7-ethoxy-7-oxoheptanoic acid

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

Procedure: N,N-dimethylformamide(1 drop) was added to a tetrahydrofuran solution(40 ml) of pimelic acid monoethyl ester(25.5 g), and thereto oxalyl chloride(18.8 g) was added dropwise. After stirring for 2 hours at room temperature, the reaction mixture was concentrated. The residue was added dropwise to a mixture of chlorobenzene(61.0 g) and aluminum chloride anhydrous (36.1 g) under ice water. After stirring for 3 hours, the reaction mixture was poured into 1N-hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried(MgSO4). The solvent was evaporated to give ethyl 6-(4-chlorobenzoyl)hexanate (37.7 g, 97%) as an oily substance. the reaction mixture was concentrated The residue was added dropwise to a mixture of chlorobenzene(61.0 g) and aluminum chloride anhydrous (36.1 g) under ice water After stirring for 3 hours the reaction mixture was poured into 1N-hydrochloric acid extracted with ethyl acetate The ethyl acetate layer was washed with water, and dried(MgSO4) The solvent was evaporated

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

Procedure: N,N-dimethylformamide(1 drop) was added to a tetrahydrofuran solution(40 ml) of pimelic acid monoethyl ester(25.5 g), and thereto oxalyl chloride(18.8 g) was added dropwise. After stirring for 2 hours at room temperature, the reaction mixture was concentrated. The residue was added dropwise to a mixture of chlorobenzene(61.0 g) and aluminum chloride anhydrous (36.1 g) under ice water. After stirring for 3 hours, the reaction mixture was poured into 1N-hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried(MgSO4). The solvent was evaporated to give ethyl 6-(4-chlorobenzoyl)hexanate (37.7 g, 97%) as an oily substance. the reaction mixture was concentrated The residue was added dropwise to a mixture of chlorobenzene(61.0 g) and aluminum chloride anhydrous (36.1 g) under ice water After stirring for 3 hours the reaction mixture was poured into 1N-hydrochloric acid extracted with ethyl acetate The ethyl acetate layer was washed with water, and dried(MgSO4) The solvent was evaporated

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

Procedure: A dried, 200 mL, 3-necked, round-bottomed flask was equipped with a Teflon-coated magnetic bar and a vacuum jacketed Dean-Stark trap which was topped with a reflux condenser fitted with a Nitrogen inlet. The reaction vessel was charged with N-isopropyl-N-phenylamine (8.11 g, 60 mmol), boric acid (0.93 g, 15 mmol,), and xylene (88 mL). To the stirred reaction mixture was added 7-ethoxy-7-oxoheptanoic acid (11.29 g, 60 mmol) in one portion. The reaction was heated to reflux using a heating mantle. The azeotroped water began to separate and was collected in the Dean-Stark trap. After 16 hours of reflux, water was collected, and the reaction was allowed to cool to ambient temperature reaction. The reaction mixture was diluted with ethyl acetate (100 mL), and was washed with an aqueous 2N solution of HCl (50 mL), and followed with a saturated solution of sodium bicarbonate (60 mL). The majority of the organic solvent was removed in vacuum. To residue was added a 2 N aqueous solution of sodium hydroxide (60 mL). The mixture was heated at 60° C. for 4 hours. Upon cooling to room temperature, the mixture was washed 60 mL of ethyl acetate. After being carefully separated from the organic layer, the aqueous phase was subjected to evaporation to remove any residual ethyl acetate. Ice was added to the aqueous solution, followed by an aqueous solution of HCl (2N, 60 mL) leading to the precipitation of a white solid. Stirring was continued for an additional 30 minutes before the precipitate was collected with a sintered funnel. The collected white solid was successfully washed with water and hexane before it was in vacuo at room temperature for 12 h to afford 7.49 g (45%) of 7-[isopropyl(phenyl)amino]-7-oxoheptanoic acid as a white solid. HPLC: single peak at 4.83 min.; Mp: 62-63° C. 1H NMR (DMSO-d6,) δ: 0.95-0.97 (d, 6H), 1.08-1.10 (m, 2H), 1.34-1.40 (m, 4H), 1.76-1.79 (m, 2H), 2.09-2.13 (m, 2H), 4.81-4.85 (m, 1H), 7.18-7.20 (m, 2H), 7.44-7.46 (m, 3H). Mass (M+1): 278. Anal. Calc'd for C16H23NO3: C, 69.29; H, 8.36; N5.05. Found: C, 69.06; H, 8.45; N, 4.99. A dried, 200 mL, 3-necked, round-bottomed flask was equipped with a Teflon-coated magnetic bar was topped with a reflux condenser fitted with a Nitrogen inlet To the stirred reaction mixture The reaction was heated to reflux to separate was collected in the Dean-Stark trap After 16 hours of reflux water was collected reaction was washed with an aqueous 2N solution of HCl (50 mL) The majority of the organic solvent was removed in vacuum To residue was added a 2 N aqueous solution of sodium hydroxide (60 mL) The mixture was heated at 60° C. for 4 hours Upon cooling to room temperature the mixture was washed 60 mL of ethyl acetate After being carefully separated from the organic layer the aqueous phase was subjected to evaporation to remove any residual ethyl acetate Ice was added to the aqueous solution leading to the precipitation of a white solid was collected with a sintered funnel The collected white solid was successfully washed with water and hexane before it was in vacuo at room temperature for 12 h

