* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Synthesis, 1998, # 8, p. 1176 - 1180
2
[ 56619-93-3 ]
[ 1611-78-5 ]
[ 6931-19-7 ]
Reference：
[1] Journal of Organic Chemistry, 1991, vol. 56, # 26, p. 7288 - 7291
3
[ 56619-93-3 ]
[ 927-63-9 ]
[ 6931-19-7 ]
Reference：
[1] Journal of Organic Chemistry, 1991, vol. 56, # 26, p. 7288 - 7291
4
[ 56619-93-3 ]
[ 112970-44-2 ]
Reference：
[1] Journal of the American Chemical Society, 2004, vol. 126, # 4, p. 1150 - 1160
5
[ 3282-30-2 ]
[ 536-90-3 ]
[ 56619-93-3 ]
Yield
Reaction Conditions
Operation in experiment
99.5%
With sodium carbonate monohydrate In water; ethyl acetate at 0℃; for 1 h; Inert atmosphere
Synthesis of N-(3-methoxyphenyl)pivalamide (1a) Under the argon atmosphere, pivaloyl chloride (25.0 mL, 205 mmol, commercial product) was slowly dropped at 0°C into a mixed solution including m-anisidine (21.9 mL, 195 mmol, commercial product), ethyl acetate (EtOAc) (300 mL) of sodium carbonate monohydrate (62.0 g, 500 mmol, commercial product), and purified water (860 mL). After the mixture was stirred at 0°C for 1 hour, the organic layer was separated and the aqueous layer was extracted with ethyl acetate (EtOAc). The combined organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was recrystallized with ethyl acetate (EtOAc), and thus N-(3-methoxyphenyl)pivalamide (compound 1a) (40.2 g, 194 mmol, 99.5percent) was obtained as a colorless solid. TLC Rf = 0.50 (n-hexane/EtOAc = 6/1)
99.5%
With sodium carbonate monohydrate In water; ethyl acetate at 0℃; for 1 h; Inert atmosphere
Synthesis of N-(3-methoxyphenyl)pivalamide (1a) Under the argon atmosphere, pivaloyl chloride (25.0 mL, 205 mmol, commercial product) was slowly dropped at 0° C. into a mixed solution including m-anisidine (21.9 mL, 195 mmol, commercial product), ethyl acetate (EtOAc) (300 mL) of sodium carbonate monohydrate (62.0 g, 500 mmol, commercial product), and purified water (860 mL). After the mixture was stirred at 0° C. for 1 hour, the organic layer was separated and the aqueous layer was extracted with ethyl acetate (EtOAc). The combined organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was recrystallized with ethyl acetate (EtOAc), and thus N-(3-methoxyphenyl)pivalamide (compound 1a) (40.2 g, 194 mmol, 99.5percent) was obtained as a colorless solid. TLC Rf=0.50 (n-hexane/EtOAc=6/1)
97%
With triethylamine In dichloromethane at 0 - 22℃; for 14 h;
Triethylamine (5. 0 mL, 35.6 mmol) was added to a flask containing the amine H1 (2.0 mL, 17.8 MMOL) and dichloromethane (100 mL) under an atmosphere of nitrogen. The contents were cooled in an ice bath and trimethylacetylchloride (3.3 mL, 26.7 MMOL) was added dropwise. The reaction was allowed to warm slowly to R. T. and stirred for 14 h. at this temperature. The reaction was quenched with NAHC03SATURATED SOLUTION and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated followed by flash column chromatography (4: 1 to 1: 1 hexane: EtOAc) to yield the desired product H2 as an off-white solid (3.7 g, 97 percent yield).
