methyl 2-(4-aminophenoxy)acetate

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 (80 mg, 0.138 mmol), was reacted with diisopropylethylamine (89 mg, 0.69 mmol), diphenylphosphinic chloride (80 mg, 0.34 mmol), then reacted with methyl 2-(4-aminophenoxy)acetate (Aldrich, 27 mg, 0.153 mmol) to give rac-(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}-phenoxy)-acetic acid methyl ester (51 mg, 59%). MS (ES+) m/z [(M+H)30]: 628

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

Procedure: A procedure similar to that described in Example 6 was repeated, except that 30.8 g of methyl 4-nitro-phenoxyacetate (prepared as described in Preparation 36), 5.0 g of 10% w/w palladium-on-charcoal and 500 ml of methanol were used, to give 25.8 g of the title compound having Rf=0.79 (on silica gel thin layer chromatography using ethyl acetate as the developing solvent).

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

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

Procedure: To a mixture of (4-aminophenoxy)-acetic acid methyl ester 3 (20 g, 110.5 mmol) and benzyloxy acetic acid (20.4 g, 123 mmol) in anhydrous dichloromethane (200 ml) under nitrogen atmosphere was added dropwise a solution of 1,3-dicyclohexyl carbo-diimide (63.2 g, 306 mmol) in anhydrous dichloromethane (80 ml) then stirred at room temp. for 12 hours. The solids were filtered off, the dichloromethane was washed with 5% sodium bicarbonate solution (100 ml), water (100 ml) added, and the solids dried over sodium sulphate and distilled to get crude 49. Crude 49 was purified by column chromatography on silica gel using benzene as eluant to get pure 49 (25 g, 68.9%) as a white powder with an m.p. between 76-77.5° C. The solids were filtered off the dichloromethane was washed with 5% sodium bicarbonate solution (100 ml), water (100 ml) added the solids dried over sodium sulphate distilled to get crude 49 Crude 49 was purified by column chromatography on silica gel

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of (4-aminophenoxy)-acetic acid methyl ester 3 (15 g, 82.87 mmol) and triethylamine (16.77 g, 165.73 mmol) in toluene (225 ml) under nitrogen atmosphere at 0° C. was added triphosgene (9 g, 30.33 mmol) in one lot. The reaction was exothermic and the temperature rose to 25° C. Later the reaction mixture was heated to 75° C. over a period of one hour and maintained at this temperature for 26 hours. The reaction mixture was cooled to room temperature, the solids were filtered off, and toluene was distilled off under vacuum to get crude 4, which was vacuum distilled to get pure 4 (10 grams, 58.3%) as a white powder with an m.p between 50-53° C. rose to 25° C maintained at this temperature for 26 hours The reaction mixture was cooled to room temperature the solids were filtered off toluene was distilled off under vacuum to get crude 4, which distilled

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 (60 mg, 0.306 mmol) was condensed with methyl 4-aminophenoxyacetate, and the resultant was purified by silica gel chromatography (0.5% methanol-chloroform) to obtain methyl 4-[(4,5-diisopropylfuran-2-carbonyl)amino]phenyloxyacetate (94 mg, 86%) as colorless needles. the resultant was purified by silica gel chromatography (0.5% methanol-chloroform)

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

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

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

Procedure: To a mixture of 4-aminophenoxyacetic acid methyl ester 15 (20 g, 110.5 mmol) and benzyloxyacetic acid (20.4 g, 123 mmol) in anhydrous dichloromethane (200 ml) under nitrogen atm. was added dropwise a solution of 1,3-dicyclohexylcarbodiimide (63.2 g, 306 mmol) in anhydrous dichloromethane (80 ml). The reaction mixture was stirred at room temp. for 12 hrs. The solids were filtered off, the dichloromethane solution was washed with 5% sodium bicarbonate solution (100 ml), water (100 ml), dried over sodium sulphate, and distilled to get crude 66. The crude 66 was purified by column chromatography on silica gel using benzene as eluant to get pure 66 (25 g, 68.9%) as a white powder. M.p: 76-77.5° C. The solids were filtered off the dichloromethane solution was washed with 5% sodium bicarbonate solution (100 ml), water (100 ml) dried over sodium sulphate distilled to get crude 66 The crude 66 was purified by column chromatography on silica gel