布瓦西坦杂质21

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared from (5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid and (S)-(−)-4-benzyl-2-oxazolidinone following the same procedure as for the synthesis of compound 39a.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a cooled (−78° C.) solution of (S)-4-benzyloxazolidin-2-one (10.26 g, 58 mmol, 1.0 equiv) in 100 mL THF was added dropwise n-BuLi (40 mL, 1.6 M, 64 mmol, 1.1 equiv). After stirring for 30 minutes, 4-fluorophenylacetyl chloride (10.0 g, 0.58 mmol, 1.0 equiv) was added dropwise. After stirring for an additional 30 minutes, the reaction mixture was allowed to warm to room temperature. The reaction was quenched with sat'd. aq. NH4Cl, extracted with DCM, and washed with brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel (10-20% EtOAc/Hexanes) provided the title compound as a thick oil (14.7 g, 81%). m/z=314.3 [M+H]+. After stirring for an additional 30 minutes The reaction was quenched with sat'd aq. NH4Cl, extracted with DCM washed with brine The organic layer was then dried over sodium sulfate filtered concentrated in vacuo Purification by silica gel (10-20% EtOAc/Hexanes)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 10 g (89 mmol) of 5-hexynoic acid and 31.0 mL (223 mmol) of triethylamine in 450 mL of anhydrous tetrahydrofuran at −25° C. under an atmosphere of nitrogen was added 12 mL (98 mmol) of trimethylacetyl chloride over 20 min. Upon addition a white precipitate formed and the resulting suspension was stirred for 2 h. Next, 4.2 g (98 mmol) of anhydrous lithium chloride and 17 g (94 mmol) of (S)-(−)-4-benzyl-2-oxazolidinone were added sequentially and the mixture was allowed to gradually warm to ambient temperature over 12 h. All volatiles were removed in vacuo and the residue was diluted with water (500 mL) and extracted with ether (3×200 mL). The combined organic layers were washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with a 10-25% ethyl acetate in hexanes gradient to afford the title compound as a colorless solid (22 g, 93%). 1H NMR (500 MHz, CDCl3): δ 7.35-7.31 (m, 2H), 7.28-7.25 (m, 1H), 7.19-7.21 (m, 2H), 4.69-4.64 (m, 1H), 4.22-4.15 (m, 2H), 3.28 (dd, J=13.4, 3.3 Hz, 1H), 3.13-3.01 (m, 2H), 2.78 (dd, J=13.4, 9.6 Hz, 1H), 2.34-2.30 (m, 2H), 1.99 (t, J=2.7 Hz, 1H), 1.96-1.88 (m, 2H). LC-MS: m/z (ES) 272.2 (MH)+, 294.3 (MNa)+. Upon addition a white precipitate formed All volatiles were removed in vacuo the residue was diluted with water (500 mL) extracted with ether (3×200 mL) The combined organic layers were washed with brine (100 mL) dried over magnesium sulfate filtered concentrated in vacuo The crude residue was purified by silica gel chromatography eluting with a 10-25% ethyl acetate in hexanes gradient

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (S)-4-Benzyloxazolidin-2-one (35 g, 0.2 mol) was dissolved in THF (500 mL) and cooled to −78° C. A solution of nBuLi in hexane (80 mL, 0.2 mol) was added dropwise. The solution was stirred at this temperature for 30 min and then (E)-but-2-enoyl chloride (19 mL, 0.2 mol) was added slowly. The cold bath was removed and the reaction was allowed to stir at room temperature for 1 h, whereupon saturated NH4Cl solution (200 mL) was added. Most of the THF was removed under vacuum and the mixture was partitioned between ether and brine. After drying over Na2SO4, the organic layer was concentrated and the residue purified by silica gel chromatography (20% EtOAc in hexanes) to give the desired product (39 g, 79% yield) as a white solid. The cold bath was removed to stir at room temperature for 1 h, whereupon saturated NH4Cl solution (200 mL) was added Most of the THF was removed under vacuum the mixture was partitioned between ether and brine After drying over Na2SO4 the organic layer was concentrated the residue purified by silica gel chromatography (20% EtOAc in hexanes)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: According to the procedure described in Example 17(a) for the preparation of 4(S)-benzyl-3-(2-thien-2-yl-acetyl)-2-oxazolidinone, 3-thiopheneacetyl chloride and (S)-(−)-4-benzyl-2-oxazolidinone furnished in 68% yield 4(S)-benzyl-3-(2-thien-3-yl-acetyl)-2-oxazolidinone as a solid, mp 80-1° C.

