methyl 2-(2-tert-butylanilino)-2-oxoacetate

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

Procedure: A 3-L, 3-necked round-bottomed flask, equipped with a mechanic stirrer and a thermal probe (under nitrogen) was charged with Methyl 2-(2-tert-Butylphenylamino)-2-oxoacetate (154 g, 655 mmoles) and MeOH (1000 mL). The resulting mixture was stirred at a moderate speed at room temperature. A solution of 1N NaOH/MeOH (800 mL) was added dropwise to the reaction mixture via addition funnel. After 1 hour, agitation was stopped, and the suspension transferred to a filtration funnel and filtered to afford a white solid. This solid was then taken up in water (1200 mL) and the pH adjusted to 1.5–2 with addition of conc. HCl with stirring. After mixing for 1 hour, filtration and drying yielded the title compound as a white crystalline mass (127 g, 574 mmoles, 87.6%). TLC (silica F254, 3/1 v/v dichloromethane/MeOH, detection 254 nm) showed one spot and HPLC confirmed that. MP 110.9–112.6° C.; IR (KBr) 3405, 2973, 1688, 1548, 1300, 757 cm−1; 1H NMR (300 MHz, CDCl3): δ (ppm): 9.37 (br, 1H), 7.91 (dd, J=7.8 Hz, J′=1.8 Hz, 1H), 7.44 (dd, J=7.8 Hz, J′=1.8 Hz, 1H), 7.25 (m, 2H), 1.46 (s, 9H); 13C (300 MHz, CDCl3): δ (ppm): 160.87, 155.24, 141.18, 133.19, 126.92, 126.69, 126.63, 124.24, 34.21, 30.49. the suspension transferred to a filtration funnel filtered to afford a white solid with stirring After mixing for 1 hour filtration drying

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 3-L, 3-necked round-bottomed flask, equipped with a mechanic stirrer and a thermal probe (under nitrogen) was charged with 2-tert-Butylaniline (109 g, 114 mL, 732 mmoles), triethylamine (81.4 g, 112 mL, 804 mmoles, 1.1 equiv.) and toluene (600 mL). The resulting mixture was stirred at a moderate speed at −30° C. An additon funnel was charged with Methyl chlorooxoacetate (100 g, 816 mmoles, 1.11 equiv.) with toluene (200 mL), and the mixture added to the reaction mixture at such a rate that the internal batch temperature is less than −20° C. After addition, the reaction was warmed to room temperature for an hour, quenched with water, then partitioned between EtOAc/water. The aqueous phase was extracted with EtOAc (200 mL), and the combined organic layers were washed successively with KHSO4 (200 mL), NaHCO3 (sat'd) (200 mL) and brine (200 mL), then dried the organic over MgSO4. The organic phase was concentrated by rotary evaporation, yielding the title compound as a pale yellow solid [Methyl 2-(2-tert-Butylphenylamino)-2-oxoacetate, 160 g, 93.1%]. MP 61.7–63.6° C. IR (KBr) 3409, 2954, 1736, 1724, 1530, 1299, 1166, 766 cm−1; 1H NMR (300 MHz, CDCl3): δ(ppm): 9.20 (br, 1H), 7.97 (dd, J=7.8 Hz, J′=1.8 Hz, 1H), 7.43 (dd, J=7.8 Hz, J′=1.8 Hz, 1H), 7.31–7.16 (m, 2H), 4.00 (s, 3H), 1.47(s, 9H). The product thus obtained can be used directly for the subsequent reaction. the mixture added to the reaction mixture at such a rate that the internal batch temperature is less than −20° C After addition the reaction was warmed to room temperature for an hour quenched with water partitioned between EtOAc/water The aqueous phase was extracted with EtOAc (200 mL) the combined organic layers were washed successively with KHSO4 (200 mL), NaHCO3 (sat'd) (200 mL) and brine (200 mL) dried the organic over MgSO4 The organic phase was concentrated by rotary evaporation

