ethyl trifluoromethanesulfonate

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

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

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

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

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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask was charged with 54 g (156 mmol) of (4R,5S)-3-[3-(2,4-difluoro-phenyl)-propionyl]-4-methyl-5-phenyl-oxazolidin-2-one and 300 mL of dry THF, and the solution was cooled to −78° C. To this solution was added 172 mL (172 mmol) of 1 M NaHMDS in THF, and the mixture was stirred cold for 1 hour. Then 30.6 g (172 mmol) of ethyl triflate was added dropwise to the enolate solution, and the reaction mixture was warmed to −40° C. to −30° C. and stirred for 1.5 hour. The reaction mixture was quenched by the addition of aqueous brine. The THF was removed under reduced pressure and the residue was partitioned between EtOAc and water. The organics were collected, and EtOAc was removed under reduced pressure. The resulting crude oil was purified by column chromatography (3:1 hexanes/EtOAc eluent) to get 29.5 g of an impure oil that was used without further purification. the reaction mixture was warmed to −40° C. to −30° C. stirred for 1.5 hour The reaction mixture was quenched by the addition of aqueous brine The THF was removed under reduced pressure the residue was partitioned between EtOAc and water The organics were collected EtOAc was removed under reduced pressure The resulting crude oil was purified by column chromatography (3:1 hexanes/EtOAc eluent)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask was charged with 54 g (156 mmol) of (4R,5S)-3-[3-(2,4-difluoro-phenyl)-propionyl]-4-methyl-5-phenyl-oxazolidin-2-one and 300 mL of dry THF, and the solution was cooled to −78° C. To this solution was added 172 mL (172 mmol) of 1 M NaHMDS in THF, and the mixture was stirred cold for 1 hour. Then 30.6 g (172 mmol) of ethyl triflate was added dropwise to the enolate solution, and the reaction mixture was warmed to 40° C. to −30° C. and stirred for 1.5 hours. The reaction mixture was quenched by the addition of aqueous brine. The THF was removed under reduced pressure and the residue was partitioned between EtOAc and water. The organics were collected, and EtOAc was removed under reduced pressure. The resulting crude oil was purified by column chromatography (3:1 hexanes/EtOAc eluent) to get 29.5 g of an impure oil that was used without further purification. the reaction mixture was warmed to 40° C. to −30° C. stirred for 1.5 hours The reaction mixture was quenched by the addition of aqueous brine The THF was removed under reduced pressure the residue was partitioned between EtOAc and water The organics were collected EtOAc was removed under reduced pressure The resulting crude oil was purified by column chromatography (3:1 hexanes/EtOAc eluent)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a −78° C. stirred solution of the (4S,5R)-4-Methyl-3-pentanoyl-5-phenyl-oxazolidin-2-one (9.20 g, 35.2 mmol) in dry THF (150 mL) was added NaHMDS (42.2 mL, 1.0 M in THF) dropwise. After 1 hour, ethyl trifluoromethanesulfonate (5.93 mL, 45.7 mmol) was added dropwise and the reaction was stirred at −78° C. for an additional 2 hours. The reaction was warmed to −30° C. for 30 minutes and quenched with sat. NH4Cl. The layers were separated and the aqueous layer was extracted with EtOAc (3×40 mL). The organic extracts were combined and washed with brine (2×40 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to yield 8.05 g of crude product. The reaction was warmed to −30° C. for 30 minutes quenched with sat. NH4Cl The layers were separated the aqueous layer was extracted with EtOAc (3×40 mL) washed with brine (2×40 mL) The organic phase was dried over MgSO4 filtered concentrated under reduced pressure