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (S)-(-)-4-benzyl-2-oxazolidinone (350 mg, 2.00 mmol) in dry THF (10 mL) at −30° C. was added dropwise n-butyllithium (2.59 M in hexanes, 0.8 mL). The mixture was cooled to −78° C. and treated with 2-thiopheneacetyl chloride (0.25 mL, 2 mmol). After stirring at −78° C. for 45 minutes, the mixture was allowed to warm to ambient temperature and stir for 1 hour. The mixture was diluted with hexanes (10 mL), quenched with 1M pH7 phosphate buffer, and stirred for 45 minutes. The layers of the resultant biphasic mixture were separated and the aqueousueous phase extracted with EtOAc. The combined organic layers were washed with 0.5N aqueous HCl two times, saturated aqueous NaHCO3 two times, and brine, dried over Na2SO4, and concentrated to provide a crude residue which was purified via flash column chromatography with 20% EtOAc/hex as eluant to yield 319 mg (53%) of 4(S)-benzyl-3-(2-thien-2-yl-acetyl)-2-oxazolidinone as a tan solid, mp 56-9° C. to warm to ambient temperature stir for 1 hour quenched with 1M pH7 phosphate buffer stirred for 45 minutes The layers of the resultant biphasic mixture were separated the aqueousueous phase extracted with EtOAc The combined organic layers were washed with 0.5N aqueous HCl two times, saturated aqueous NaHCO3 two times, and brine dried over Na2SO4 concentrated to provide a crude residue which was purified via flash column chromatography with 20% EtOAc/hex as eluant

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: As in Example 14(a) for 1-(4(S)-benzyl-oxazolidin-2-on-3-yl)-2-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]-ethanone 2-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-acetic acid and 4(S)-benzyl-2-oxazolidinone were coupled. Flash column chromatography with 10-25% EtOAc/hex to CH2Cl2 stepwise gradient eluant and subsequent trituration with EtOAc/MTBE/hex provided in 59% yield 1-(4(S)-benzyl-oxazolidin-2-on-3-yl)-2-[1-(4′-cyanobiphenyl4-yl)-1H-pyrrol-3-yl]-ethanone as a pale yellow amorphous solid.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (S)-(−)-4-benzyl-2-oxazolidinone (710 mg, 4 mmol) in dry THF (10 mL) at −78° C. was added n-butyllithium (2.5 mL of 1.6 M in hexanes). In a separate reaction vessel, to a solution of 2-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]-acetic acid (920 mg, 4.2 mmol) and triethylamine (0.7 mL, 5 mmol) in dry THF (20 mL) at −78° C. was added dropwise pivaloyl chloride (0.5 mL, 4 mmol). After stirring at −78° to 0° C. over 1 hour, then recooling to −78° C., the above solution was added via cannula. The resultant mixture was allowed to warm to ambient temperature over 17 hours, then partitioned with EtOAc and aqueous NH4Cl. The separated aqueousueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to an oil, which was purified via flash column chromatography with 15-20% EtOAc/hex gradient eluant. The oily product crystallized from benzene to give 1.04 g (69%) of 1-(4(S)-benzyl-oxazolidin-2-on-3-yl)-2-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]-ethanone as a solid, mp 106-8° C. In a separate reaction vessel recooling to −78° C. the above solution was added via cannula partitioned with EtOAc and aqueous NH4Cl The separated aqueousueous phase was extracted with EtOAc The combined organic layers were washed with brine dried over Na2SO4 concentrated to an oil, which was purified via flash column chromatography with 15-20% EtOAc/hex gradient eluant The oily product crystallized from benzene

