反应详情

A 500 mL 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser. The reaction vessel was charged with (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine N-acetyl-L-leucine salt (25 g, 56 mmol, 98% ee), 3-acetamidophthalic anhydride (12.1 g 58.8 mmol), and glacial acetic acid (250 mL). The mixture was refluxed over night and then cooled to <50° C. After the solvent was removed in vacuum, the residue was dissolved in ethyl acetate. The resulting solution was washed with water (250 mL×2), saturated aqueous NaHCO3 (250 mL×2), and brine (250 mL×2), and then dried over anhydrous sodium sulfate. After the solvent was evaporated in vacuum, the residue was recrystallized from a binary solvent containing a mixture of ethanol (150 mL) and acetone (75 mL). The solid was isolated by vacuum filtration and washed with ethanol (100 mL×2). The product was dried in vacuum at 60° C. to a constant weight, affording 19.4 g (75% yield) of (S)-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-inoisoindoline-1,3-dione with 98% ee. Chiral HPLC (15/85 EtOH/20 mM KH2PO4 @pH 0.5, Ultron Chiral ES-OVS from Agilent Technology, 150 mm×4.6 mm, 0.4 mL/min., @240 nm): 25.4 min (S-isomer, 98.7%), 29.5 min (R-isomer, 1.2%). The product in CDCl3 was characterized by a 1H NMR spectrum showing the following chemical shifts (6 in ppm): 1.47 (t, 3H), 2.26 (s, 3H), 2.87 (s, 3H), 3.68-3.75 (dd, 1H), 3.85 (s, 3H), 4.07-4.15 (q, 2H), 4.51-4.61 (dd, 1H), 5.84-5.90 (dd, 1H), 6.82-8.77 (m, 6H), 9.46 (s, 1H). The product in DMSO-d6 was characterized by a 13C NMR spectrum showing the following chemical shifts (δ in ppm): 14.66, 24.92, 41.61, 48.53, 54.46, 55.91, 64.51, 111.44, 112.40, 115.10, 118.20, 120.28, 124.94, 129.22, 131.02, 136.09, 137.60, 148.62, 149.74, 167.46, 169.14, 169.48.

1. customA 500 mL 3-necked round bottom flask was equipped with a mechanical stirrer
2. temperatureThe mixture was refluxed over night
3. temperaturecooled to <50° C
4. customAfter the solvent was removed in vacuum
5. dissolutionthe residue was dissolved in ethyl acetate
6. washThe resulting solution was washed with water (250 mL×2), saturated aqueous NaHCO3 (250 mL×2), and brine (250 mL×2)
7. dry with materialdried over anhydrous sodium sulfate
8. customAfter the solvent was evaporated in vacuum
9. customthe residue was recrystallized from a binary solvent
10. additioncontaining
11. additiona mixture of ethanol (150 mL) and acetone (75 mL)
12. customThe solid was isolated by vacuum filtration
13. washwashed with ethanol (100 mL×2)
14. customThe product was dried in vacuum at 60° C. to a constant weight
15. customaffording 19.4 g (75% yield) of (S)-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-inoisoindoline-1,3-dione with 98% ee
16. custom25.4 min (S-isomer, 98.7%), 29.5 min (R-isomer, 1.2%)