tert-butyl 2-phenylacetate

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:; See reaction.notes.procedure_details.

Procedure: A solution of 2-phenylacetic acid (12 g, 88 mmol) in t-BuOAc (250 mL) in a 1 L round-bottomed flask was treated with perchloric acid (70% redistilled, 0.212 mL, 3.53 mmol) and stirred at room temperature for 20 hours. The solution was transferred very slowly to stirred mixture of saturated aqueous NaHCO3 and Et2O. Gas evolution was observed. The resulting layers were separated and the organic layer was washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, and concentrated to give Intermediate S-3D (11.6 g, 68% yield): 1H NMR (500 MHz, chloroform-d) δ 7.34-7.29 (m, 2H), 7.28-7.22 (m, 3H), 3.52 (s, 2H), 1.44 (s, 9H). to stirred The resulting layers were separated the organic layer was washed with saturated aqueous NaHCO3 dried over MgSO4 filtered concentrated to give Intermediate S-3D (11.6 g, 68% yield)

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

Procedure: A solution of 2-phenylacetic acid (12 g, 88 mmol) in t-BuOAc (250 mL) in a 1 L round-bottomed flask was treated with perchloric acid (70% redistilled, 0.212 mL, 3.53 mmol) and stirred at room temperature for 20 hours. The solution was transferred very slowly to stirred mixture of saturated aqueous NaHCO3 and Et2O. Gas evolution was observed. The resulting layers were separated and the organic layer was washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, and concentrated to give Intermediate S-3D (11.6 g, 68% yield): 1H NMR (500 MHz, chloroform-d) δ 7.34-7.29 (m, 2H), 7.28-7.22 (m, 3H), 3.52 (s, 2H), 1.44 (s, 9H). to stirred The resulting layers were separated the organic layer was washed with saturated aqueous NaHCO3 dried over MgSO4 filtered concentrated to give Intermediate S-3D (11.6 g, 68% yield)

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

Procedure: The target compound was prepared as a colorless solid substance in an amount 5.94 g at a yield of 70.2% in the same manner as in Example 1 except that 5.0 g (19.9 mmol) of 5-(N-benzyloxycarbonylamino)pentanoic acid was dissolved in 50 ml of THF and 3.55 g (21.9 mmol) of CDI was added; 7.83 ml (59.7 mmol) of diisopropylamine and 30 ml of THF were added and 37 ml (59.7 mmol) of 1.63N BA solution was added dropwise; 11.5 g (59.7 mmol) of t-butyl phenylacetate instead of methyl phenylacetate was dissolved in 30 ml of THF; and 50 ml of saturated aqueous ammonium chloride solution was added to the reaction solution, the reaction was terminated, 40 g of 4N hydrochloric acid was added, and 140 ml of ethyl acetate was further added. The analytical results on the target compound are given below. 37 ml (59.7 mmol) of 1.63N BA solution was added dropwise the reaction was terminated 40 g of 4N hydrochloric acid was added 140 ml of ethyl acetate was further added The analytical results on the target compound

