Reference of 15799-79-8, These common heterocyclic compound, 15799-79-8, name is 3-Methoxy-N,N-dimethylaniline, its traditional synthetic route has been very mature, but the traditional synthetic route has various shortcomings, such as complicated route, low yield, poor purity, etc, below Introduce a new synthetic route.
[0134] (R)-4-Oxo-2-(4-dimethylamino-2-methoxyphenyl)-butyric acid methyl ester (Table 2, entries 11 & 12): To an amber 2-dram vial equipped with a magnetic stir bar was added (2S, 5S)-5-benzyl-2-tert-butyl-3-methylimidazolidin-4-one (6.13 mg, 0.0250 mmol, 0.100 equiv), 4-methyl ester (28.5 mg, 0.250 mmol, 1.00 equiv), CHCl3 (0.25 ml), HCl (as a 4N solution in 1,4-dioxane, 6.25 uL, 0.0250 mmol, 0.100 equiv), and 3-dimethylamino-anisole (44 uL, 0.30 mmol, 1.2 equiv). The solution was stirred for 5 min at ambient temperature and subjected directly to silica gel chromatography. Gradient elution with 20-40% EtOAc in hexanes afforded the product as a colorless oil in 73% yield (48.2 mg, 0.182 mmol); 91% ee. IR (film) 2950, 2903, 2838, 2727, 1730, 1616, 1569, 1519, 1462, 1440, 1356, 1242, 1171, 1114, 1033, 979.4, 814.6, 642.5 cm-1; 1H NMR (300 MHz, CDCl3) ?9.77 (t, J=1.1 Hz, 1H, CHO), 6.99 (d, J=8.2 Hz, 1H, ArH), 6.27 (dd, J=2.5, 8.5 Hz, 1H, ArH), 6.22 (d, J=2.5 Hz, 1H, ArH) 4.38 (dd, J=5.2, 9.1 Hz, 1H, ArCH), 3.81 (s, 3H, ArOCH3), 3.66 (s, 3H, CO2CH3), 3.52 (ddd, J=1.4, 9.1, 18.1 Hz, 1H, CH2CO), 2.94 (s, 6H, N(CH3)2), 2.67 (ddd, J=0.8, 4.9, 17.8 Hz, 1H CH2CO); 13C NMR (75 MHz, CDCl3) ?201.0, 174.4, 157.5, 151.5, 129.3, 114.6, 104.9, 96.2, 55.6, 52.5, 46.7, 40.9, 39.2. HRMS (CI) exact mass calcd for (C21H23NO3) requires m/z 266.1392 for [M+H]+, found m/z 266.1387. [?]D=-149.0 (c=1.0, CHCl3). [0135] The enantiomeric ratio of the product was determined by HPLC analysis of the corresponding alcohol (obtained by NaBH4 reduction in ethanol at 0o C.) using a Chiracel AD and AD guard column (6.0% ethanol/hexanes, 1 mL/min); S isomer tr=26.0 min, R isomer tr=27.8 min. The same reaction conducted at -20o C. on 0.5-mmol scale was complete after 8 h and purified in identical fashion to give the product in 90% yield (119 mg, 0.448 mmol) and 92% ee. EXAMPLE 8 [0104] (R)-4-Oxo-2-(4-dimethylamino-2-methoxyphenyl)-butyric acid methyl ester (Table 1, entry 6): To an amber 2-dram vial equipped with a magnetic stir bar was added (2S,5S)-5-benzyl-2-tert-butyl-3-methylimidazolidin-4-one (6.13 mg, 0.0250 mmol, 0.100 equiv), CHCl3 (0.25 ml), HCl (as a 4N solution in 1,4-dioxane, 6.25 uL, 0.0250 mmol, 0.100 equiv), and 3-dimethylamino-anisole (44 uL, 0.30 mmol, 1.2 equiv). The solution was cooled to -20o C. before oxobutenoic acid methyl ester (28.5 mg, 0.250 mmol, 1.00 equiv) was added. The resulting solution was maintained at -20o C. for 8 h and then subjected directly silica gel chromatography. Gradient elution with 20-40% EtOAc in hexanes afforded the product as a colorless oil in 73% yield (48.2 mg, 0.182 mmol); 91% ee. IR (film) 2950, 2903, 2838, 2727, 1730, 1616, 1569, 1519, 1462, 1440, 1356, 1242, 1171, 1114, 1033, 979.4, 814.6, 642.5 cm-1; 1H NMR (300 MHz, CDCl3) ?9.77 (t, J=1.1 Hz, 1H, CHO), 6.99 (d, J=8.2 Hz, 1H, ArH), 6.27 (dd, J=2.5, 8.5 Hz, 1H, ArH), 6.22 (d, J=2.5 Hz, 1H, ArH), 4.38 (dd, J=5.2, 9.1 Hz, 1H, ArCH), 3.81 (s, 3H, ArOCH3), 3.66 (s, 3H, CO2CH3), 3.52 (ddd, J=1.4, 9.1, 18.1 Hz, 1H, CH2CO), 2.94 (s, 6H, N(CH3)2), 2.67 (ddd, J=0.8, 4.9, 17.8 Hz, 1H, CH2CO); 13C NMR (75 MHz, CDCl3) ?201.0, 174.4, 157.5, 151.5, 129.3, 114.6, 104.9, 96.2, 55.6, 52.5, 46.7, 40.9, 39.2. HRMS (CI) exact mass calcd for (C21H23NO3) requires m/z 266.1392 for [M+H]+, found m/z 266.1387. [?]D=-149.0 (c=1.0, CHCl3). The enantiomeric ratio of the product was determined by HPLC analysis of the corresponding alcohol (obtained by NaBH4 reduction in ethanol at 0o C.) using a Chiracel AD and AD guard column (6.0% ethanol/hexanes, 1 mL/min); S isomer tr=26.0 min, R isomer tr=27.8 min.
The synthetic route of 15799-79-8 has been constantly updated, and we look forward to future research findings.
Reference:
Patent; MacMillan, David W.C.; Paras, Nick A.; US2003/236438; (2003); A1;,
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