94%
at 0℃; for 12 h;
To a solution of m-Anisidine (123.2 g, 1 mol), pyridine (161.1 mL, 2 mol) and 4-dimethylaminopyridine (1.2 g, 10 mmol) in dry CH2Cl2 (300 mL) was added pivaloyl chloride (135.4 mL, 1.1 mol) dropwise at 0 °C. The resulting mixture was stirred for 12 hours at that temperature, and poured into ice-cooled 1 M HCl. The organic layer was separated and the aqueous phase was extractedwith CH2Cl2. The combined organic extracts were washed with 1 M HCl and brine, and dried over Na2SO4. The solvents wereremoved under reduced pressure, pure white 3-Methoxy-N-pivaloylaniline was obtained after crystallization from hexanes. Colorless solid 194 g, mp 132-133 °C (Lit1: 132-133 °C), 94percent yield. 1H NMR (300 MHz, CDCl3): δ = 7.39 (s, 1H), 7.32 (bs, 1H), 7.20(t, J = 8.1 Hz, 1H), 6.94 (t, J = 8.1 Hz, 1H), 6.66 (dd, J = 1.5, 8.1 Hz, 1H), 3.80 (s, 3H), 1.31 (s, 9H); LRMS (ESI) for [C12H17NO2 + H]+ :208.1; for [C12H17NO2 + Na]+: 230.1.
Reference：
[1] Journal of the American Chemical Society, 2004, vol. 126, # 4, p. 1150 - 1160
[2] Patent: EP2881397, 2015, A1, . Location in patent: Paragraph 0053; 0054; 0055
[3] Patent: US2016/303089, 2016, A1, . Location in patent: Paragraph 0161; 0162; 0163; 0164
[4] Patent: WO2004/103996, 2004, A1, . Location in patent: Page 51
[5] Synlett, 2011, # 7, p. 1018 - 1022
[6] Journal of Heterocyclic Chemistry, 1980, vol. 17, # 9, p. 1333 - 1335
[7] Synthesis (Germany), 2017, vol. 49, # 1, p. 181 - 187
[8] Angewandte Chemie - International Edition, 2008, vol. 47, # 5, p. 888 - 890
[9] Synthesis (Germany), 2014, vol. 46, # 13, p. 1773 - 1778
[10] Journal of Organic Chemistry, 1988, vol. 53, # 12, p. 2844 - 2847
[11] Journal of Organic Chemistry, 2018, vol. 83, # 8, p. 4812 - 4823
[12] European Journal of Medicinal Chemistry, 2010, vol. 45, # 7, p. 2726 - 2732
[13] Journal of Fluorine Chemistry, 2010, vol. 131, # 7, p. 800 - 804
[14] Journal of the American Chemical Society, 2010, vol. 132, # 37, p. 12862 - 12864
[15] Tetrahedron Letters, 2011, vol. 52, # 36, p. 4681 - 4685
[16] Chemical Communications, 2014, vol. 50, # 94, p. 14862 - 14865
[17] Angewandte Chemie - International Edition, 2015, vol. 54, # 49, p. 14866 - 14870[18] Angew. Chem., 2015, vol. 127, # 49, p. 15079 - 15083,5
[19] Patent: WO2016/34512, 2016, A1, . Location in patent: Page/Page column 72
[20] Green Chemistry, 2017, vol. 19, # 9, p. 2111 - 2117
[21] Organic Letters, 2018, vol. 20, # 3, p. 676 - 679
[22] Angewandte Chemie - International Edition, 2018, vol. 57, # 29, p. 9108 - 9112[23] Angew. Chem., 2018, vol. 130, p. 9246 - 9250,5
6
[ 75151-82-5 ]
[ 74-88-4 ]
[ 56619-93-3 ]
Yield
Reaction Conditions
Operation in experiment
91%
With potassium carbonate In acetone for 3 h; Heating / reflux
Synthesis of N-(3-methoxyphenyl)pivalamide Into a 1000 mL round-bottom flask, was placed a solution of N-(3-hydroxyphenyl)pivalamide (13.4 g, 69.43 mmol, 1.00 equiv) in acetone (500 mL). To this was added K2CO3 (28.5 g, 206.52 mmol, 3.00 equiv). To the mixture was added MeI (39.4 g, 277.46 mmol, 4.00 equiv). The resulting solution was allowed to react, with stirring, for 3 h while the temperature was maintained at reflux in a bath of oil. The reaction progress was monitored by TLC (EtOAc/PE=1:2). A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. The resulting mixture was washed with hexane. A filtration was performed. This resulted in 13.9 g (91percent) of N-(3-methoxyphenyl)pivalamide as a white solid.
