ethyl 4-(3-oxopropyl)benzoate

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

Procedure: To a stirred mixture of 2.25 (37 mmol) of nitromethane, 1.2 mL of ethanol and 0.06 mL of 10N aqueous sodium hydroxide solution was added 7.18 g (37 mmol) of 3-(4-ethoxycarbonylphenyl)-1-propanal at room temperature. After addition of the aldehyde, 0.06 mL of 10N aqueous sodium hydroxide and 0.23 mL of ethanol were added, and the resulting mixture was stirred at 38° C. for 48 hours and then poured into a mixture of ethyl acetate (100 mL) and hexanes (100 mL). The resulting solution was washed with water (2×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual solid was purified by column chromatography on silica gel, eluting with 1:4 ethyl acetate:hexanes, to afford 4.1 g (72%) of 1-nitro-4-(4-ethoxycarbonylphenyl)-2-butanol as a white solid, IR (KBr) 3439, 2929, 1700, 1619, 1553, 1362, 1289, 1180, 1137, 1105, 1019, 882, 739 cm-1. 1H NMR (CDCl3) δ 7.98 (2H, d, J=8.5 Hz), 7.28 (2H, d, J=8.0 Hz), 4.42 (2H, d, J=5.5 Hz), 4.38 (2H, q, J=7.0 Hz), 4.34-4.29 (1H, m), 3.03 (1H, br s), 2.96-2.90 (1H, m), 2.84-2.78 (1H, m), 1.92-1.78 (2H, m), 1.40 (3H, t, J=7.0 Hz); 13C NMR (CDCl3) 8166.86, 146.36, 130.05, 128.70, 128.61, 80.76, 67.85, 61.15, 34.99, 31.50, 14.46; EIMS m/z 267 (M+), 265, 252, 249, 232, 222, 206, 177, 161, 149, 133, 105, 91, 77; HRMS calc'd for C13H17NO5 267.1107, found 267.1095. were added The resulting solution was washed with water (2×20 mL) dried over anhydrous sodium sulfate concentrated under reduced pressure The residual solid was purified by column chromatography on silica gel eluting with 1:4 ethyl acetate

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

Procedure: To a solution of 20 g (69.9 mmol) of ethyl 4-iodobenzoate, 0.47 g (2.1 mmol) of palladium acetate, 14.7 g (175 mmol) of sodium bicarbonate, and 22.5 g (70 mmol) of tetrabutylammonium bromide in 200 mL of dimethyl formamide were added, under nitrogen, 6.89 g (118.8 mmol) of allyl alcohol. The reaction mixture was stirred at room temperature for 42 hours. The dimethyl formamide was then removed by evaporation under reduced pressure and the residue was dissolved in 300 mL of ethyl acetate. This was washed with water (3×50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residual solid was purified by column chromatography on silica gel, eluting with 7:3 hexane:ethyl acetate to give 13.3 g (98%) of 3-(4-ethoxycarbonylphenyl)-1-propanal as a light yellow oil. 1H NMR (CDCl3) δ 10.02 (1H, s), 8.18 (2H, d, J=7.3 Hz), 7 47 (2H, d, J=7.3 Hz), 4.56 (2H, q, J=6.5 Hz), 3,21 (2H, t, J=6.5 Hz), 3.02 (2H, t, J=6.5 Hz), 1,59 (3H, t, J=6.5 Hz), Taylor, E. C. et al., J. Org. Chem., 57, 3218 (1992); J. Org. Chem., 60, 6684 (1995). The dimethyl formamide was then removed by evaporation under reduced pressure the residue was dissolved in 300 mL of ethyl acetate This was washed with water (3×50 mL) dried over anhydrous sodium sulfate concentrated under reduced pressure The residual solid was purified by column chromatography on silica gel eluting with 7:3 hexane