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

Procedure: A dried, 200 mL, 3-necked, round-bottomed flask was equipped with a Teflon-coated magnetic bar and a vacuum jacketed Dean-Stark trap which was topped with a reflux condenser fitted with a Nitrogen inlet. The reaction vessel was charged with N-isopropyl-N-phenylamine (8.11 g, 60 mmol), boric acid (0.93 g, 15 mmol,), and xylene (88 mL). To the stirred reaction mixture was added 7-ethoxy-7-oxoheptanoic acid (11.29 g, 60 mmol) in one portion. The reaction was heated to reflux using a heating mantle. The azeotroped water began to separate and was collected in the Dean-Stark trap. After 16 hours of reflux, water was collected, and the reaction was allowed to cool to ambient temperature reaction. The reaction mixture was diluted with ethyl acetate (100 mL), and was washed with an aqueous 2N solution of HCl (50 mL), and followed with a saturated solution of sodium bicarbonate (60 mL). The majority of the organic solvent was removed in vacuum. To residue was added a 2 N aqueous solution of sodium hydroxide (60 mL). The mixture was heated at 60° C. for 4 hours. Upon cooling to room temperature, the mixture was washed 60 mL of ethyl acetate. After being carefully separated from the organic layer, the aqueous phase was subjected to evaporation to remove any residual ethyl acetate. Ice was added to the aqueous solution, followed by an aqueous solution of HCl (2N, 60 mL) leading to the precipitation of a white solid. Stirring was continued for an additional 30 minutes before the precipitate was collected with a sintered funnel. The collected white solid was successfully washed with water and hexane before it was in vacuo at room temperature for 12 h to afford 7.49 g (45%) of 7-[isopropyl(phenyl)amino]-7-oxoheptanoic acid as a white solid. HPLC: single peak at 4.83 min.; Mp: 62-63° C. 1H NMR (DMSO-d6,) δ: 0.95-0.97 (d, 6H), 1.08-1.10 (m, 2H), 1.34-1.40 (m, 4H), 1.76-1.79 (m, 2H), 2.09-2.13 (m, 2H), 4.81-4.85 (m, 1H), 7.18-7.20 (m, 2H), 7.44-7.46 (m, 3H). Mass (M+1): 278. Anal. Calc'd for C16H23NO3: C, 69.29; H, 8.36; N5.05. Found: C, 69.06; H, 8.45; N, 4.99. A dried, 200 mL, 3-necked, round-bottomed flask was equipped with a Teflon-coated magnetic bar was topped with a reflux condenser fitted with a Nitrogen inlet To the stirred reaction mixture The reaction was heated to reflux to separate was collected in the Dean-Stark trap After 16 hours of reflux water was collected reaction was washed with an aqueous 2N solution of HCl (50 mL) The majority of the organic solvent was removed in vacuum To residue was added a 2 N aqueous solution of sodium hydroxide (60 mL) The mixture was heated at 60° C. for 4 hours Upon cooling to room temperature the mixture was washed 60 mL of ethyl acetate After being carefully separated from the organic layer the aqueous phase was subjected to evaporation to remove any residual ethyl acetate Ice was added to the aqueous solution leading to the precipitation of a white solid was collected with a sintered funnel The collected white solid was successfully washed with water and hexane before it was in vacuo at room temperature for 12 h