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

Procedure: A 3-L, 3-necked round-bottomed flask, equipped with a mechanic stirrer and a thermal probe (under nitrogen) was charged with Methyl 2-(2-tert-Butylphenylamino)-2-oxoacetate (154 g, 655 mmoles) and MeOH (1000 mL). The resulting mixture was stirred at a moderate speed at room temperature. A solution of 1N NaOH/MeOH (800 mL) was added dropwise to the reaction mixture via addition funnel. After 1 hour, agitation was stopped, and the suspension transferred to a filtration funnel and filtered to afford a white solid. This solid was then taken up in water (1200 mL) and the pH adjusted to 1.5–2 with addition of conc. HCl with stirring. After mixing for 1 hour, filtration and drying yielded the title compound as a white crystalline mass (127 g, 574 mmoles, 87.6%). TLC (silica F254, 3/1 v/v dichloromethane/MeOH, detection 254 nm) showed one spot and HPLC confirmed that. MP 110.9–112.6° C.; IR (KBr) 3405, 2973, 1688, 1548, 1300, 757 cm−1; 1H NMR (300 MHz, CDCl3): δ (ppm): 9.37 (br, 1H), 7.91 (dd, J=7.8 Hz, J′=1.8 Hz, 1H), 7.44 (dd, J=7.8 Hz, J′=1.8 Hz, 1H), 7.25 (m, 2H), 1.46 (s, 9H); 13C (300 MHz, CDCl3): δ (ppm): 160.87, 155.24, 141.18, 133.19, 126.92, 126.69, 126.63, 124.24, 34.21, 30.49. the suspension transferred to a filtration funnel filtered to afford a white solid with stirring After mixing for 1 hour filtration drying

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 3-L, 3-necked round-bottomed flask, equipped with a mechanic stirrer and a thermal probe (under nitrogen) was charged with 2-tert-Butylaniline (109 g, 114 mL, 732 mmoles), triethylamine (81.4 g, 112 mL, 804 mmoles, 1.1 equiv.) and toluene (600 mL). The resulting mixture was stirred at a moderate speed at −30° C. An additon funnel was charged with Methyl chlorooxoacetate (100 g, 816 mmoles, 1.11 equiv.) with toluene (200 mL), and the mixture added to the reaction mixture at such a rate that the internal batch temperature is less than −20° C. After addition, the reaction was warmed to room temperature for an hour, quenched with water, then partitioned between EtOAc/water. The aqueous phase was extracted with EtOAc (200 mL), and the combined organic layers were washed successively with KHSO4 (200 mL), NaHCO3 (sat'd) (200 mL) and brine (200 mL), then dried the organic over MgSO4. The organic phase was concentrated by rotary evaporation, yielding the title compound as a pale yellow solid [Methyl 2-(2-tert-Butylphenylamino)-2-oxoacetate, 160 g, 93.1%]. MP 61.7–63.6° C. IR (KBr) 3409, 2954, 1736, 1724, 1530, 1299, 1166, 766 cm−1; 1H NMR (300 MHz, CDCl3): δ(ppm): 9.20 (br, 1H), 7.97 (dd, J=7.8 Hz, J′=1.8 Hz, 1H), 7.43 (dd, J=7.8 Hz, J′=1.8 Hz, 1H), 7.31–7.16 (m, 2H), 4.00 (s, 3H), 1.47(s, 9H). The product thus obtained can be used directly for the subsequent reaction. the mixture added to the reaction mixture at such a rate that the internal batch temperature is less than −20° C After addition the reaction was warmed to room temperature for an hour quenched with water partitioned between EtOAc/water The aqueous phase was extracted with EtOAc (200 mL) the combined organic layers were washed successively with KHSO4 (200 mL), NaHCO3 (sat'd) (200 mL) and brine (200 mL) dried the organic over MgSO4 The organic phase was concentrated by rotary evaporation

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

Procedure: A 3-L, 3-necked round-bottomed flask, equipped with a mechanic stirrer and a thermal probe (under nitrogen) was charged with Methyl 2-(2-tert-Butylphenylamino)-2-oxoacetate (154 g, 655 mmoles) and MeOH (1000 mL). The resulting mixture was stirred at a moderate speed at room temperature. A solution of 1N NaOH/MeOH (800 mL) was added dropwise to the reaction mixture via addition funnel. After 1 hour, agitation was stopped, and the suspension transferred to a filtration funnel and filtered to afford a white solid. This solid was then taken up in water (1200 mL) and the pH adjusted to 1.5–2 with addition of conc. HCl with stirring. After mixing for 1 hour, filtration and drying yielded the title compound as a white crystalline mass (127 g, 574 mmoles, 87.6%). TLC (silica F254, 3/1 v/v dichloromethane/MeOH, detection 254 nm) showed one spot and HPLC confirmed that. MP 110.9–112.6° C.; IR (KBr) 3405, 2973, 1688, 1548, 1300, 757 cm−1; 1H NMR (300 MHz, CDCl3): δ (ppm): 9.37 (br, 1H), 7.91 (dd, J=7.8 Hz, J′=1.8 Hz, 1H), 7.44 (dd, J=7.8 Hz, J′=1.8 Hz, 1H), 7.25 (m, 2H), 1.46 (s, 9H); 13C (300 MHz, CDCl3): δ (ppm): 160.87, 155.24, 141.18, 133.19, 126.92, 126.69, 126.63, 124.24, 34.21, 30.49. the suspension transferred to a filtration funnel filtered to afford a white solid with stirring After mixing for 1 hour filtration drying