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

Procedure: A solution of tert-butyl 2-phenylacetate (8.5 g, 44.2 mmol) in THF (400 mL) in a 1 L round-bottomed flask was cooled in −78° C. bath and treated with a solution of KHMDS, 0.5M in toluene (97 mL, 48.6 mmol) via cannula over 10 minutes. After 10 minutes the mixture was removed from the bath and placed in a room temperature water bath and stirred for 15 minutes and then again cooled in −78° C. bath. After 15 minutes a solution of Preparation 4D (R)-benzyl 5,5,5-trifluoro-2-(((trifluoromethyl)sulfonyl)oxy)pentanoate (19.18 g, 48.6 mmol) in THF (50 mL) in a 100 ml, round bottom flask was added over 10 min via cannula with a 20 mL THF rinse. The reaction mixture turned cloudy. The reaction mixture was stirred at −78° C. for 1 hour and then quenched with saturated aqueous NH4Cl. The mixture was removed from −78° C. bath, diluted with 10% LiCl aq and extracted with Et2O. The organic layer was dried over MgSO4, filtered and concentrated. The resulting light brown residue was dissolved in 100 mL CH2Cl2 and treated with charcoal and MgSO4. The mixture was filtered to give an almost colorless solution. The CH2Cl2 solution was concentrated and diluted with hexane and cooled in −20° C. freezer. The resulting solids were filtered and rinsed with cold hexane (containing 5% MTBE) and dried on a fitted filter funnel under a stream of nitrogen to give 8.16 g. The solid was triturated with 40 mL hexane and 4 mL MTBE stirring the white suspension at room temperature for 1 hour and then cooling at −20° C. for 3 hours before filtering the white solid and washing with cold solvent (10:1 hexane:MTBE) to give (2R,3R)-1-benzyl 4-tert-butyl 3-phenyl-2-(3,3,3-trifluoropropyl)succinate (7.16 g, 37% yield) as a white solid. 1H NMR (500 MHz, chloroform-d) δ 7.32-7.23 (m, 8H), 7.05-6.97 (m, 2H), 4.89-4.76 (m, 2H), 3.69 (d, J=11.4 Hz, 1H), 3.23 (ddd, J=11.2, 9.9, 3.9 Hz, 1H), 2.19-2.04 (m, 2H), 2.03-1.88 (m, 2H), 1.40 (s, 9H). After 10 minutes the mixture was removed from the bath placed in a room temperature rinse The reaction mixture was stirred at −78° C. for 1 hour quenched with saturated aqueous NH4Cl The mixture was removed from −78° C. bath diluted with 10% LiCl aq extracted with Et2O The organic layer was dried over MgSO4 filtered concentrated The resulting light brown residue was dissolved in 100 mL CH2Cl2 treated with charcoal and MgSO4 The mixture was filtered to give an almost colorless solution The CH2Cl2 solution was concentrated diluted with hexane cooled in −20° C. freezer The resulting solids were filtered rinsed with cold hexane (containing 5% MTBE) dried on a fitted filter funnel under a stream of nitrogen to give 8.16 g The solid was triturated with 40 mL hexane and 4 mL MTBE stirring the white suspension at room temperature for 1 hour cooling at −20° C. for 3 hours before filtering the white solid washing with cold solvent (10:1 hexane:MTBE)

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

Procedure: A solution of tert-butyl 2-phenylacetate (8.5 g, 44.2 mmol) in THF (400 mL) in a 1 L round-bottomed flask was cooled in −78° C. bath and treated with a solution of KHMDS, 0.5M in toluene (97 mL, 48.6 mmol) via cannula over 10 minutes. After 10 minutes the mixture was removed from the bath and placed in a room temperature water bath and stirred for 15 minutes and then again cooled in −78° C. bath. After 15 minutes a solution of Preparation 4D (R)-benzyl 5,5,5-trifluoro-2-(((trifluoromethyl)sulfonyl)oxy)pentanoate (19.18 g, 48.6 mmol) in THF (50 mL) in a 100 ml, round bottom flask was added over 10 min via cannula with a 20 mL THF rinse. The reaction mixture turned cloudy. The reaction mixture was stirred at −78° C. for 1 hour and then quenched with saturated aqueous NH4Cl. The mixture was removed from −78° C. bath, diluted with 10% LiCl aq and extracted with Et2O. The organic layer was dried over MgSO4, filtered and concentrated. The resulting light brown residue was dissolved in 100 mL CH2Cl2 and treated with charcoal and MgSO4. The mixture was filtered to give an almost colorless solution. The CH2Cl2 solution was concentrated and diluted with hexane and cooled in −20° C. freezer. The resulting solids were filtered and rinsed with cold hexane (containing 5% MTBE) and dried on a fitted filter funnel under a stream of nitrogen to give 8.16 g. The solid was triturated with 40 mL hexane and 4 mL MTBE stirring the white suspension at room temperature for 1 hour and then cooling at −20° C. for 3 hours before filtering the white solid and washing with cold solvent (10:1 hexane:MTBE) to give (2R,3R)-1-benzyl 4-tert-butyl 3-phenyl-2-(3,3,3-trifluoropropyl)succinate (7.16 g, 37% yield) as a white solid. 1H NMR (500 MHz, chloroform-d) δ 7.32-7.23 (m, 8H), 7.05-6.97 (m, 2H), 4.89-4.76 (m, 2H), 3.69 (d, J=11.4 Hz, 1H), 3.23 (ddd, J=11.2, 9.9, 3.9 Hz, 1H), 2.19-2.04 (m, 2H), 2.03-1.88 (m, 2H), 1.40 (s, 9H). After 10 minutes the mixture was removed from the bath placed in a room temperature rinse The reaction mixture was stirred at −78° C. for 1 hour quenched with saturated aqueous NH4Cl The mixture was removed from −78° C. bath diluted with 10% LiCl aq extracted with Et2O The organic layer was dried over MgSO4 filtered concentrated The resulting light brown residue was dissolved in 100 mL CH2Cl2 treated with charcoal and MgSO4 The mixture was filtered to give an almost colorless solution The CH2Cl2 solution was concentrated diluted with hexane cooled in −20° C. freezer The resulting solids were filtered rinsed with cold hexane (containing 5% MTBE) dried on a fitted filter funnel under a stream of nitrogen to give 8.16 g The solid was triturated with 40 mL hexane and 4 mL MTBE stirring the white suspension at room temperature for 1 hour cooling at −20° C. for 3 hours before filtering the white solid washing with cold solvent (10:1 hexane:MTBE)

