methyl 6-chloro-6-oxohexanoate

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:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 2.59 g (19.4.10−3 mol) of aluminum chloride in 4 ml of dichloromethane is prepared. It is cooled to −5° C. and a mixture of 0.97 ml (10.3.10−3 mol) of fluorobenzene and 1.31 ml (8.4.10−3 mol) of methyl 6-chloro-6-oxohexanoate in 3 ml of dichloromethane is added gradually, the temperature being maintained between −4 and −7° C. The temperature is then allowed to rise to 20° C. and, after 15 hours, the mixture is hydrolyzed in acidified iced water. It is extracted with dichloromethane and the organic phase obtained is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The 2 g of crude product recovered in this way are purified by chromatography on silica gel using a petroleum ether/ethyl acetate mixture (96/4) as the eluent to give 1.26 g of the expected product in the form of a white powder (yield=63%). is prepared is added gradually the temperature being maintained between −4 and −7° C It is extracted with dichloromethane the organic phase obtained is washed with water dried over magnesium sulfate concentrated under reduced pressure The 2 g of crude product recovered in this way are purified by chromatography on silica gel using a petroleum ether/ethyl acetate mixture (96/4) as the eluent

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

Procedure: 5-(Methoxycarbonyl)pentanoyl chloride (2.82 g, 0.017 mol) and triethylamine (3.47 g, 0.034 mol) were added to a solution of 2-(3,4-dichlorophenyl)-2-hydroxy-1-[phenyl]ethanone (Step 1) (4.77 g, 0.017 mmol) in 40 mL of methylene chloride. The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with 100 mL of methylene chloride. The organic solution was washed with water (1×100 mL), saturated brine (1×100 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was dried under high vacuum, then ammonium acetate (4.6 g, 0.06 mol) and 30 mL of acetic acid were added. The reaction mixture was heated at 100° C. for 2.5 h. The reaction mixture was cooled to room temperature, and the excess acetic acid was removed under vacuum. The resulting residue was partitioned between water (100 mL) and ethyl acetate (200 mL). The organic layer was separated, washed with saturated aqueous sodium bicarbonate (2×100 mL), saturated brine (1×100 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was purified by flash chromatography on silica gel (eluting with 1:9 ethyl acetate:hexane) to give 2.82 g (42.6%) of methyl [(4-phenyl)-5-(3,4-dichlorophenyl)oxazole]-2-butanoate as a yellow oil: HRMS calcd. for C20H17N1O3Cl2 390.0664. Found 390.0648. The organic solution was washed with water (1×100 mL), saturated brine (1×100 mL) dried over magnesium sulfate filtered concentrated The concentrated residue was dried under high vacuum The reaction mixture was heated at 100° C. for 2.5 h The reaction mixture was cooled to room temperature the excess acetic acid was removed under vacuum The resulting residue was partitioned between water (100 mL) and ethyl acetate (200 mL) The organic layer was separated washed with saturated aqueous sodium bicarbonate (2×100 mL), saturated brine (1×100 mL) dried over magnesium sulfate filtered concentrated The concentrated residue was purified by flash chromatography on silica gel (eluting with 1:9 ethyl acetate:hexane)

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

Procedure: 5-(Methoxycarbonyl)pentanoyl chloride (2.82 g, 0.017 mol) and triethylamine (3.47 g, 0.034 mol) were added to a solution of 2-(3,4-dichlorophenyl)-2-hydroxy-1-[phenyl]ethanone (Step 1) (4.77 g, 0.017 mmol) in 40 mL of methylene chloride. The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with 100 mL of methylene chloride. The organic solution was washed with water (1×100 mL), saturated brine (1×100 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was dried under high vacuum, then ammonium acetate (4.6 g, 0.06 mol) and 30 mL of acetic acid were added. The reaction mixture was heated at 100° C. for 2.5 h. The reaction mixture was cooled to room temperature, and the excess acetic acid was removed under vacuum. The resulting residue was partitioned between water (100 mL) and ethyl acetate (200 mL). The organic layer was separated, washed with saturated aqueous sodium bicarbonate (2×100 mL), saturated brine (1×100 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was purified by flash chromatography on silica gel (eluting with 1:9 ethyl acetate:hexane) to give 2.82 g (42.6%) of methyl [(4-phenyl)-5-(3,4-dichlorophenyl)oxazole]-2-butanoate as a yellow oil: HRMS calcd. for C20H17N1O3Cl2 390.0664. Found 390.0648. The organic solution was washed with water (1×100 mL), saturated brine (1×100 mL) dried over magnesium sulfate filtered concentrated The concentrated residue was dried under high vacuum The reaction mixture was heated at 100° C. for 2.5 h The reaction mixture was cooled to room temperature the excess acetic acid was removed under vacuum The resulting residue was partitioned between water (100 mL) and ethyl acetate (200 mL) The organic layer was separated washed with saturated aqueous sodium bicarbonate (2×100 mL), saturated brine (1×100 mL) dried over magnesium sulfate filtered concentrated The concentrated residue was purified by flash chromatography on silica gel (eluting with 1:9 ethyl acetate:hexane)

