methyl 2-[(2-chlorobenzoyl)amino]acetate

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

Procedure: To a solution of above (2-chloro-benzoylamino)-acetic acid methyl ester (6 g, 26 mmol) in 30 mL of methanol, was added three equivalents of lithium hydroxide hydrate in 10 mL of water. The solution was stirred at room temperature for 1 hour, concentrated and mixed with water. Citric acid was added until pH of the solution was adjusted to pH 2 to 3. The mixture was extracted with ethyl acetate and the organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated to dryness to give (2-chloro-benzoylamino)-acetic acid as a solid. To a solution of (2-chloro-benzoylamino)-acetic acid in 40 mL of acetone at −20° C. was added excess of trifluoroacetic anhydride. The mixture was warmed up to room temperature and stirred overnight. The solvent was removed under vacuum. The residue was poured into 400 mL of water and stirred for 20 min. The solid was filtered out and washed with 2×100 mL of water, and dried under vacuum to give 2-(2-chloro-benzoylamino)-4,4,4-trifluoro-3,3-dihydroxy-butyric acid as a red solid. This red solid was suspended in 80 mL of methanol, and heated to reflux for 30 min. The solvent was removed and the mixture was purified by flash chromatography using ethyl acetate/hexane to give 2-(2-chloro-benzoylamino)-4,4,4-trifluoro-3,3-dihydroxy-butyric acid methyl ester as a light yellow solid. The methyl ester was suspended in 100 g of phosphorus oxychloride, and stirred at 80° C. overnight. The reaction mixture was concentrated to remove excess POCl3. The remaining oil was diluted with toluene, and poured into a mixture of ice-water. The layers were separated and the organic layer was washed with water and diluted sodium bicarbonate and then concentrated to dryness. The solid was dissolved in 30 mL of methanol and treated with 2.5 equivalent of lithium hydroxide in 30 mL of water, and stirred for 30 min. Methanol was removed under vacuum, and the mixture was diluted with water. pH of the solution was adjusted to about 3 with 12 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was concentrated and purified by flash chromatography to give 1.67 g of 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid as a light yellow solid. LCMS calcd for C11H5ClF3NO3 (m/e) 291, obsd 292 (M+H). concentrated mixed with water Citric acid was added until pH of the solution The mixture was extracted with ethyl acetate the organic layer was washed with water and brine dried over MgSO4 filtered concentrated to dryness

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

Procedure: To a solution of above (2-chloro-benzoylamino)-acetic acid methyl ester (6 g, 26 mmol) in 30 mL of methanol, was added three equivalents of lithium hydroxide hydrate in 10 mL of water. The solution was stirred at room temperature for 1 hour, concentrated and mixed with water. Citric acid was added until pH of the solution was adjusted to pH 2 to 3. The mixture was extracted with ethyl acetate and the organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated to dryness to give (2-chloro-benzoylamino)-acetic acid as a solid. To a solution of (2-chloro-benzoylamino)-acetic acid in 40 mL of acetone at −20° C. was added excess of trifluoroacetic anhydride. The mixture was warmed up to room temperature and stirred overnight. The solvent was removed under vacuum. The residue was poured into 400 mL of water and stirred for 20 min. The solid was filtered out and washed with 2×100 mL of water, and dried under vacuum to give 2-(2-chloro-benzoylamino)-4,4,4-trifluoro-3,3-dihydroxy-butyric acid as a red solid. This red solid was suspended in 80 mL of methanol, and heated to reflux for 30 min. The solvent was removed and the mixture was purified by flash chromatography using ethyl acetate/hexane to give 2-(2-chloro-benzoylamino)-4,4,4-trifluoro-3,3-dihydroxy-butyric acid methyl ester as a light yellow solid. The methyl ester was suspended in 100 g of phosphorus oxychloride, and stirred at 80° C. overnight. The reaction mixture was concentrated to remove excess POCl3. The remaining oil was diluted with toluene, and poured into a mixture of ice-water. The layers were separated and the organic layer was washed with water and diluted sodium bicarbonate and then concentrated to dryness. The solid was dissolved in 30 mL of methanol and treated with 2.5 equivalent of lithium hydroxide in 30 mL of water, and stirred for 30 min. Methanol was removed under vacuum, and the mixture was diluted with water. pH of the solution was adjusted to about 3 with 12 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was concentrated and purified by flash chromatography to give 1.67 g of 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid as a light yellow solid. LCMS calcd for C11H5ClF3NO3 (m/e) 291, obsd 292 (M+H). concentrated mixed with water Citric acid was added until pH of the solution The mixture was extracted with ethyl acetate the organic layer was washed with water and brine dried over MgSO4 filtered concentrated to dryness