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

Procedure: A solution of 2-phenylacetic acid (12 g, 88 mmol) in tBuOAc (250 mL) in a 1 L round-bottomed flask was treated with perchloric acid, 70% redistilled (0.212 mL, 3.53 mmol), and stirred at room temperature for 20 hours. The solution was transferred very slowly to stirred mixture of saturated aqueous NaHCO3 and Et2O, which resulted in bubbling. The resulting layers were separated and the organic layer washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, and concentrated to give tert-butyl 2-phenylacetate (11.6 g, 68% yield). 1H NMR (500 MHz, chloroform-d) δ 7.34-7.29 (m, 2H), 7.28-7.22 (m, 3H), 3.52 (s, 2H), 1.44 (s, 9H). redistilled (0.212 mL, 3.53 mmol) to stirred mixture of saturated aqueous NaHCO3 and Et2O, which resulted in bubbling The resulting layers were separated the organic layer washed with saturated aqueous NaHCO3 dried over MgSO4 filtered concentrated

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

Procedure: A solution of 2-phenylacetic acid (12 g, 88 mmol) in tBuOAc (250 mL) in a 1 L round-bottomed flask was treated with perchloric acid, 70% redistilled (0.212 mL, 3.53 mmol), and stirred at room temperature for 20 hours. The solution was transferred very slowly to stirred mixture of saturated aqueous NaHCO3 and Et2O, which resulted in bubbling. The resulting layers were separated and the organic layer washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, and concentrated to give tert-butyl 2-phenylacetate (11.6 g, 68% yield). 1H NMR (500 MHz, chloroform-d) δ 7.34-7.29 (m, 2H), 7.28-7.22 (m, 3H), 3.52 (s, 2H), 1.44 (s, 9H). redistilled (0.212 mL, 3.53 mmol) to stirred mixture of saturated aqueous NaHCO3 and Et2O, which resulted in bubbling The resulting layers were separated the organic layer washed with saturated aqueous NaHCO3 dried over MgSO4 filtered concentrated

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

Procedure: A solution of 2-phenylacetic acid (12 g, 88 mmol) in tBuOAc (250 mL) in a 1 L round-bottomed flask was treated with perchloric acid, 70% redistilled (0.212 mL, 3.53 mmol) stirred at room temperature for 20 hours. The solution was transferred very slowly to stirred mixture of saturated aqueous NaHCO3 and Et2O. Extensive bubbling was observed. The resulting layers were separated and the organic layer washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, and concentrated to give tert-butyl 2-phenylacetate, Intermediate S5A (11.6 g, 68% yield). 1H NMR (500 MHz, chloroform-d) δ 7.34-7.29 (m, 2H), 7.28-7.22 (m, 3H), 3.52 (s, 2H), 1.44 (s, 9H). redistilled (0.212 mL, 3.53 mmol) to stirred mixture of saturated aqueous NaHCO3 and Et2O Extensive bubbling The resulting layers were separated the organic layer washed with saturated aqueous NaHCO3 dried over MgSO4 filtered concentrated

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

Procedure: To a suspended toluene (2 ml) solution of 2-bromo-1-methylpyridinium iodide (720 mg, 2.4 mmol) was added a mixture of tert-butyl alcohol (148 mg, 2.0 mmol), phenylacetic acid (272 mg, 2.0 mmol) and tri-n-butylamine (888 mg, 4.8 mmol) in toluene (2 ml), and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and tert-butyl phenylacetate was isolated in 82% yield. the resulting mixture was refluxed for 3 hours After evaporation of the solvent the residue was separated by silica gel column chromatography