91%
With potassium carbonate In acetone for 3 h; Heating / reflux
Methyl iodide (277 mmol) was added to a suspension of N-(3-hydroxyphenyl)pivalamide (69.4 mmol) and potassium carbonate (207 mmol) in acetone (500 mL) and the reaction mixture was heated at reflux for 3 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was extracted with hexane (3 x 300 mL) and the combined extracts were concentrated to provide N-(3-methoxyphenyl)pivalamide in 91percent yield as a white solid.
91%
With potassium carbonate In acetone for 3 h; Heating / reflux
Synthesis of N-(3-methoxyphenyl)pivalamide Into a 1000 mL round-bottom flask, was placed a solution of N-(3-hydroxyphenyl)pivalamide (13.4 g, 69.43 mmol, 1.00 equiv) in acetone (500 mL). To this was added K2CO3 (28.5 g, 206.52 mmol, 3.00 equiv). To the mixture was added MeI (39.4 g, 277.46 mmol, 4.00 equiv). The resulting solution was allowed to react, with stirring, for 3 h while the temperature was maintained at reflux in a bath of oil. The reaction progress was monitored by TLC (EtOAc/PE=1.2). A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. The resulting mixture was washed with hexane. A filtration was performed. This resulted in 13.9 g (91percent) of N-(3-methoxyphenyl)pivalamide as a white solid.
91%
With potassium carbonate In acetone for 3 h; Reflux
2. Synthesis of N-(3-methoxyphenyl)pivalamide; Methyl iodide (277 mmol) was added to a suspension of N-(3-hydroxyphenyl)pivalamide (69.4 mmol) and potassium carbonate (207 mmol) in acetone (500 mL) and the reaction mixture was heated at reflux for 3 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was extracted with hexane (3.x.300 mL) and the combined extracts were concentrated to provide N-(3-methoxyphenyl)pivalamide in 91percent yield as a white solid.
91%
With potassium carbonate In acetone for 3 h; Reflux
2. Synthesis of 7V-(3-methoxyphenyl)pivalamide.Methyl iodide (277 mmol) was added to a suspension of 7V-(3 -hydro xyphenyl)pivalamide (69.4 mmol) and potassium carbonate (207 mmol) in acetone (500 mL) and the reaction mixture was heated at reflux for 3 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was extracted with hexane (3 x 300 mL) and the combined extracts were concentrated to provide 7V-(3-methoxyphenyl)pivalamide in 91percent yield as a white solid.
91%
With potassium carbonate In acetone for 3 h; Reflux
Methyl iodide (277 mmol) was added to a suspension of N-(3-hydroxyphenyl)pivalamide (69.4 mmol) and potassium carbonate (207 mmol) in acetone (500 mL) and the reaction mixture was heated at reflux for 3 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was extracted with hexane (3.x.300 mL) and the combined extracts were concentrated to provide N-(3-methoxyphenyl)pivalamide in 91percent yield as a white solid
91%
With potassium carbonate In acetone for 3 h; Reflux
2. Synthesis of 7V-(3-methoxyphenyl)pivalamide. Methyl iodide (277 mmol) was added to a suspension of 7V-(3-hydroxyphenyl)pivalamide(69.4 mmol) and potassium carbonate (207 mmol) in acetone (500 mL) and the reaction mixture was heated at reflux for 3 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was extracted with hexane (3 x 300 mL) and the combined extracts were concentrated to provide N-(3-methoxyphenyl)pivalamide in 91percent yield as a white solid. 3. Synthesis of iV-(2-(2-hvdroxyethv0-3-methoxyphenyl)pivalamide.
91%
With potassium carbonate In acetone for 3 h; Reflux
Methyl iodide (277 mmol) was added to a suspension of N-(3-hydroxyphenyl)pivalamide (69.4 mmol) and potassium carbonate (207 mmol) in acetone (500 mL) and the reaction mixture was heated at reflux for 3 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was extracted with hexane (3*300 mL) and the combined extracts were concentrated to provide N-(3-methoxyphenyl)pivalamide in 91percent yield as a white solid.
