methyl (2R)-2-chloropropanoate

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

Procedure: In accordance with the process of Example 2, a condensation reaction was performed by using 2,3,4-trifluoroaniline (100 mg), potassium carbonate (188 mg), methyl (2R)-chloropropionate (92 mg) and tetrahexylammonium chloride (40 mg). As the result of the analysis by reversed phase HPLC with the use of the compound of Example 1 as a specimen, the product corresponded to 56 mg (36%) of the title compound. In accordance with the process of Example 2, a condensation reaction

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

Procedure: In accordance with the process of Example 2, a condensation reaction was performed by using 2,3,4-trifluoroaniline (100 mg), potassium carbonate (188 mg), methyl (2R)-chloropropionate (92 mg) and tetrahexylammonium chloride (40 mg). As the result of the analysis by reversed phase HPLC with the use of the compound of Example 1 as a specimen, the product corresponded to 56 mg (36%) of the title compound. In accordance with the process of Example 2, a condensation reaction

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

Procedure: In accordance with the process of Example 2, a condensation reaction was performed by using 2,3,4-trifluoroaniline (100 mg), potassium carbonate (188 mg), methyl (2R)-chloropropionate (92 mg) and tetrahexylammonium chloride (40 mg). As the result of the analysis by reversed phase HPLC with the use of the compound of Example 1 as a specimen, the product corresponded to 56 mg (36%) of the title compound. In accordance with the process of Example 2, a condensation reaction

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 4-fluoro-3-(3-hydroxypropyl)phenol (1.5 g), methyl (2R)-2-chloropropanoate (1.30 g) in DMSO (7.5 mL) was added Cs2CO3 (3.45 g) at ambient temperature. The mixture was stirred at 60° C. for 3 hours. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc (50 mL) and washed successively with water (30 mL) two times and brine (30 mL). The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo to give crude oil. The crude oil was purified by silica gel column chromatography (n-hexane:EtOAc=4:1-2:1) to give methyl(2S)-2-[4-fluoro-3-(3-hydroxypropyl)phenoxy]propanoate (1.51 g) as a colorless oil. After cooling to ambient temperature washed successively with water (30 mL) two times and brine (30 mL) The organic layer was dried over anhydrous MgSO4 filtered evaporated in vacuo to give crude oil The crude oil was purified by silica gel column chromatography (n-hexane:EtOAc=4:1-2:1)

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

Procedure: A solution of 3-amino-4-fluorophenol (4.1 g) in N,N-dimethylformamide (15 mL) was added dropwise to a stirred suspension of sodium hydride (60% in oil, 1.3 g) in N,N-dimethylformamide (35 mL) at 0° C. The mixture was stirred a room temperature for 30 minutes, cooled 0° C. and then (R)-2-chloropropionic acid methyl ester (4.0 g) was added in one portion. The resulting mixture was stirred at room temperature overnight and then treated with saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate and the combined extracts, washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 3:2 by volume) to give the mixture of title compounds as golden oil, 2.5 g. cooled 0° C. The resulting mixture was stirred at room temperature overnight The mixture was extracted with ethyl acetate the combined extracts, washed with saturated aqueous sodium chloride solution dried over magnesium sulfate The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 3:2 by volume) to give the mixture of title compounds as golden oil, 2.5 g

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-(2,4-dichlorobenzyl)-8-fluoro-5-hydroxy-4-methyl-1H-quinolin-2-one (0.40 g), N,N-dimethylformamide (5.0 mL), potassium carbonate (0.17 g) and (R)-2-chloropropionic acid methyl ester (0.15 g) was stirred at 40° C. for 24 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of toluene, dichloromethane and ethyl acetate (1:1:0 to 0:1:0 to 0:10:1 by volume) to afford title compound as a cream solid, 0.21 g. extracted with ethyl acetate The combined extracts were washed saturated aqueous sodium chloride solution dried over magnesium sulfate the solvent removed under reduced pressure The residue was purified by column chromatography on silica gel eluting with a mixture of toluene, dichloromethane and ethyl acetate (1:1:0 to 0:1:0 to 0:10:1 by volume)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-(2,4-dichlorobenzyl)-8-fluoro-5-hydroxy-4-methyl-1H-quinolin-2-one (0.40 g), N,N-dimethylformamide (5.0 mL), potassium carbonate (0.17 g) and (R)-2-chloropropionic acid methyl ester (0.15 g) was stirred at 40° C. for 24 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of toluene, dichloromethane and ethyl acetate (1:1:0 to 0:1:0 to 0:10:1 by volume) to afford title compound as a cream solid, 0.21 g. extracted with ethyl acetate The combined extracts were washed saturated aqueous sodium chloride solution dried over magnesium sulfate the solvent removed under reduced pressure The residue was purified by column chromatography on silica gel eluting with a mixture of toluene, dichloromethane and ethyl acetate (1:1:0 to 0:1:0 to 0:10:1 by volume)

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

Procedure: A mixture of 2-cyclopropyl-8-fluoro-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-ol (0.064 g), (N-dimethylformamide (0.86 mL), potassium carbonate (0.071 g) and (R)-2-chloropropionic acid methyl ester (0.032 g) was stirred at 40° C. for 3 days. The mixture was cooled to 0° C., diluted with water (40 mL) and extracted with ethyl acetate (3×10 mL). The combined extracts were washed saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (0:1 to 4:6 by volume) gave title compound as a colourless oil (0.033 g). extracted with ethyl acetate (3×10 mL) The combined extracts were washed saturated aqueous sodium chloride solution dried over magnesium sulfate concentrated under reduced pressure Purification of the residue by column chromatography on silica gel eluting with a mixture of ethyl acetate and cyclohexane (0:1 to 4:6 by volume)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-cyclopropyl-8-fluoro-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-ol (0.064 g), N,N-dimethylformamide (0.86 mL), potassium carbonate (0.071 g) and (R)-2-chloropropionic acid methyl ester (0.032 g) was stirred at 40° C. for 3 days. The mixture was cooled to 0° C., diluted with water (40 mL) and extracted with ethyl acetate (3×10 mL). The combined extracts were washed saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (0:1 to 4:6 by volume) gave title compound as a colourless oil (0.033 g). The mixture was cooled to 0° C. extracted with ethyl acetate (3×10 mL) The combined extracts were washed saturated aqueous sodium chloride solution dried over magnesium sulfate concentrated under reduced pressure Purification of the residue by column chromatography on silica gel eluting with a mixture of ethyl acetate and cyclohexane (0:1 to 4:6 by volume)

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

Procedure: In accordance with the process of Example 2, a condensation reaction was performed by using 2,3,4-trifluoroaniline (100 mg), potassium carbonate (188 mg), methyl (2R)-chloropropionate (92 mg) and tetrahexylammonium chloride (40 mg). As the result of the analysis by reversed phase HPLC with the use of the compound of Example 1 as a specimen, the product corresponded to 56 mg (36%) of the title compound. In accordance with the process of Example 2, a condensation reaction

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

Procedure: In accordance with the process of Example 2, a condensation reaction was performed by using 2,3,4-trifluoroaniline (100 mg), potassium carbonate (188 mg), methyl (2R)-chloropropionate (92 mg) and tetrahexylammonium chloride (40 mg). As the result of the analysis by reversed phase HPLC with the use of the compound of Example 1 as a specimen, the product corresponded to 56 mg (36%) of the title compound. In accordance with the process of Example 2, a condensation reaction