Ethyl Hippurate

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

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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution comprised of N,N-diisopropylamine (3.97 mL, 22.8 mmol) in dry THF (57 mL) was cooled to −78° C. under nitrogen and then solutions of n-butyl lithium in hexanes (14.25 mL, 22.8 mmol) and ethyl benzoylaminoacetate (2.37 g, 11.4 mmol) in dry THF (23 mL) were added dropwise sequentially. The mixture was stirred for 1 hour and then a solution comprised of 2,6-dichlorobenzyl bromide (1.87 g, 11.4 mmol) in dry THF (2 mL) was added dropwise. The mixture was stirred for 1 hour at −78° C. and then for 30 minutes while allowing to warm. The mixture then was quenched with water (8 mL) and extracted with ethyl acetate (2×54 mL). The combined extracts were washed with 1M hydrochloric acid (1×27 mL) and saturated sodium chloride solution (1×27 mL), dried (Na2SO4) and concentrated on a rotary evaporator. Product was purified from the residue by flash column (silica gel, 10:90 to 50:50 v/v EtOAc-hexane) to provide crude ethyl 2-benzoylamino-3-(2,6-dichlorophenyl)propionate. The propionate ester was treated with lithium hydroxide (118.8 mg, 4.96 mmol) in ethanol (12 mL) and water (50 mL) for 15 hours. The mixture was then diluted with 1M hydrochloric acid (12 mL) and ethyl acetate (24 mL). The aqueous layer was separated and extracted with ethyl acetate (2×4 mL). The combined organic layers were washed with saturated sodium chloride solution (25 mL), dried (Na2SO4), filtered and concentrated on a rotary evaporator to provide 2-benzoylamino-3-(2,6-dichlorophenyl)propionic acid. was added dropwise The mixture was stirred for 1 hour at −78° C. for 30 minutes while allowing to warm The mixture then was quenched with water (8 mL) extracted with ethyl acetate (2×54 mL) The combined extracts were washed with 1M hydrochloric acid (1×27 mL) and saturated sodium chloride solution (1×27 mL) dried (Na2SO4) concentrated on a rotary evaporator Product was purified from the residue by flash column (silica gel, 10:90 to 50:50 v/v EtOAc-hexane)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution comprised of N,N-diisopropylamine (3.97 mL, 22.8 mmol) in dry THF (57 mL) was cooled to −78° C. under nitrogen and then solutions of n-butyl lithium in hexanes (14.25 mL, 22.8 mmol) and ethyl benzoylaminoacetate (2.37 g, 11.4 mmol) in dry THF (23 mL) were added dropwise sequentially. The mixture was stirred for 1 hour and then a solution comprised of 2,6-dichlorobenzyl bromide (1.87 g, 11.4 mmol) in dry THF (2 mL) was added dropwise. The mixture was stirred for 1 hour at −78° C. and then for 30 minutes while allowing to warm. The mixture then was quenched with water (8 mL) and extracted with ethyl acetate (2×54 mL). The combined extracts were washed with 1M hydrochloric acid (1×27 mL) and saturated sodium chloride solution (1×27 mL), dried (Na2SO4) and concentrated on a rotary evaporator. Product was purified from the residue by flash column (silica gel, 10:90 to 50:50 v/v EtOAc-hexane) to provide crude ethyl 2-benzoylamino-3-(2,6-dichlorophenyl)propionate. The propionate ester was treated with lithium hydroxide (118.8 mg, 4.96 mmol) in ethanol (12 mL) and water (50 mL) for 15 hours. The mixture was then diluted with 1M hydrochloric acid (12 mL) and ethyl acetate (24 mL). The aqueous layer was separated and extracted with ethyl acetate (2×4 mL). The combined organic layers were washed with saturated sodium chloride solution (25 mL), dried (Na2SO4), filtered and concentrated on a rotary evaporator to provide 2-benzoylamino-3-(2,6-dichlorophenyl)propionic acid. was added dropwise The mixture was stirred for 1 hour at −78° C. for 30 minutes while allowing to warm The mixture then was quenched with water (8 mL) extracted with ethyl acetate (2×54 mL) The combined extracts were washed with 1M hydrochloric acid (1×27 mL) and saturated sodium chloride solution (1×27 mL) dried (Na2SO4) concentrated on a rotary evaporator Product was purified from the residue by flash column (silica gel, 10:90 to 50:50 v/v EtOAc-hexane)