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

Procedure: A 3-L, 3-necked round-bottomed flask, equipped with a mechanic stirrer and a thermal probe (under nitrogen) was charged with Methyl 2-(2-tert-Butylphenylamino)-2-oxoacetate (154 g, 655 mmoles) and MeOH (1000 mL). The resulting mixture was stirred at a moderate speed at room temperature. A solution of 1N NaOH/MeOH (800 mL) was added dropwise to the reaction mixture via addition funnel. After 1 hour, agitation was stopped, and the suspension transferred to a filtration funnel and filtered to afford a white solid. This solid was then taken up in water (1200 mL) and the pH adjusted to 1.5–2 with addition of conc. HCl with stirring. After mixing for 1 hour, filtration and drying yielded the title compound as a white crystalline mass (127 g, 574 mmoles, 87.6%). TLC (silica F254, 3/1 v/v dichloromethane/MeOH, detection 254 nm) showed one spot and HPLC confirmed that. MP 110.9–112.6° C.; IR (KBr) 3405, 2973, 1688, 1548, 1300, 757 cm−1; 1H NMR (300 MHz, CDCl3): δ (ppm): 9.37 (br, 1H), 7.91 (dd, J=7.8 Hz, J′=1.8 Hz, 1H), 7.44 (dd, J=7.8 Hz, J′=1.8 Hz, 1H), 7.25 (m, 2H), 1.46 (s, 9H); 13C (300 MHz, CDCl3): δ (ppm): 160.87, 155.24, 141.18, 133.19, 126.92, 126.69, 126.63, 124.24, 34.21, 30.49. the suspension transferred to a filtration funnel filtered to afford a white solid with stirring After mixing for 1 hour filtration drying

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 3-L, 3-necked round-bottomed flask, equipped with a mechanic stirrer and a thermal probe (under nitrogen) was charged with 2-tert-Butylaniline (109 g, 114 mL, 732 mmoles), triethylamine (81.4 g, 112 mL, 804 mmoles, 1.1 equiv.) and toluene (600 mL). The resulting mixture was stirred at a moderate speed at −30° C. An additon funnel was charged with Methyl chlorooxoacetate (100 g, 816 mmoles, 1.11 equiv.) with toluene (200 mL), and the mixture added to the reaction mixture at such a rate that the internal batch temperature is less than −20° C. After addition, the reaction was warmed to room temperature for an hour, quenched with water, then partitioned between EtOAc/water. The aqueous phase was extracted with EtOAc (200 mL), and the combined organic layers were washed successively with KHSO4 (200 mL), NaHCO3 (sat'd) (200 mL) and brine (200 mL), then dried the organic over MgSO4. The organic phase was concentrated by rotary evaporation, yielding the title compound as a pale yellow solid [Methyl 2-(2-tert-Butylphenylamino)-2-oxoacetate, 160 g, 93.1%]. MP 61.7–63.6° C. IR (KBr) 3409, 2954, 1736, 1724, 1530, 1299, 1166, 766 cm−1; 1H NMR (300 MHz, CDCl3): δ(ppm): 9.20 (br, 1H), 7.97 (dd, J=7.8 Hz, J′=1.8 Hz, 1H), 7.43 (dd, J=7.8 Hz, J′=1.8 Hz, 1H), 7.31–7.16 (m, 2H), 4.00 (s, 3H), 1.47(s, 9H). The product thus obtained can be used directly for the subsequent reaction. the mixture added to the reaction mixture at such a rate that the internal batch temperature is less than −20° C After addition the reaction was warmed to room temperature for an hour quenched with water partitioned between EtOAc/water The aqueous phase was extracted with EtOAc (200 mL) the combined organic layers were washed successively with KHSO4 (200 mL), NaHCO3 (sat'd) (200 mL) and brine (200 mL) dried the organic over MgSO4 The organic phase was concentrated by rotary evaporation