8-methoxy-8-oxooctanoic acid

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

Procedure: A stirring solution of 4-(3-nitrophenyl)-thiazol-2-ylamine (11) (2.21 g, 10 mmol) and suberic acid monomethyl ester (13) (1.88 g, 10 mmol) in dry pyridine (20 ml) was cooled to −15° C. and POCl3 (1.2 ml, 13 mmol) was added dropwise over 30 minutes. After stirring for another 1 hour at same temperature, the reaction mixture was diluted with EtOAc and washed thoroughly with 1N HCl solution and brine. The organic phase was dried over Na2SO4. The solvent was removed by rotary evaporation. The crude solid was washed with EtOAc to give compound 14 (2.40 g, 61.5%). 1H NMR (400 MHz, DMSO-d6) δ12.3 (1H, s), 8.74 (1H, d, J=1.4 Hz), 8.35 (1H, d, J=7.1 Hz), 8.18 (1H, d, J=7.8 Hz), 7.93 (1H, s), 7.74 (1H, t, J=7.9 Hz), 3.58 (3H, s), 2.46 (2H, t, J=7.5 Hz), 2.30 (2H, t, J=7.3 Hz), 1.61 (2H, t, J=6.5 Hz), 1.53 (2H, t, J=6.8 Hz), 1.30 (4H, brs). 13C NMR (100 MHz, DMSO-d6) δ172.1, 158.8, 148.7, 146.7, 136.2, 132.1, 130.8, 122.7, 120.5, 110.8, 51.6, 35.2, 33.6, 28.6, 28.5, 24.8, 24.6. washed thoroughly with 1N HCl solution and brine The organic phase was dried over Na2SO4 The solvent was removed by rotary evaporation The crude solid was washed with EtOAc

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

Procedure: A stirring solution of 4-(3-nitrophenyl)-thiazol-2-ylamine (11) (2.21 g, 10 mmol) and suberic acid monomethyl ester (13) (1.88 g, 10 mmol) in dry pyridine (20 ml) was cooled to −15° C. and POCl3 (1.2 ml, 13 mmol) was added dropwise over 30 minutes. After stirring for another 1 hour at same temperature, the reaction mixture was diluted with EtOAc and washed thoroughly with 1N HCl solution and brine. The organic phase was dried over Na2SO4. The solvent was removed by rotary evaporation. The crude solid was washed with EtOAc to give compound 14 (2.40 g, 61.5%). 1H NMR (400 MHz, DMSO-d6) δ12.3 (1H, s), 8.74 (1H, d, J=1.4 Hz), 8.35 (1H, d, J=7.1 Hz), 8.18 (1H, d, J=7.8 Hz), 7.93 (1H, s), 7.74 (1H, t, J=7.9 Hz), 3.58 (3H, s), 2.46 (2H, t, J=7.5 Hz), 2.30 (2H, t, J=7.3 Hz), 1.61 (2H, t, J=6.5 Hz), 1.53 (2H, t, J=6.8 Hz), 1.30 (4H, brs). 13C NMR (100 MHz, DMSO-d6) δ172.1, 158.8, 148.7, 146.7, 136.2, 132.1, 130.8, 122.7, 120.5, 110.8, 51.6, 35.2, 33.6, 28.6, 28.5, 24.8, 24.6. washed thoroughly with 1N HCl solution and brine The organic phase was dried over Na2SO4 The solvent was removed by rotary evaporation The crude solid was washed with EtOAc

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

Procedure: Add triethylamine (8.1 g, 79.9 mmol) dropwise to a solution of 2-amino-1-(2-methoxyphenyl)ethanone hydrochloride (13.6 g, 67.4 mmol) and octanedioic acid monomethyl ester (14.0 g, 74.2 mmol) in methylene chloride (600 mL) at 0° C. under nitrogen, and then add EDC HCl (15.5 g, 81.0 mmol). Stir the mixture for 4 hours and warm to room temperature with stirring for an additional 18 hours. Dilute the mixture in ethyl acetate (1.2 L), wash sequentially with water (300 mL), 1 N HCl (300 mL), brine (300 mL), saturated sodium, bicarbonate solution (300 mL) and brine (300 mL), and dry over sodium sulfate. Remove the solvent under reduced pressure to afford 7-[2-(2-methoxyphenyl)-2-oxoethylcarbamoyl]heptanoic acid methyl ester (20.0 g, 88%), which is used in the next step without further purification. with stirring for an additional 18 hours wash sequentially with water (300 mL), 1 N HCl (300 mL), brine (300 mL), saturated sodium, bicarbonate solution (300 mL) and brine (300 mL) dry over sodium sulfate Remove the solvent under reduced pressure