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

Procedure: Add 5-chlorocarbonylpentanoic acid methyl ester (15.30 g, 86 mmol) to a solution of N-hydroxy-2-methoxybenzamidine (12.0 g, 71 mmol) in pyridine (40 mL) and under nitrogen at a rate to keep the mixture at a gentle reflux. Then, heat the mixture at reflux for 4 hours. Dilute the mixture with water (300 mL) and extract with methylene chloride (3×200 mL). Wash the combined organic extracts with brine (100 mL), dry over sodium sulfate and remove the solvent under reduced pressure. Purify the residue by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:19), to afford 5-[3-(2-methoxyphenyl)-[1,2,4]oxadiazol-5-yl]pentanoic acid methyl ester (12.8 g, 55%). Then, heat the mixture at reflux for 4 hours extract with methylene chloride (3×200 mL) Wash the combined organic extracts with brine (100 mL) dry over sodium sulfate remove the solvent under reduced pressure Purify the residue by flash column chromatography on silica gel eluting with ethyl acetate/hexanes (1:19)

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

Procedure: To a solution of {[4-(6′-amino-2′-methyl-4′-nitro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 295: step h) 130 mg, 0.23 mmol), and Et3N (192 μL, 1.38 mmol) in DCM (5 mL) at 0° C. was added 5-chlorocarbonyl-pentanoic acid methyl ester (53 mg, 0.29). After stirring for 1 h, the solution was partitioned between EtOAc (70 mL) and aq NH4Cl (30 mL) and the layers were separated. The organic layer was washed with NaHCO3 (20 mL) and brine (30 mL) and was dried over sodium sulfate. The solution was concentrated and the residue was purified by SiO2 flash column chromatography to yield 36 mg of the amide product. The residue dissolved in EtOH (5 mL). Saturated aqueous NH4Cl (1.5 mL) was added followed by iron powder (110 mg, 2 mmol). The mixture was vigorously stirred at 80° C. for 30 min. The solution was filtered through a 0.22 μm filter and was then partitioned between EtOAc (70 mL) and water (20 mL). The layers were separated, the organic solution was dried over sodium sulfate, and the solution was concentrated to give the crude title compound which was used without further purification. 1H-NMR (CDCl3): δ 8.0 (m, 2H), 7.84 (s, 1H), 7.96 (m, 2H), 7.59 (t, 1H, J=7.7 Hz), 7.43 (m, 1H), 7.23 (br s, 1H), 6.86 (br s, 1H), 6.45 (br s, 1H), 3.85 (br s, 2H), 3.65 (s, 3H), 2.60 (m, 3H), 2.35 (m, 2H), 2.00 (m, 2H), 1.90 (s, 3H), 1.67 (m, 2H), 1.90 (s, 3H), 1.53 (s, 9H). the solution was partitioned between EtOAc (70 mL) and aq NH4Cl (30 mL) the layers were separated The organic layer was washed with NaHCO3 (20 mL) and brine (30 mL) was dried over sodium sulfate The solution was concentrated the residue was purified by SiO2 flash column chromatography

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

Procedure: {[4-(2′-Amino-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (100 mg, 0.19 mmol, Example 25: step c) was dissolved into THF (3 mL). To this was added 5-Chlorocarbonyl-pentanoic acid methyl ester (41.5 mg, 0.23 mmol) and the reaction was stirred at RT for 2 hours. The reaction was dissolved into EtOAc and washed with brine. The combined organic layers were dried (MgSO4) followed by removal of solvents in vacuo resulted in the title compound that was used without further purification. ESI-MS (m/z): Calcd. for C31H37N3O7S3: 660.2 (M+1); found: 660.8. washed with brine The combined organic layers were dried (MgSO4) followed by removal of solvents in vacuo

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

Procedure: {[4-(2′-Amino-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (100 mg, 0.19 mmol, Example 25: step c) was dissolved into THF (3 mL). To this was added 5-Chlorocarbonyl-pentanoic acid methyl ester (41.5 mg, 0.23 mmol) and the reaction was stirred at RT for 2 hours. The reaction was dissolved into EtOAc and washed with brine. The combined organic layers were dried (MgSO4) followed by removal of solvents in vacuo resulted in the title compound that was used without further purification. ESI-MS (m/z): Calcd. for C31H37N3O7S3: 660.2 (M+1); found: 660.8. washed with brine The combined organic layers were dried (MgSO4) followed by removal of solvents in vacuo