Synthesis of N-[2-(2-hydroxyethyl)-3-methoxyphenyl]pivalamide (1b) Under the argon atmosphere, n-butyllithium (nBuLi) (2.6 M in THF, 111 mL, 289 mmol, commercial product) was slowly dropped at 0C into a tetrahydrofuran (THF) (400 mL, dehydrated, commercial product) solution of the compound 1a (30.0 g, 145 mmol). After the mixture was stirred at 0C for 2 hours, ethylene oxide (1.3 M ether solution, 175 mL, 228 mmol, commercial product) was slowly added to the mixture and stirred at 0C for 1 hour. The temperature was raised to room temperature, and then the mixture was further stirred for 2 hours. The mixture was concentrated under reduced pressure, to which a saturated ammonium chloride aqueous solution (sat. NH4Cl aq.) was added. Subsequently, the mixture was extracted with ethyl acetate (EtOAc) (100 mL * 4). The combined organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was recrystallized with ethyl acetate (EtOAc), and thus N-[2-(2-hydroxyethyl)-3-methoxyphenyl]pivalamide (compound 1b) (28.1 g, 112 mmol, 77.1%) was obtained as a colorless solid. TLC Rf= 0.40 (n-hexane/EtOAc = 3/1)
77.1%
Synthesis of N-[2-(2-hydroxyethyl)-3-methoxyphenyl]pivalamide (1b) Under the argon atmosphere, n-butyllithium (nBuLi) (2.6 M in THF, 111 mL, 289 mmol, commercial product) was slowly dropped at 0 C. into a tetrahydrofuran (THF) (400 mL, dehydrated, commercial product) solution of the compound 1a (30.0 g, 145 mmol). After the mixture was stirred at 0 C. for 2 hours, ethylene oxide (1.3 M ether solution, 175 mL, 228 mmol, commercial product) was slowly added to the mixture and stirred at 0 C. for 1 hour. The temperature was raised to room temperature, and then the mixture was further stirred for 2 hours. The mixture was concentrated under reduced pressure, to which a saturated ammonium chloride aqueous solution (sat. NH4Cl aq.) was added. Subsequently, the mixture was extracted with ethyl acetate (EtOAc) (100 mL*4). The combined organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was recrystallized with ethyl acetate (EtOAc), and thus N-[2-(2-hydroxyethyl)-3-methoxyphenyl]pivalamide (compound 1b) (28.1 g, 112 mmol, 77.1%) was obtained as a colorless solid. TLC Rf=0.40 (n-hexane/EtOAc=3/1)
53%
Synthesis of N-(2-(2-hydroxyethyl)-3-methoxyphenylpivalamide Into a 250 mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of <strong>[56619-93-3]N-(3-methoxyphenyl)pivalamide</strong> (11.8 g, 57.00 mmol, 1.00 equiv) in THF (200 mL). To the above was added n-BuLi (60 mL) dropwise with stirring while the temperature was maintained at 0 C. in a bath of H2O/ice. The resulting solution was allowed to react, with stirring, for 2 h. To the above was added oxirane (7 mL, 1.50 equiv) dropwise with stirring while the temperature was maintained at 0 C. in a bath of H2O/ice. The resulting solution was allowed to react, with stirring, for 1 h while the temperature was maintained at 0 C. in a bath of H2O/ice. The resulting solution was allowed to react for 2 h while the temperature was maintained at room temperature. The reaction mixture was then quenched by the adding H2O. The mixture was concentrated by evaporation under vacuum using a rotary evaporator. The resulting solution was extracted with EtOAc and the organic layers combined. The organic phase was washed with Na2CO3. The mixture was dried over Na2SO4 and concentrated by evaporation under vacuum using a rotary evaporator. The final product was purified by recrystallization from DCM/hexane. This resulted in 10.5 g (53%) of N-(2-(2-hydroxyethyl)-3-methoxyphenyl)pivalamide as a white solid.