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

Procedure: Add triethylamine (8.1 g, 79.9 mmol) dropwise to a solution of 2-amino-1-(2-methoxyphenyl)ethanone hydrochloride (13.6 g, 67.4 mmol) and octanedioic acid monomethyl ester (14.0 g, 74.2 mmol) in methylene chloride (600 mL) at 0° C. under nitrogen, and then add EDC HCl (15.5 g, 81.0 mmol). Stir the mixture for 4 hours and warm to room temperature with stirring for an additional 18 hours. Dilute the mixture in ethyl acetate (1.2 L), wash sequentially with water (300 mL), 1 N HCl (300 mL), brine (300 mL), saturated sodium, bicarbonate solution (300 mL) and brine (300 mL), and dry over sodium sulfate. Remove the solvent under reduced pressure to afford 7-[2-(2-methoxyphenyl)-2-oxoethylcarbamoyl]heptanoic acid methyl ester (20.0 g, 88%), which is used in the next step without further purification. with stirring for an additional 18 hours wash sequentially with water (300 mL), 1 N HCl (300 mL), brine (300 mL), saturated sodium, bicarbonate solution (300 mL) and brine (300 mL) dry over sodium sulfate Remove the solvent under reduced pressure

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

Procedure: Add diisopropylethylamine (99 ml, 568 mmol) dropwise to a solution of EDC HCl (38.01 g, 198 mmol), HOBt (19.19 g, 142 mmol) and octanedioic acid monomethyl ester (53.44 g, 1.42 mmol) in methylene chloride (800 mL) at 0° C. under nitrogen. Warm the mixture to room temperature and stir for 1 hour. Add 2-amino-1-(5-chloro-2-isopropoxyphenyl)ethanone hydrochloride (53.44 g, 142 mmol) to the mixture and stir for 18 hours. Remove the solvent under reduced pressure, dilute the residue in ethyl acetate (300 mL), wash with water (100 mL) and brine (100 mL), and dry over magnesium sulfate. Remove the solvent under reduced pressure and purify the residue by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (4:6 to 0:10), to afford 7-[2-(5-chloro-2-isopropoxyphenyl)-2-oxoethylcarbamoyl]-heptanoic acid methyl ester (23.87 g, 23% over three steps). Remove the solvent under reduced pressure dilute the residue in ethyl acetate (300 mL) wash with water (100 mL) and brine (100 mL) dry over magnesium sulfate Remove the solvent under reduced pressure purify the residue by flash column chromatography on silica gel eluting with hexanes/ethyl acetate (4:6 to 0:10)

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

Procedure: Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(EDC) (8.5 g, 44.3 mL) to a solution of 2-amino-1-phenylethanol (5.0 g, 36.4 mmol), suberic acid monomethyl ester (6.85 g, 36.4 mmol) and 1-hydroxybenzotriazole (HOBt, 5.0 g, 37.0 mmol) in THF (200 mL) at room temperature under nitrogen. Stir the mixture for 12 hours. Dilute the mixture with ethyl acetate (600 mL), wash with 1N HCl (2×150 mL), brine (2×150 mL), NaHCO3 (2×150 mL) and brine (150 mL) solutions and dry over sodium sulfate. Remove the solvent under reduced pressure to provide 7-(2-hydroxy-2-phenylethylcarbamoyl)heptanoic acid methyl ester (10.3 g, 91%), which is used in the following step without purification. wash with 1N HCl (2×150 mL), brine (2×150 mL), NaHCO3 (2×150 mL) and brine (150 mL) solutions dry over sodium sulfate Remove the solvent under reduced pressure

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

Procedure: Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(EDC) (8.5 g, 44.3 mL) to a solution of 2-amino-1-phenylethanol (5.0 g, 36.4 mmol), suberic acid monomethyl ester (6.85 g, 36.4 mmol) and 1-hydroxybenzotriazole (HOBt, 5.0 g, 37.0 mmol) in THF (200 mL) at room temperature under nitrogen. Stir the mixture for 12 hours. Dilute the mixture with ethyl acetate (600 mL), wash with 1N HCl (2×150 mL), brine (2×150 mL), NaHCO3 (2×150 mL) and brine (150 mL) solutions and dry over sodium sulfate. Remove the solvent under reduced pressure to provide 7-(2-hydroxy-2-phenylethylcarbamoyl)heptanoic acid methyl ester (10.3 g, 91%), which is used in the following step without purification. wash with 1N HCl (2×150 mL), brine (2×150 mL), NaHCO3 (2×150 mL) and brine (150 mL) solutions dry over sodium sulfate Remove the solvent under reduced pressure