Conditions: temp:-9.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of boron trifluoride etherate (55 g, 0.387 mol) and methylene chloride (75 mL) was added over 10 min to a stirred, cooled (−20° C.) mixture of N-[2-(1-benzhydryl-5-chloro-1H-indol-2-yl)-ethyl]-C-(2,6-dimethylphenyl)-methanesulfonamide (300 g, 0.552 mol), triethylsilane (192 g,1.66 mol), 4-(3-oxo-propyl)-benzoic acid ethyl ester (250 g, 1.21 mol), and methylene chloride (2.8 L). An exotherm was observed and the reaction temperature increased to −9° C. The reaction mixture was cooled to and maintained at −20° C. Trifluoroacetic acid (63 g, 0.553 mol) was added to the reaction mixture 30 min after complete addition of boron trifluoride. The reaction mixture was stirred at −20° C. for 2 h. The reaction mixture was added to a stirred solution of sodium bicarbonate (138 g, 1.64 mol) and water (1.50 L). The mixture was filtered through a celite pad and the pad was washed with methylene chloride (150 mL). The layers were separated. The aqueous layer was washed with methylene chloride (300 mL). The combined organic layers were concentrated to 1.2 L at ambient pressure. Ethanol (1.50 L) was added to the mixture. The mixture was concentrated to 1.2 L at ambient pressure. The stirred mixture was cooled to 50° C. and tetrahydrofuran (450 mL) and 50% aqueous sodium hydroxide (221 g, 2.76 mol) was added. The mixture was warmed to reflux for 30 min. The mixture was cooled to 50° C. and toluene (1.50 L), water (300 mL), and acetic acid (166 g, 2.76 mol) was added. The mixture was stirred for 30 min. The mixture was filtered through a celite pad. The layers were separated and the aqueous layer was washed with a solution of tetrahydrofuran and toluene (1/1 v/v, 100 mL). The organic layer was washed consecutively with 3% aqueous sodium bicarbonate (100 ml), saturated sodium chloride (100 mL), and water (2×125 mL). The organic layer was concentrated to 1.2 L at ambient pressure. Toluene (600 mL) was added and the mixture was concentrated to 1.2 L at ambient pressure. The mixture was allowed to cool to room temperature and stirred overnight. Heptane (100 mL) was added to the stirred mixture after precipitation of solid product was observed. The solid product was collected by filtration and washed with cold toluene (3×300 mL). The product was vacuum dried at 66° C. to give 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)sulfonyl]-amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid (317 g, 81%) with a purity of 96% (as determined by HPLC). The product can be recrystallized from ethanol/water in 91% recovery. MP 193° C. cooled The reaction mixture was cooled to and maintained at −20° C The mixture was filtered through a celite pad the pad was washed with methylene chloride (150 mL) The layers were separated The aqueous layer was washed with methylene chloride (300 mL) The combined organic layers were concentrated to 1.2 L at ambient pressure Ethanol (1.50 L) was added to the mixture The mixture was concentrated to 1.2 L at ambient pressure The stirred mixture was cooled to 50° C. The mixture was warmed to reflux for 30 min The mixture was cooled to 50° C. The mixture was stirred for 30 min The mixture was filtered through a celite pad The layers were separated the aqueous layer was washed with a solution of tetrahydrofuran and toluene (1/1 v/v, 100 mL) The organic layer was washed consecutively with 3% aqueous sodium bicarbonate (100 ml), saturated sodium chloride (100 mL), and water (2×125 mL) The organic layer was concentrated to 1.2 L at ambient pressure Toluene (600 mL) was added the mixture was concentrated to 1.2 L at ambient pressure to cool to room temperature stirred overnight Heptane (100 mL) was added to the stirred mixture after precipitation of solid product The solid product was collected by filtration washed with cold toluene (3×300 mL) dried at 66° C.