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of (4S)-(-)-4-benzyl-2-oxazolidinone (3.903 g, 22.0 mmol) in THF (23 ml) is cooled at -78° and butyl lithium (1.6M in hexane, 14.7 ml, 23.5 mmol) is added. The mixture is stirred for 50 min and then the portion of 2-phenylpropionic acid chloride (XL) from above, in THF (8 ml) is added dropwise to the mixture. The mixture is stirred for 1 hr at -78° and then allowed to warm to 20-25°. Saturated aqueous sodium bicarbonate solution (100 ml) is added and the phases separated. The aqueous phase is washed with ether and the combined organic phases are then washed several times with saturated aqueous sodium bicarbonate followed by a saline wash. The organic phase is dried over magnesium sulfate and concentrated. The resulting diastereomers are separated on silica gel eluting with ethyl acetate/hexane (7/93) followed by ethyl acetate/hexane (12/88). The appropriate fractions are pooled and concentrated to give (4S)-4-(phenylmethyl)-3-(2-phenylpropionyl)-2-oxazolidinone (XLI, Isomer I, less polar isomer), NMR (CDCl3) 1.55, 2.79, 3.35, 4.09, 4.58, 5.12 and 7.30 δ; and (4S)-4-(phenylmethyl)-3-(2-phenylpropionyl)-2-oxazolidinone (XLII, Isomer II, more polar isomer), NMR (CDCl3) δ 1.52, 2.58, 3.09, 4.08, 4.19, 4.75, 5.11, 6.95 and 7.31 δ. is cooled at -78° The mixture is stirred for 1 hr at -78° to warm to 20-25° the phases separated The aqueous phase is washed with ether the combined organic phases are then washed several times with saturated aqueous sodium bicarbonate wash The organic phase is dried over magnesium sulfate concentrated The resulting diastereomers are separated on silica gel eluting with ethyl acetate/hexane (7/93) concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To (S)(-)-4-benzyl-2-oxazolidinone (2.65 g, 1.8 equiv) dissolved in tetrahydrofuran (25 mL) at -78° C. was added 2.5M butyl lithium (5.98 mL, 1.8 equiv). After 5 minutes, this solution was cannulated into the above solution. The reaction mixture was allowed to come to room temperature and stirred for 2 hours. The reaction mixture was diluted with chloroform (150 mL), washed with 10% sodium bisulfite (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 3:2 hexane/ethyl acetate to afford the title compound in 58% yield. to come to room temperature washed with 10% sodium bisulfite (100 mL) dried over sodium sulfate concentrated under reduced pressure The residue obtained was chromatographed on silica gel eluting with 3:2 hexane/ethyl acetate

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (S)-4-Benzyl-2-oxazolidinone (15.1 g, 85.0 mmol) was dissolved in THF (200 mL, 2.5 mol), cooled at −78° C. under nitrogen, and stirred for 10 minutes. 1.6 M of n-butyllithium in hexane (53.1 mL) was added dropwise and stirred for 15 minutes. 4-Methylpentanoyl chloride (12.6 g, 93.5 mmol) was added dropwise, stirred for 30 minutes at −78° C., then warmed to 0° C. for 2 hours. 150 mL of saturated NaHCO3 was added and the mixture was warmed to room temperature for 30 minutes. The mixture was extracted with DCM, washed with Na2CO3 (5%) and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Excess oxazolidinone was removed using hexanes to provide intermediate (2a) (14.5 g). stirred for 15 minutes stirred for 30 minutes at −78° C. warmed to 0° C. for 2 hours the mixture was warmed to room temperature for 30 minutes The mixture was extracted with DCM washed with Na2CO3 (5%) and saturated aqueous NaCl dried over MgSO4 filtered concentrated Excess oxazolidinone was removed

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To (S)(-)-4-benzyl-2-oxazolidinone (2.65 g, 1.8 equiv) dissolved in tetrahydrofuran (25 mL) at -78° C. was added 2.5M butyl lithium (5.98 mL, 1.8 equiv). After 5 minutes, this solution was cannulated into the above solution. The reaction mixture was allowed to come to room temperature and stirred for 2 hours. The reaction mixture was diluted with chloroform (150 mL), washed with 10% sodium bisulfite (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 3:2 hexane/ethyl acetate to afford the title compound in 58% yield. to come to room temperature washed with 10% sodium bisulfite (100 mL) dried over sodium sulfate concentrated under reduced pressure The residue obtained was chromatographed on silica gel eluting with 3:2 hexane/ethyl acetate