Conditions: temp:-74.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 8.65 ml (5.2 mmol) KHMDS (0.6M solution in toluene) in 50 ml dry THF was added 1.96 g (4.0 mmol) of dimethyl N-benzyl-N-(9-phenylfluorenyl)-aspartate of Example 3 dissolved in 8 ml THF drop by drop at -74° C. under N2. The pale yellow solution was stirred at -74° C. for 45 minutes then 568 μl (4.4 mmol) EtOTf were added neat at once at -76° C. After 10 minutes the reaction was quenched with 3 ml MeOH and partitioned between 40 ml 1M H3PO4 and 50 ml Et2O. The water layer was extracted with 40 ml Et2O and the combined organic layers were dried (MgSO4) and evaporated. The residue was purified by flash-chromatography (Kieselgel, Hexane/EtAc 8:1) to yield a mixture of dimethyl 3-ethyl N-benzyl-N-(9-phenylfluorenyl)-aspartate (20:1 mixture of diastereomers). The diastereomers were separated by MPLC (Kieselgel, Hexane/EtOAc 15:1) to yield the desired compound. After 10 minutes the reaction was quenched with 3 ml MeOH partitioned between 40 ml 1M H3PO4 and 50 ml Et2O The water layer was extracted with 40 ml Et2O the combined organic layers were dried (MgSO4) evaporated The residue was purified by flash-chromatography (Kieselgel, Hexane/EtAc 8:1) to yield The diastereomers were separated by MPLC (Kieselgel, Hexane/EtOAc 15:1)

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

Procedure: To a solution of 3-(2-chloro-5-trifluoromethyl-phenylmethanesulfonylamino)-pyrazine-2-carboxylic acid methyl ester (Example 2.1) (1.5 g) in acetonitrile (20 ml) was added N,N-diisopropylethylamine (“Hunig's base”) (0.71 ml) at ambient temperature. The mixture was stirred for 5 minutes at ambient temperature before dropwise addition of a solution of ethyltrifluoromethanesulfonate (0.71 ml) in acetonitrile (5 ml) at ambient to temperature. The reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated and the residue purified by column chromatography on silica gel (eluent: dichloromethane) to give 3-[(2-chloro-5-trifluoromethyl-phenyl-methanesulfonyl)-ethyl-amino]-pyrazine-2-carboxylic acid methyl ester as a beige solid (0.968 g). 1H-NMR (400 MHz, CDCl3): 8.57 (d, 1H), 8.52 (d, 1H), 7.77 (m, 1H), 7.50-7.56 (m, 2H), 4.64 (m, 2H), 4.01 (q, 2H), 4.00 (s, 3H), 1.23 (t, 3H) ppm. The reaction mixture was concentrated the residue purified by column chromatography on silica gel (eluent: dichloromethane)

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

Procedure: Ethyl triflate (11 ml, 83.2 mmol) was added dropwise over 15 minutes to a solution of 1-(triphenylmethyl)-2-methyl-4-acetylimidazole (Method 34; 23.4 g, 64 mmol) in DCM (300 ml) and the mixture stirred for 5 hours at ambient temperature. The solution was diluted with DCM (100 ml) and extracted with 1M aqueous citric acid solution (5×75 ml). The aqueous extracts were combined, basified with solid sodium hydrogen carbonate and the extracted with DCM (5×75 ml). The organic extracts were combined, dried and evaporated to give the title compound (8.59 g, 88%) as a pale yellow oil. NMR 1.32 (t, 3H), 2.41 (s, 6H), 4.29 (q, 2H), 7.68 (s, 1H); m/z 153. extracted with 1M aqueous citric acid solution (5×75 ml) the extracted with DCM (5×75 ml) dried evaporated

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

Procedure: Ethyl triflate (11 ml, 83.2 mmol) was added dropwise over 15 minutes to a solution of 1-(triphenylmethyl)-2-methyl-4-acetylimidazole (Method 34; 23.4 g, 64 mmol) in DCM (300 ml) and the mixture stirred for 5 hours at ambient temperature. The solution was diluted with DCM (100 ml) and extracted with 1M aqueous citric acid solution (5×75 ml). The aqueous extracts were combined, basified with solid sodium hydrogen carbonate and the extracted with DCM (5×75 ml). The organic extracts were combined, dried and evaporated to give the title compound (8.59 g, 88%) as a pale yellow oil. NMR 1.32 (t, 3H), 2.41 (s, 6H), 4.29 (q, 2H), 7.68 (s, 1H); m/z 153. extracted with 1M aqueous citric acid solution (5×75 ml) the extracted with DCM (5×75 ml) dried evaporated