Conditions: temp:77.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 4-iodobenzoate (200 g, 0.725 mol) and allyl alcohol (63 g, 1.087 mol) are added to a stirred suspension of Sodium bicarbonate (152 g, 1.812 mol), tetrabutyl-ammounium bromide (117 g, 0.362 mol) and Palladium (II) acetate (3.2 g, 0.014 mol) in DMF (600 mL). The reaction mixture is warmed to 75-80° C. for 3-3.5 hours and cooled to 40° C. -50° C. Toluene (1 L) is added to the reaction mixture with vigorous agitation and the mixture is stirred for 15 min at room temperature. The resulting mixture is filtered through a celite pad. The pad is washed with toluene (2×200 mL). The filtrate and wash are combined, washed with water (3×1 L), evaporated to constant weight at 30° C.-40° C. and 10 mmHg. The crude product 147.5 g (98.8%, 84% by HPLC) of 4-(3-Oxo-propyl)-benzoic acid ethyl ester as dark brown oil is obtained. 1H NMR (DMSO-d6): δ1.38 (t, 3H), 2.81 (t, 2H), 3.03 (t, 2H), 4.39 (q, 2H), 7.27 (d, 2H), 7.98 (d, 2H), 9.81 (s, 1H). cooled to 40° C. -50° C The resulting mixture is filtered through a celite pad The pad is washed with toluene (2×200 mL) The filtrate and wash washed with water (3×1 L) evaporated to constant weight at 30° C.-40° C.

Conditions: temp:77.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 4-iodobenzoate (200 g, 0.725 mol) and allyl alcohol (63 g, 1.087 mol) are added to a stirred suspension of Sodium bicarbonate (152 g, 1.812 mol), tetrabutyl-ammounium bromide (117 g, 0.362 mol) and Palladium (II) acetate (3.2 g, 0.014 mol) in DMF (600 mL). The reaction mixture is warmed to 75-80° C. for 3-3.5 hours and cooled to 40° C. -50° C. Toluene (1 L) is added to the reaction mixture with vigorous agitation and the mixture is stirred for 15 min at room temperature. The resulting mixture is filtered through a celite pad. The pad is washed with toluene (2×200 mL). The filtrate and wash are combined, washed with water (3×1 L), evaporated to constant weight at 30° C.-40° C. and 10 mmHg. The crude product 147.5 g (98.8%, 84% by HPLC) of 4-(3-Oxo-propyl)-benzoic acid ethyl ester as dark brown oil is obtained. 1H NMR (DMSO-d6): δ1.38 (t, 3H), 2.81 (t, 2H), 3.03 (t, 2H), 4.39 (q, 2H), 7.27 (d, 2H), 7.98 (d, 2H), 9.81 (s, 1H). cooled to 40° C. -50° C The resulting mixture is filtered through a celite pad The pad is washed with toluene (2×200 mL) The filtrate and wash washed with water (3×1 L) evaporated to constant weight at 30° C.-40° C.