53%
A solution of n-butyllithium in hexane (60 mL) was added dropwise to a solution of N-(3- methoxyphenyl)pivalamide (57.0 mmol) in tetrahydrofuran (200 mL) at 0 C and was maintained for 2 h. Oxirane (86 mmol) was added dropwise and the reaction mixture was maintained for 1 h at 0 C and for an additional 2 h at rt. The reaction mixture was concentrated and the residue was diluted with water (100 mL) and extracted with ethyl acetate (3 x 75 mL). The combined organic layers were washed with saturated aqueous sodium carbonate, dried (sodium sulfate), and concentrated. The final product was purified by recrystallization (dichloromethane/cyclohexane) to provide N-(2-(2-hydroxyethyl)-3- methoxyphenyl)pivalamide in 53% yield as a white solid.
53%
Synthesis of N-(2-(2-hydroxyethyl)-3-methoxyphenyl)pivalamide Into a 250 mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of <strong>[56619-93-3]N-(3-methoxyphenyl)pivalamide</strong> (11.8 g, 57.00 mmol, 1.00 equiv) in THE (200 mL). To the above was added n-BuLi (60 mL) dropwise with stirring while the temperature was maintained at 0 C. in a bath of H2O/ice. The resulting solution was allowed to react with stirring, for 2 h. To the above was added oxirane (7 mL, 1.50 equiv) dropwise with stirring while the temperature was maintained at 0 C. in a bath of H2O/ice. The resulting solution was allowed to react with stirring, for 1 h while the temperature was maintained at 0 C. in a bath of H2O/ice. The resulting solution was allowed to react for 2 h while the temperature was maintained at room temperature. The reaction mixture was then quenched by the adding H2O. The mixture was concentrated by evaporation under vacuum using a rotary evaporator. The resulting solution was extracted with EtOAc and the organic layers combined. The organic phase was washed with Na2CO3. The mixture was dried over Na2SO4 and concentrated by evaporation under vacuum using a rotary evaporator. The final product was purified by recrystallization from DCM/hexane. This resulted in 10.5 g (53%) of N-(2-(2-hydroxyethyl)-3-methoxyphenyl)pivalamide as a white solid.
53%
3. Synthesis of N-(2-(2-hydroxyethyl)-3-methoxyphenyl)pivalamide; A solution of n-butyllithium in hexane (60 mL) was added dropwise to a solution of <strong>[56619-93-3]N-(3-methoxyphenyl)pivalamide</strong> (57.0 mmol) in tetrahydrofuran (200 mL) at 0 C. and was maintained for 2 h. Oxirane (86 mmol) was added dropwise and the reaction mixture was maintained for 1 h at 0 C. and for an additional 2 h at rt. The reaction mixture was concentrated and the residue was diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined organic layers were washed with saturated aqueous sodium carbonate, dried (sodium sulfate), and concentrated. The final product was purified by recrystallization (dichloromethane/cyclohexane) to provide N-(2-(2-hydroxyethyl)-3-methoxyphenyl)pivalamide in 53% yield as a white solid.
53%
3. Synthesis of A/-(2-(2-hydroxyethyl)-3-methoxyphenyl)pivalamide.A solution of r°-butyllithium in hexane (60 mL) was added dropwise to a solution of N-(3- methoxyphenyl)pivalamide (57.0 mmol) in tetrahydrofuran (200 mL) at 0 0C and was maintained for 2 h. Oxirane (86 mmol) was added dropwise and the reaction mixture was maintained for 1 h at 0 0C and for an additional 2 h at rt. The reaction mixture was concentrated and the residue was diluted with water (100 mL) and extracted with ethyl acetate (3 x 75 mL). The combined organic layers were washed with saturated aqueous sodium carbonate, dried (sodium sulfate), and concentrated. The final product was purified by recrystallization(dichloromethane/cyclohexane) to provide N-(2-(2-hydroxyethyl)-3-methoxyphenyl)pivalamide in 53% yield as a white solid.
