methyl 3-(4-aminophenyl)propanoate

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:; See reaction.notes.procedure_details.

Procedure: In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (100 mg, 0.173 mmol), was reacted with diisopropylethylamine (112 mg, 0.863 mmol), diphenylphosphinic chloride (106 mg, 0.446 mmol), then reacted with methyl 3-(4-aminophenyl)propanoate (31 mg, 0.173 mmol) to give rac-3-(4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-phenyl)-propionic acid methyl ester (108 mg, 56%). MS (ES+) m/z [(M+H)+]: 626

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

Procedure: Thionyl chloride (Aldrich, 4.08 g, 2.5 ml, 34.3 mmol) was added dropwise to anhydrous MeOH (10mL) in ice-water-salt bath. After 20 min, 3-(4-aminophenyl)propionic acid (Trans World Chemicals, 1.7 g, 10.3 mmol) was added and the reaction mixture was allowed to stir at rt overnight. The resulting reaction mixture was concentrated in vacuo and the residue was diluted with EtOAc, washed with sat. aqueous NaHCO3, water, and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to give methyl 3-(4-aminophenyl)propanoate (1.80 g, 98%). The resulting reaction mixture was concentrated in vacuo the residue was diluted with EtOAc washed with sat. aqueous NaHCO3, water, and brine The organic layer was dried over Na2SO4 concentrated in vacuo

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl (E)-3-(4-nitrophenyl)acrylate (S31, 4.10 g, 19.8 mmol) in MeOH (30 mL) and THF (30 mL) was treated with 10% Pd/C (400 mg). The reaction mixture was purged with H2 and was stirred at 25° C. for 10 h. The suspension was filtered through diatomaceous earth and concentrated to afford S32 (3.40 g, 19.0 mmol, 95%) as a yellow solid: 1H NMR (CDCl3, 500 MHz) 6.99 (d, 2H, J=8.2 Hz), 6.63 (d, 2H, J=8.4 Hz), 3.60 (s, 3H), 2.85 (t, 2H, J=7.7 Hz), 2.58 (t, 2H, J=7.7 Hz); 13C NMR (CDCl3, 125 MHz) 173.5, 144.6, 130.5, 129.1, 115.3, 51.5, 36.1, 30.1. The reaction mixture was purged with H2 The suspension was filtered through diatomaceous earth concentrated to afford S32 (3.40 g, 19.0 mmol, 95%) as a yellow solid

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

Procedure: In the same manner as that of Example 2, 4,5-diisopropylfuran-2-carboxylic acid (90 mg, 0.459 mmol) was condensed with methyl 3-[4-aminophenyl]propionate, and the resultant was purified by silica gel chromatography [benzene-ethyl acetate (14:1)] to obtain methyl 3-[4-[(4,5-diisopropylfuran-2-carbonyl)amino]phenyl]propionate (138 mg, 84%) as colorless needles. the resultant was purified by silica gel chromatography [benzene-ethyl acetate (14:1)]

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

Procedure: By using 2-bromomethyl-5-nitrobenzoic acid ethyl ester and 3-(4-amino-phenyl)propionic acid methyl ester instead of 2-bromomethyl-6-nitro-benzoic acid methyl ester and aniline in Example 25, synthesis was performed in the same manner as that of Example 25 to obtain 3-[4-(6-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-phenyl]-propionic acid methyl ester as yellow crystals. in Example 25, synthesis

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

Procedure: By using 2-bromomethyl-5-nitrobenzoic acid ethyl ester and 3-(4-amino-phenyl)propionic acid methyl ester instead of 2-bromomethyl-6-nitro-benzoic acid methyl ester and aniline in Example 25, synthesis was performed in the same manner as that of Example 25 to obtain 3-[4-(6-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-phenyl]-propionic acid methyl ester as yellow crystals. in Example 25, synthesis

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

Procedure: To a 50 mL RB flask fitted with magnetic stirrer was charged 5 mL of dichloroethane. To the stirred solvent was added 4-(2-methoxyimino-2-phenyl-ethoxy)-benzaldehyde (0.4 g, 1.5 mmol), 3-(4-amino-phenyl)-propanoic acid methyl ester (0.27 g, 1.5 mmol). RM was cooled to 0° C. and sodium triacetoxyborohydride (0.47 g, 2.25 mmol) was added portion wise over a period of 15 minutes. The reaction mixture was stirred at RT for 2 h. The RM was quenched with NaHCO3 solution (40 mL 10% solution in water) and extracted with ethyl acetate (20 mL×2). The organic layer washed with saturated brine solution (25 mL), dried over anhydrous Na2SO4 and evaporated in vacuum to dryness. The resulting crude compound was purified by column chromatography on silica gel (100/200 mesh), using petroleum ether (60-80) and ethyl acetate as eluent to give the product (0.450 g, Yield: 69.4%): MS (ESI, 120 eV): m/z=433.1 (M+H)+. To a 50 mL RB flask fitted with magnetic stirrer The RM was quenched with NaHCO3 solution (40 mL 10% solution in water) extracted with ethyl acetate (20 mL×2) The organic layer washed with saturated brine solution (25 mL) dried over anhydrous Na2SO4 evaporated in vacuum to dryness The resulting crude compound was purified by column chromatography on silica gel (100/200 mesh)

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

Procedure: To a 50 mL RB flask fitted with magnetic stirrer was charged 5 mL of dichloroethane. To the stirred solvent was added 4-(2-methoxyimino-2-phenyl-ethoxy)-benzaldehyde (0.4 g, 1.5 mmol), 3-(4-amino-phenyl)-propanoic acid methyl ester (0.27 g, 1.5 mmol). RM was cooled to 0° C. and sodium triacetoxyborohydride (0.47 g, 2.25 mmol) was added portion wise over a period of 15 minutes. The reaction mixture was stirred at RT for 2 h. The RM was quenched with NaHCO3 solution (40 mL 10% solution in water) and extracted with ethyl acetate (20 mL×2). The organic layer washed with saturated brine solution (25 mL), dried over anhydrous Na2SO4 and evaporated in vacuum to dryness. The resulting crude compound was purified by column chromatography on silica gel (100/200 mesh), using petroleum ether (60-80) and ethyl acetate as eluent to give the product (0.450 g, Yield: 69.4%): MS (ESI, 120 eV): m/z=433.1 (M+H)+. To a 50 mL RB flask fitted with magnetic stirrer The RM was quenched with NaHCO3 solution (40 mL 10% solution in water) extracted with ethyl acetate (20 mL×2) The organic layer washed with saturated brine solution (25 mL) dried over anhydrous Na2SO4 evaporated in vacuum to dryness The resulting crude compound was purified by column chromatography on silica gel (100/200 mesh)