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: To a suspension of ethyl 2-amino-acetate (1.0 g, 7.16 mmol) in anhydrous CH2Cl2 (5 ml) was added TEA (1.82 g, 17.96 mmol). The reaction mixture was cooled in an ice bath, and a solution of benzoyl chloride (1.0 g, 7.17 mmol) in CH2Cl2 (2 ml) was added dropwise. After addition was completed, stirring was continued at RT for two more hours. The reaction mixture was washed with water, dried with MgSO4, filtered, and concentrated. Column chromatography (silica, 30% EtOAc in hexanes) gave benzoylaminoacetic acid ethyl ester (intermediate XXa, 1.24 g) as a white solid. The reaction mixture was cooled in an ice bath After addition was continued at RT for two more hours The reaction mixture was washed with water dried with MgSO4 filtered concentrated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution comprised of N,N-diisopropylamine (3.97 mL, 22.8 mmol) in dry THF (57 mL) was cooled to −78° C. under nitrogen and then solutions of n-butyl lithium in hexanes (14.25 mL, 22.8 mmol) and ethyl benzoylaminoacetate (2.37 g, 11.4 mmol) in dry THF (23 mL) were added dropwise sequentially. The mixture was stirred for 1 hour and then a solution comprised of 2,6-dichlorobenzyl bromide (1.87 g, 11.4 mmol) in dry TMF (2 mL) was added dropwise. The mixture was stirred for 1 hour at −78° C. and then for 30 minutes while allowing to warm. The mixture then was quenched with water (8 mL) and extracted with ethyl acetate (2×54 mL). The combined extracts were washed with 1M hydrochloric acid (1×27 mL) and saturated sodium chloride solution (1×27 mL), dried (Na2SO4) and concentrated on a rotary evaporator. Product was purified from the residue by flash column (silica gel, 10:90 to 50:50 v/v EtOAc-hexane) to provide crude ethyl 2-benzoylamino-3-(2,6-dichlorophenyl)propionate. The propionate ester was treated with lithium hydroxide (118.8 mg, 4.96 mmol) in ethanol (12 mL) and water (50 mL) for 15 hours. The mixture was then diluted with 1M hydrochloric acid (12 mL) and ethyl acetate (24 mL). The aqueous layer was separated and extracted with ethyl acetate (2×4 mL). The combined organic layers were washed with saturated sodium chloride solution (25 mL), dried (Na2SO4), filtered and concentrated on a rotary evaporator to provide 2-benzoylamino-3-(2,6-dichlorophenyl)propionic acid. was added dropwise The mixture was stirred for 1 hour at −78° C. for 30 minutes while allowing to warm The mixture then was quenched with water (8 mL) extracted with ethyl acetate (2×54 mL) The combined extracts were washed with 1M hydrochloric acid (1×27 mL) and saturated sodium chloride solution (1×27 mL) dried (Na2SO4) concentrated on a rotary evaporator Product was purified from the residue by flash column (silica gel, 10:90 to 50:50 v/v EtOAc-hexane)

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

Procedure: LiOH.H2O (73 mg, 1.74 mmol) was added to a solution of benzoylamino-acetic acid ethyl ester (90 mg, 0.43 mmol) in a mixture of MeOH (5 mL), THF (2 mL) and H2O (2 mL). The resulting mixture was stirred for 3 hrs at room temperature. The MeOH and THF were evaporated and the resulting residue was diluted with water (2 mL), acidified with citric acid and extracted with EtOAc. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford benzoylamino-acetic acid in 77% yield. LC-MS purity: 92% The MeOH and THF were evaporated the resulting residue was diluted with water (2 mL) extracted with EtOAc The organic layer was washed with brine solution dried over Na2SO4 concentrated under reduced pressure

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

Procedure: DIPEA (0.425 mL, 2.46 mmol) was added to a stirred solution of benzoic acid (100 mg, 0.82 mmol) in DMF (2 mL). HOBT (132 mg, 0.98 mmol) and EDCI.HCl (188 mg, 0.98) were then added, followed by the addition of ethyl glycine ester hydrochloride (0.82 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification using column chromatography (using silica gel, 60-120 A° and 20% methanol in chloroform as the eluent) afforded Benzoylamino-acetic acid ethyl ester in 53% yield, LC-MS purity: 98% the product was extracted with EtOAc The organic layer was washed with brine dried over Na2SO4 concentrated under reduced pressure to afford the crude product Purification

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution comprised of N,N-diisopropylamine (3.97 mL, 22.8 mmol) in dry THF (57 mL) was cooled to −78° C. under nitrogen and then solutions of n-butyl lithium in hexanes (14.25 mL, 22.8 mmol) and ethyl benzoylaminoacetate (2.37 g, 11.4 mmol) in dry THF (23 mL) were added dropwise sequentially. The mixture was stirred for 1 hour and then a solution comprised of 2,6-dichlorobenzyl bromide (1.87 g, 11.4 mmol) in dry THF (2 mL) was added dropwise. The mixture was stirred for 1 hour at −78° C. and then for 30 minutes while allowing to warm. The mixture then was quenched with water (8 mL) and extracted with ethyl acetate (2×54 mL). The combined extracts were washed with 1M hydrochloric acid (1×27 mL) and saturated sodium chloride solution (1×27 mL), dried (Na2SO4) and concentrated on a rotary evaporator. Product was purified from the residue by flash column (silica gel, 10:90 to 50:50 v/v EtOAc-hexane) to provide crude ethyl 2-benzoylamino-3-(2,6-dichlorophenyl)propionate. The propionate ester was treated with lithium hydroxide (118.8 mg, 4.96 mmol) in ethanol (12 mL) and water (50 mL) for 15 hours. The mixture was then diluted with 1M hydrochloric acid (12 mL) and ethyl acetate (24 mL). The aqueous layer was separated and extracted with ethyl acetate (2×4 mL). The combined organic layers were washed with saturated sodium chloride solution (25 mL), dried (Na2SO4), filtered and concentrated on a rotary evaporator to provide 2-benzoylamino-3-(2,6-dichlorophenyl)propionic acid. was added dropwise The mixture was stirred for 1 hour at −78° C. for 30 minutes while allowing to warm The mixture then was quenched with water (8 mL) extracted with ethyl acetate (2×54 mL) The combined extracts were washed with 1M hydrochloric acid (1×27 mL) and saturated sodium chloride solution (1×27 mL) dried (Na2SO4) concentrated on a rotary evaporator Product was purified from the residue by flash column (silica gel, 10:90 to 50:50 v/v EtOAc-hexane)