydrofurane (2 ml). The reaction mixture was stirred for 10 minutes, then cooled to 0° C in an ice-bath and sodium borohydride (0.042 g; 1.10 mmole) was added. After addition, the cooling bath was removed. The mixture was stirred overnight and then evaporated to remove tetrahydrofurane. Ethyl acetate and water were added into the residue and the organic phase was separated, washed with brine, dried with magnesium sulfate. The solvent was then evaporated. Chromatography on silica gel(Isolute, SI ) using dichloromethane and then 1% methanol in dichloromethane as eluant gave 0.13 g (40% yield) of (S)-2-ethoxy-3-(4-{2-[4-(3,3,3-trifluoro-2-methyl-(R/S)-propylamino)phenyl]ethoxy}phenyl)propanoic acid. The reaction mixture was stirred for 10 minutes After addition the cooling bath was removed The mixture was stirred overnight evaporated to remove tetrahydrofurane Ethyl acetate and water were added into the residue the organic phase was separated washed with brine dried with magnesium sulfate The solvent was then evaporated

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

Procedure: 2-(Trifluoromethyl)propionaldehyde (0.0724 g; 0.574 mmole) was dissolved in tetrahydrofurane (3 ml) and sulfuric acid (4 M; 0.041 ml; 0.164 mmole) was added under stirring, followed by addition of 3-{4-[2-(4-aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid hydro chloride (described in Example 56a) (0.2 g; 0.547 mmole) dissolved in tetrahydrofurane (2 ml). The reaction mixture was stirred for 10 minutes, then cooled to 0° C in an ice-bath and sodium borohydride (0.042 g; 1.10 mmole) was added. After addition, the cooling bath was removed. The mixture was stirred overnight and then evaporated to remove tetrahydrofurane. Ethyl acetate and water were added into the residue and the organic phase was separated, washed with brine, dried with magnesium sulfate. The solvent was then evaporated. Chromatography on silica gel(Isolute, SI ) using dichloromethane and then 1% methanol in dichloromethane as eluant gave 0.13 g (40% yield) of (S)-2-ethoxy-3-(4-{2-[4-(3,3,3-trifluoro-2-methyl-(R/S)-propylamino)phenyl]ethoxy}phenyl)propanoic acid. The reaction mixture was stirred for 10 minutes After addition the cooling bath was removed The mixture was stirred overnight evaporated to remove tetrahydrofurane Ethyl acetate and water were added into the residue the organic phase was separated washed with brine dried with magnesium sulfate The solvent was then evaporated

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

Procedure: (2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was reductively alkylated with rac-2-methyl-trifluoropropionaldehyde in analogy to experiment L3 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(3,3,3-trifluoro-2-methyl-propyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless solid. MS: 464.1 [M+H]+.

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

Procedure: A solution of tert-butyl 2-(dimethoxyphosphoryl)acetate (9.78 g, 43.6 mmol) in THF (10 mL) was slowly transferred to a suspension of NaH (60% dispersion in mineral oil) (1.903 g, 47.6 mmol) in THF (30 mL) at 0° C. under a nitrogen atmosphere. After the addition was complete, the reaction mixture was stirred at 0° C. for 10 min, and then warmed to room temperature. After being stirred for 30 min, the reaction mixture was cooled to 0° C. again, and a solution of 3,3,3-trifluoro-2-methylpropanal (5 g, 39.7 mmol) in THF (10 mL) was added, and the ice bath was removed. After 12 h at 25° C., the mixture was partitioned between water (60 mL) and EtOAc (60 mL). The aqueous layer was extracted with EtOAc (60 mL), and the combined organic layers were successively washed with water (60 mL) and brine. The resulting solution was dried over MgSO4, concentration under reduced pressure, and purified by silica gel flash chromatography (330 g column, 0% to 15% EtOAc in hexane over 20 min) to obtain Intermediate S-5A (3.61 g, 16.10 mmol, 40.6% yield). 1H NMR (400 MHz, chloroform-d) δ 6.77 (dd, J=15.8, 7.7 Hz, 1H), 5.95 (dd, J=15.7, 0.6 Hz, 1H), 3.12-2.93 (m, 1H), 1.56-1.47 (m, 9H), 1.37-1.27 (m, 3H). After the addition warmed to room temperature After being stirred for 30 min the reaction mixture was cooled to 0° C. again the ice bath was removed After 12 h at 25° C. the mixture was partitioned between water (60 mL) and EtOAc (60 mL) The aqueous layer was extracted with EtOAc (60 mL) the combined organic layers were successively washed with water (60 mL) and brine The resulting solution was dried over MgSO4, concentration under reduced pressure purified by silica gel flash chromatography (330 g column, 0% to 15% EtOAc in hexane over 20 min) to obtain Intermediate S-5A (3.61 g, 16.10 mmol, 40.6% yield)

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

Procedure: 2-(Trifluoromethyl)propionaldehyde (0.0724 g; 0.574 mmole) was dissolved in tetrahydrofurane (3 ml) and sulfuric acid (4 M; 0.041 ml; 0.164 mmole) was added under stirring, followed by addition of 3-{4-[2-(4-aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid hydro chloride (described in Example 56a) (0.2 g; 0.547 mmole) dissolved in tetrahydrofurane (2 ml). The reaction mixture was stirred for 10 minutes, then cooled to 0° C in an ice-bath and sodium borohydride (0.042 g; 1.10 mmole) was added. After addition, the cooling bath was removed. The mixture was stirred overnight and then evaporated to remove tetrahydrofurane. Ethyl acetate and water were added into the residue and the organic phase was separated, washed with brine, dried with magnesium sulfate. The solvent was then evaporated. Chromatography on silica gel(Isolute, SI ) using dichloromethane and then 1% methanol in dichloromethane as eluant gave 0.13 g (40% yield) of (S)-2-ethoxy-3-(4-{2-[4-(3,3,3-trifluoro-2-methyl-(R/S)-propylamino)phenyl]ethoxy}phenyl)propanoic acid. The reaction mixture was stirred for 10 minutes After addition the cooling bath was removed The mixture was stirred overnight evaporated to remove tetrahydrofurane Ethyl acetate and water were added into the residue the organic phase was separated washed with brine dried with magnesium sulfate The solvent was then evaporated