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

Procedure: A dried, 200 mL, 3-necked, round-bottomed flask was equipped with a Teflon-coated magnetic bar and a vacuum jacketed Dean-Stark trap which was topped with a reflux condenser fitted with a Nitrogen inlet. The reaction vessel was charged with N-isopropyl-N-phenylamine (8.11 g, 60 mmol), boric acid (0.93 g, 15 mmol,), and xylene (88 mL). To the stirred reaction mixture was added 7-ethoxy-7-oxoheptanoic acid (11.29 g, 60 mmol) in one portion. The reaction was heated to reflux using a heating mantle. The azeotroped water began to separate and was collected in the Dean-Stark trap. After 16 hours of reflux, water was collected, and the reaction was allowed to cool to ambient temperature reaction. The reaction mixture was diluted with ethyl acetate (100 mL), and was washed with an aqueous 2N solution of HCl (50 mL), and followed with a saturated solution of sodium bicarbonate (60 mL). The majority of the organic solvent was removed in vacuum. To residue was added a 2 N aqueous solution of sodium hydroxide (60 mL). The mixture was heated at 60° C. for 4 hours. Upon cooling to room temperature, the mixture was washed 60 mL of ethyl acetate. After being carefully separated from the organic layer, the aqueous phase was subjected to evaporation to remove any residual ethyl acetate. Ice was added to the aqueous solution, followed by an aqueous solution of HCl (2N, 60 mL) leading to the precipitation of a white solid. Stirring was continued for an additional 30 minutes before the precipitate was collected with a sintered funnel. The collected white solid was successfully washed with water and hexane before it was in vacuo at room temperature for 12 h to afford 7.49 g (45%) of 7-[isopropyl(phenyl)amino]-7-oxoheptanoic acid as a white solid. HPLC: single peak at 4.83 min.; Mp: 62-63° C. 1H NMR (DMSO-d6,) δ: 0.95-0.97 (d, 6H), 1.08-1.10 (m, 2H), 1.34-1.40 (m, 4H), 1.76-1.79 (m, 2H), 2.09-2.13 (m, 2H), 4.81-4.85 (m, 1H), 7.18-7.20 (m, 2H), 7.44-7.46 (m, 3H). Mass (M+1): 278. Anal. Calc'd for C16H23NO3: C, 69.29; H, 8.36; N5.05. Found: C, 69.06; H, 8.45; N, 4.99. A dried, 200 mL, 3-necked, round-bottomed flask was equipped with a Teflon-coated magnetic bar was topped with a reflux condenser fitted with a Nitrogen inlet To the stirred reaction mixture The reaction was heated to reflux to separate was collected in the Dean-Stark trap After 16 hours of reflux water was collected reaction was washed with an aqueous 2N solution of HCl (50 mL) The majority of the organic solvent was removed in vacuum To residue was added a 2 N aqueous solution of sodium hydroxide (60 mL) The mixture was heated at 60° C. for 4 hours Upon cooling to room temperature the mixture was washed 60 mL of ethyl acetate After being carefully separated from the organic layer the aqueous phase was subjected to evaporation to remove any residual ethyl acetate Ice was added to the aqueous solution leading to the precipitation of a white solid was collected with a sintered funnel The collected white solid was successfully washed with water and hexane before it was in vacuo at room temperature for 12 h

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

Procedure: N,N-dimethylformamide(1 drop) was added to a tetrahydrofuran solution(40 ml) of pimelic acid monoethyl ester(25.5 g), and thereto oxalyl chloride(18.8 g) was added dropwise. After stirring for 2 hours at room temperature, the reaction mixture was concentrated. The residue was added dropwise to a mixture of chlorobenzene(61.0 g) and aluminum chloride anhydrous (36.1 g) under ice water. After stirring for 3 hours, the reaction mixture was poured into IN-hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried(MgSO4). The solvent was evaporated to give ethyl 6-(4-chlorobenzoyl)hexanate (37.7 g, 97%) as an oily substance. the reaction mixture was concentrated The residue was added dropwise to a mixture of chlorobenzene(61.0 g) and aluminum chloride anhydrous (36.1 g) under ice water After stirring for 3 hours the reaction mixture was poured into IN-hydrochloric acid extracted with ethyl acetate The ethyl acetate layer was washed with water, and dried(MgSO4) The solvent was evaporated