Conditions: temp:-13.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of boron trifluoride etherate (50.7 g, 0.357 mol) and methylene chloride (83 mL) was added over 10 min to a stirred, cooled (−20° C.) mixture of N-[2-(1-benzhydryl-5-chloro-1H-indol-2-yl)-ethyl]-C-(3,4-dichloro-phenyl)-methanesulfonamide (275 g, 0.471 mol), triethylsilane (1.42 mol), 4-(3-oxo-propyl)-benzoic acid ethyl ester (213.6 g, 1.04 mol), and methylene chloride (2.6 L). An exotherm was observed and the reaction temperature increased to −13° C. The reaction mixture was cooled to and maintained at −20° C. Trifluoroacetic acid (53.7 g, 0.471 mol) was added to the reaction mixture 30 min after complete addition of boron trifluoride. The reaction mixture was stirred at −20° C. for 2 h. The reaction mixture was added to a stirred solution of sodium bicarbonate (127 g, 1.51 mol) and water (1.37 L). The mixture was filtered through a celite pad and the pad was washed with methylene chloride (50 mL). The layers were separated. The aqueous layer was washed with methylene chloride (200 mL). The combined organic layers were concentrated to 1.1 L at ambient pressure. Ethanol (1.38 L) was added to the mixture. The mixture was concentrated to 1.1 L at ambient pressure. The stirred mixture was cooled to 50° C. and tetrahydrofuran (275 mL) and 50% aqueous sodium hydroxide (188 g, 2.35 mol) was added. The mixture was warmed to reflux for 30 min. The mixture was cooled to 50° C. and toluene (1.38 L), water (225 mL), and acetic acid (141 g, 2.35 mol) was added. The mixture was stirred for 30 min. The mixture was filtered through a celite pad. The layers were separated and the aqueous layer was washed with a solution of tetrahydrofuran and toluene (1/1 v/v, 100 mL). The organic layer was washed consecutively with 3% aqueous sodium bicarbonate (100 ml), saturated sodium chloride (100 mL), and water (2×125 mL). The organic layer was concentrated to 1.1 L at ambient pressure. Toluene (550 mL) was added and the mixture was concentrated to 1.1 L at ambient pressure. The mixture was allowed to cool to room temperature and stirred overnight. Heptane (110 mL) was added to the stirred mixture after precipitation of solid product was observed. The solid product was collected by filtration and washed with cold toluene (2×275 mL). The product was vacuum dried at 66° C. to give 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid (227 g, 65%) with a purity of 99% (as determined by HPLC). The product can be recrystallized from ethanol in 91% recovery. MP 190° C. cooled The reaction mixture was cooled to and maintained at −20° C The mixture was filtered through a celite pad the pad was washed with methylene chloride (50 mL) The layers were separated The aqueous layer was washed with methylene chloride (200 mL) The combined organic layers were concentrated to 1.1 L at ambient pressure Ethanol (1.38 L) was added to the mixture The mixture was concentrated to 1.1 L at ambient pressure The stirred mixture was cooled to 50° C. The mixture was warmed to reflux for 30 min The mixture was cooled to 50° C. The mixture was stirred for 30 min The mixture was filtered through a celite pad The layers were separated the aqueous layer was washed with a solution of tetrahydrofuran and toluene (1/1 v/v, 100 mL) The organic layer was washed consecutively with 3% aqueous sodium bicarbonate (100 ml), saturated sodium chloride (100 mL), and water (2×125 mL) The organic layer was concentrated to 1.1 L at ambient pressure Toluene (550 mL) was added the mixture was concentrated to 1.1 L at ambient pressure to cool to room temperature stirred overnight Heptane (110 mL) was added to the stirred mixture after precipitation of solid product The solid product was collected by filtration washed with cold toluene (2×275 mL) dried at 66° C.

Conditions: temp:77.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 4-iodobenzoate (200 g, 0.725 mol) and allyl alcohol (63 g, 1.087 mol) are added to a stirred suspension of Sodium bicarbonate (152 g, 1.812 mol), tetrabutyl-ammounium bromide (117 g, 0.362 mol) and Palladium (II) acetate (3.2 g, 0.014 mol) in DMF (600 mL). The reaction mixture is warmed to 75-80° C. for 3-3.5 hours and cooled to 40° C.-50° C. Toluene (1 L) is added to the reaction mixture with vigorous agitation and the mixture is stirred for 15 min at room temperature. The resulting mixture is filtered through a celite pad. The pad is washed with toluene (2×200 mL). The filtrate and wash are combined, washed with water (3×1 L), evaporated to constant weight at 30° C.-40° C. and 10 mmHg. The crude product 147.5 g (98.8%, 84% by HPLC) of 4-(3-Oxo-propyl)-benzoic acid ethyl ester as dark brown oil is obtained and can be used in the next step without further purification. 1H NMR (DMSO-d6): δ1.38(t, 3H), 2.81(t, 2H), 3.03(t, 2H), 4.39(q, 2H), 7.27(d, 2H), 7.98(d, 2H), 9.81 (s, 1H). cooled to 40° C.-50° C The resulting mixture is filtered through a celite pad The pad is washed with toluene (2×200 mL) The filtrate and wash washed with water (3×1 L) evaporated to constant weight at 30° C.-40° C.