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

Procedure: Amino-acetic acid methyl ester (5 g, 40 mmol) was suspended in DMF and treated with triethylamine (13.9 mL, 100 mmol) and 2-chloro-benzoyl chloride (5 mL, 40 mmol). The reaction mixture was stirred at room temperature overnight. Water was added to the reaction, and the mixture was extracted with ethyl acetate three times. The organic layers were combined and dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography using ethyl acetate/hexane to yield (2-chloro-benzoylamino)-acetic acid methyl ester as a light yellow solid. LCMS calcd for C10H10ClNO3 (m/e) 227, obsd 228 (M+H). the mixture was extracted with ethyl acetate three times dried over sodium sulfate filtered concentrated The residue was purified by flash chromatography

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

Procedure: Amino-acetic acid methyl ester (5 g, 40 mmol) was suspended in DMF and treated with triethylamine (13.9 mL, 100 mmol) and 2-chloro-benzoyl chloride (5 mL, 40 mmol). The reaction mixture was stirred at room temperature overnight. Water was added to the reaction, and the mixture was extracted with ethyl acetate three times. The organic layers were combined and dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography using ethyl acetate/hexane to yield (2-chloro-benzoylamino)-acetic acid methyl ester as a light yellow solid. LCMS calcd for C10H10ClNO3 (m/e) 227, obsd 228 (M+H). the mixture was extracted with ethyl acetate three times dried over sodium sulfate filtered concentrated The residue was purified by flash chromatography

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

Procedure: Amino-acetic acid methyl ester (5 g, 40 mmol) was suspended in DMF and treated with triethylamine (13.9 mL, 100 mmol) and 2-chloro-benzoyl chloride (5 mL, 40 mmol). The reaction mixture was stirred at room temperature overnight. Water was added to the reaction, and the mixture was extracted with ethyl acetate three times. The organic layers were combined and dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography using ethyl acetate/hexane to yield (2-chloro-benzoylamino)-acetic acid methyl ester as a light yellow solid. LCMS calcd for C10H10ClNO3 (m/e) 227, obsd 228 (M+H). the mixture was extracted with ethyl acetate three times dried over sodium sulfate filtered concentrated The residue was purified by flash chromatography

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

Procedure: To a solution of above (2-chloro-benzoylamino)-acetic acid methyl ester (6 g, 26 mmol) in 30 mL of methanol, was added three equivalents of lithium hydroxide hydrate in 10 mL of water. The solution was stirred at room temperature for 1 hour, concentrated and mixed with water. Citric acid was added until pH of the solution was adjusted to pH 2-3. The mixture was extracted with ethyl acetate and the organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated to dryness to give (2-chloro-benzoylamino)-acetic acid as a solid. To a solution of (2-chloro-benzoylamino)-acetic acid in 40 mL of acetone at −20° C. was added excess of trifluoroacetic anhydride. The mixture was warmed up to room temperature and stirred overnight. The solvent was removed under vacuum. The residue was poured into 400 mL of water and stirred for 20 min. The solid was filtered out and washed with 2×100 mL of water, and dried under vacuum to give 2-(2-chloro-benzoylamino)-4,4,4-trifluoro-3,3-dihydroxy-butyric acid as a red solid. This red solid was suspended in 80 mL of methanol, and heated to reflux for 30 min. The solvent was removed and the mixture was purified by flash chromatography using ethyl acetate/hexane to give 2-(2-chloro-benzoylamino)-4,4,4-trifluoro-3,3-dihydroxy-butyric acid methyl ester as a light yellow solid. The methyl ester was suspended in 100 g of phosphorus oxychloride, and stirred at 80° C. overnight. The reaction mixture was concentrated to remove excess POCl3. The remaining oil was diluted with toluene, and poured into a mixture of ice-water. The layers were separated and the organic layer was washed with water and diluted sodium bicarbonate and then concentrated to dryness. The solid was dissolved in 30 mL of methanol and treated with 2.5 equivalent of lithium hydroxide in 30 mL of water, and stirred for 30 min. Methanol was removed under vacuum, and the mixture was diluted with water. pH of the solution was adjusted to about 3 with 12 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was concentrated and purified by flash chromatography to give 1.67 g of 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid as a light yellow solid. LCMS calcd for C11H5ClF3NO3 (m/e) 291, obsd 292 (M+H). concentrated mixed with water Citric acid was added until pH of the solution The mixture was extracted with ethyl acetate the organic layer was washed with water and brine dried over MgSO4 filtered concentrated to dryness

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

Procedure: Amino-acetic acid methyl ester (5 g, 40 mmol) was suspended in DMF and treated with triethylamine (13.9 mL, 100 mmol) and 2-chloro-benzoyl chloride (5 mL, 40 mmol). The reaction mixture was stirred at room temperature overnight. Water was added to the reaction, and the mixture was extracted with ethyl acetate three times. The organic layers were combined and dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography using ethyl acetate/hexane to yield (2-chloro-benzoylamino)-acetic acid methyl ester as a light yellow solid. LCMS calcd for C10H10ClNO3 (m/e) 227, obsd 228 (M+H). the mixture was extracted with ethyl acetate three times dried over sodium sulfate filtered concentrated The residue was purified by flash chromatography