53%
With (2-methylpropyl)lithium; In tetrahydrofuran; hexane; at 0 - 20℃;
A solution of i-butyllithium in hexane (60 mL) was added dropwise to a solution of <strong>[56619-93-3]N-(3-methoxyphenyl)pivalamide</strong> (57.0 mmol) in tetrahydrofuran (200 mL) at 0 C. and was maintained for 2 h. Oxirane (86 mmol) was added dropwise and the reaction mixture was maintained for 1 h at 0 C. and for an additional 2 h at rt. The reaction mixture was concentrated and the residue was diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined organic layers were washed with saturated aqueous sodium carbonate, dried (sodium sulfate), and concentrated. The final product was purified by recrystallization (dichloromethane/cyclohexane) to provide N-(2-(2-hydroxyethyl)-3-methoxyphenyl)pivalamide in 53% yield as a white solid.
53%
3. Synthesis of iV-(2-(2-hvdroxyethv0-3-methoxyphenyl)pivalamide.A solution of w-butyllithium in hexane (60 mL) was added dropwise to a solution of N-(3- methoxyphenyl)pivalamide (57.0 mmol) in tetrahydrofuran (200 mL) at 0 0C and was maintained for 2 h. Oxirane (86 mmol) was added dropwise and the reaction mixture was maintained for 1 h at 0 0C and for an additional 2 h at rt. The reaction mixture was concentrated and the residue was diluted with water (100 mL) and extracted with ethyl acetate (3 x 75 mL). The combined organic layers were washed with saturated aqueous sodium carbonate, dried (sodium sulfate), and concentrated. The final product was purified by recrystallization(dichloromethane/cyclohexane) to provide N-(2-(2-hydroxyethyl)-3-methoxyphenyl)pivalamide in 53% yield as a white solid.
53%
A solution of n-butyllithium in hexane (60 mL) was added dropwise to a solution of <strong>[56619-93-3]N-(3-methoxyphenyl)pivalamide</strong> (57.0 mmol) in tetrahydrofuran (200 mL) at 0 C. and was maintained for 2 h. Oxirane (86 mmol) was added dropwise and the reaction mixture was maintained for 1 h at 0 C. and for an additional 2 h at rt. The reaction mixture was concentrated and the residue was diluted with water (100 mL) and extracted with ethyl acetate (3*75 mL). The combined organic layers were washed with saturated aqueous sodium carbonate, dried (sodium sulfate), and concentrated. The final product was purified by recrystallization (dichloromethane/cyclohexane) to provide N-(2-(2-hydroxyethyl)-3-methoxyphenyl)pivalamide in 53% yield as a white solid.
With sodium carbonate monohydrate; In water; ethyl acetate; at 0℃; for 1h;Inert atmosphere;
Synthesis of N-(3-methoxyphenyl)pivalamide (1a) Under the argon atmosphere, pivaloyl chloride (25.0 mL, 205 mmol, commercial product) was slowly dropped at 0C into a mixed solution including m-anisidine (21.9 mL, 195 mmol, commercial product), ethyl acetate (EtOAc) (300 mL) of sodium carbonate monohydrate (62.0 g, 500 mmol, commercial product), and purified water (860 mL). After the mixture was stirred at 0C for 1 hour, the organic layer was separated and the aqueous layer was extracted with ethyl acetate (EtOAc). The combined organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was recrystallized with ethyl acetate (EtOAc), and thus N-(3-methoxyphenyl)pivalamide (compound 1a) (40.2 g, 194 mmol, 99.5%) was obtained as a colorless solid. TLC Rf = 0.50 (n-hexane/EtOAc = 6/1)
99.5%
With sodium carbonate monohydrate; In water; ethyl acetate; at 0℃; for 1h;Inert atmosphere;
Synthesis of N-(3-methoxyphenyl)pivalamide (1a) Under the argon atmosphere, pivaloyl chloride (25.0 mL, 205 mmol, commercial product) was slowly dropped at 0 C. into a mixed solution including m-anisidine (21.9 mL, 195 mmol, commercial product), ethyl acetate (EtOAc) (300 mL) of sodium carbonate monohydrate (62.0 g, 500 mmol, commercial product), and purified water (860 mL). After the mixture was stirred at 0 C. for 1 hour, the organic layer was separated and the aqueous layer was extracted with ethyl acetate (EtOAc). The combined organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was recrystallized with ethyl acetate (EtOAc), and thus N-(3-methoxyphenyl)pivalamide (compound 1a) (40.2 g, 194 mmol, 99.5%) was obtained as a colorless solid. TLC Rf=0.50 (n-hexane/EtOAc=6/1)
97%
With triethylamine; In dichloromethane; at 0 - 22℃; for 14h;
Triethylamine (5. 0 mL, 35.6 mmol) was added to a flask containing the amine H1 (2.0 mL, 17.8 MMOL) and dichloromethane (100 mL) under an atmosphere of nitrogen. The contents were cooled in an ice bath and trimethylacetylchloride (3.3 mL, 26.7 MMOL) was added dropwise. The reaction was allowed to warm slowly to R. T. and stirred for 14 h. at this temperature. The reaction was quenched with NAHC03SATURATED SOLUTION and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated followed by flash column chromatography (4: 1 to 1: 1 hexane: EtOAc) to yield the desired product H2 as an off-white solid (3.7 g, 97 % yield).