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

Procedure: N,N-dimethylformamide(1 drop) was added to a tetrahydrofuran solution(40 ml) of pimelic acid monoethyl ester(25.5 g), and thereto oxalyl chloride(18.8 g) was added dropwise. After stirring for 2 hours at room temperature, the reaction mixture was concentrated. The residue was added dropwise to a mixture of chlorobenzene(61.0 g) and aluminum chloride anhydrous (36.1 g) under ice water. After stirring for 3 hours, the reaction mixture was poured into IN-hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried(MgSO4). The solvent was evaporated to give ethyl 6-(4-chlorobenzoyl)hexanate (37.7 g, 97%) as an oily substance. the reaction mixture was concentrated The residue was added dropwise to a mixture of chlorobenzene(61.0 g) and aluminum chloride anhydrous (36.1 g) under ice water After stirring for 3 hours the reaction mixture was poured into IN-hydrochloric acid extracted with ethyl acetate The ethyl acetate layer was washed with water, and dried(MgSO4) The solvent was evaporated

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

Procedure: To a solution of 7-ethoxy-7-oxoheptanoic acid (7.23 g, 385 mmol) in DMF (150 mL) was added tert-butyl(2-aminophenyl)carbamate (8 g, 385 mmol), HBTU (14.6 g, 385 mmol), DIEA (20 mL, 1155 mmol). The mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into water and extracted by EtOAc (200 mL×3). The organic layers were combined and washed with saturated aqueous solution of Na2CO3, dried over Na2SO4 and then concentrated to give the desired compound (14 g, yield 96.3%). extracted by EtOAc (200 mL×3) washed with saturated aqueous solution of Na2CO3 dried over Na2SO4 concentrated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diethyl heptanedioate (65 g, 0.30 mol) in Ethanol (400 mL) was added KOH (16.8 g, 0.30 mmol). The mixture was stirred at 80° C. for 24 hours, and concentrated under reduced pressure. The resulting mixture was poured into water and the pH value of the solution was adjusted to 1 by concentrated H2SO4. After removal of the solvent, the crude product was purified by flash chromatography SiO2(EtOH:EtOAc=1:10) to give the desired compound (38 g, yield 67%). concentrated under reduced pressure The resulting mixture was poured into water After removal of the solvent the crude product was purified by flash chromatography SiO2(EtOH:EtOAc=1:10)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diethyl heptanedioate (65 g, 0.30 mol) in Ethanol (400 mL) was added KOH (16.8 g, 0.30 mmol). The mixture was stirred at 80° C. for 24 hours, and concentrated under reduced pressure. The resulting mixture was poured into water and the pH value of the solution was adjusted to 1 by concentrated H2SO4. After removal of the solvent, the crude product was purified by flash chromatography SiO2(EtOH:EtOAc=1:10) to give the desired compound (38 g, yield 67%). concentrated under reduced pressure The resulting mixture was poured into water After removal of the solvent the crude product was purified by flash chromatography SiO2(EtOH:EtOAc=1:10)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diethyl heptanedioate (65 g, 0.30 mol) in Ethanol (400 mL) was added KOH (16.8 g, 0.30 mmol). The mixture was stirred at 80° C. for 24 hours, and concentrated under reduced pressure. The resulting mixture was poured into water and the pH value of the solution was adjusted to 1 by concentrated H2SO4. After removal of the solvent, the crude product was purified by flash chromatography SiO2(EtOH:EtOAc=1:10) to give the desired compound (38 g, yield 67%). concentrated under reduced pressure The resulting mixture was poured into water After removal of the solvent the crude product was purified by flash chromatography SiO2(EtOH:EtOAc=1:10)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diethyl heptanedioate (65 g, 0.30 mol) in ethanol (400 mL) was added KOH (16.8 g, 0.30 mmol). The mixture was stirred at 80° C. for 24 hours and concentrated under reduced pressure. The resulting mixture was poured into water and the pH value of the solution was adjusted to 1 by concentrated H2SO4. After removal of the solvent, the crude product was purified by flash chromatography SiO2 (EtOH:EtOAc=1:10) to give the desired compound (38 g, yield 67%). concentrated under reduced pressure The resulting mixture was poured into water After removal of the solvent the crude product was purified by flash chromatography SiO2 (EtOH:EtOAc=1:10)