94%
With dmap; at 0℃; for 12h;
To a solution of m-Anisidine (123.2 g, 1 mol), pyridine (161.1 mL, 2 mol) and 4-dimethylaminopyridine (1.2 g, 10 mmol) in dry CH2Cl2 (300 mL) was added pivaloyl chloride (135.4 mL, 1.1 mol) dropwise at 0 C. The resulting mixture was stirred for 12 hours at that temperature, and poured into ice-cooled 1 M HCl. The organic layer was separated and the aqueous phase was extractedwith CH2Cl2. The combined organic extracts were washed with 1 M HCl and brine, and dried over Na2SO4. The solvents wereremoved under reduced pressure, pure white 3-Methoxy-N-pivaloylaniline was obtained after crystallization from hexanes. Colorless solid 194 g, mp 132-133 C (Lit1: 132-133 C), 94% yield. 1H NMR (300 MHz, CDCl3): delta = 7.39 (s, 1H), 7.32 (bs, 1H), 7.20(t, J = 8.1 Hz, 1H), 6.94 (t, J = 8.1 Hz, 1H), 6.66 (dd, J = 1.5, 8.1 Hz, 1H), 3.80 (s, 3H), 1.31 (s, 9H); LRMS (ESI) for [C12H17NO2 + H]+ :208.1; for [C12H17NO2 + Na]+: 230.1.
With sodium carbonate; In dichloromethane; at 20 - 25℃; for 4.5h;Inert atmosphere;
To a stirred suspension of 3-methoxyaniline (1.4 mL, 12.2 mmol), saturated sodium carbonate solution (15 mL) and DCM (15 mL) was added pivaloyl chloride (1.5 mL, 12.3 mmol) dropwise over 0.5 h at a rate such that the temperature was maintained below 25 oC. After stirred at room temperature for 4 h, the mixture was diluted further with water and DCM. The organic phase was separated and the aqueous layer was extracted with DCM. The combined organic extracts were dried over anhydrous Na2SO4. Concentration under reduced pressure and purification by recrystallization afforded the product 1j.1H NMR (400 MHz, CDCl3): 7.39 (t, J = 1.6 Hz, 1H), 7.34 (brs, 1H), 7.20 (t, J = 8.4 Hz, 1H), 6.94 (dd, J = 8.0, 1.2 Hz, 1H), 6.66 (dd, J = 8.4, 1.6 Hz, 1H), 3.80 (s, 3H), 1.32 (s, 9H).
Acetic acid (R)-1-((10S,13S)-5-hexyl-10-isopropyl-9-methyl-11-oxo-3-oxa-9,12-diaza-tricyclo[6.6.1.04,15]pentadeca-1,4(15),5,7-tetraen-13-yl)-ethyl ester[ No CAS ]
(4S,5S)-4-[4-((S)-1-Carboxy-2-methyl-propylamino)-7-hexyl-benzofuran-3-ylmethyl]-2,2,5-trimethyl-oxazolidine-3-carboxylic acid tert-butyl ester[ No CAS ]
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