In the chemical reaction process, reaction time, type of solvent, can easily affect the result of the reaction, thereby determining the yield and properties of the reaction product. An updated downstream synthesis route of 496-12-8 as follows. 496-12-8
A literature procedure1 was modified by replacing triethylamine with N,N-diisopropylethylamine. To a stirred mixture of tetrahydroisoindoline (0.11 mL, 1.0 mmol), N-Boc-(R)-phenylalanine (265 mg, 1.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (182 mg, 1.0 mmol) and anhydrous 1-hydroxybenzotriazole (203 mg, 1.5 mmol) in N,N-dimethylformamide (3.0 mL) was added N,N-diisopropylethylamine (1.3 mL, 7.5 mmol). The mixture was stirred at 20 for 16 h. The solvent was evaporated and the residue was dissolved in ethyl acetate (20 mL) and the solution was washed with water (2 x 20 mL). The combined aqueous fractions were re-extracted with ethyl acetate (2 x 20 mL) and all the combined organic layers were washed with saturated aqueous sodium hydrogen carbonate (2 x 20 mL) then with brine (20 mL) filtered and dried (MgSO4). Column chromatography (25:75 ethyl acetate: dichloromethane) of the residue gave 7c (175 mg, 48%) as a cream solid, m.p. 156-160 (decomp.); 1H NMR (500 MHz, CDCl3) delta 7.30-7.20 (7H, m), 7.16-7.14 (1H, m), 7.22-7.00 (1H, m), 5.36 (1H, d, J=9.0 Hz), 4.88 (1H, d, J=13.8 Hz), 4.82 (1H, d, J=15.9 Hz), 4.68-4.77 (1H, m), 4.63 (1H, d, J=15.9 Hz), 4.06 (1H, d, J=13.8 Hz), 3.10-2.98 (2H, m), 1.40 (9H, s); 13C NMR (125 MHz, CDCl3) delta 170.2, 155.1, 150.8, 136.5, 130.0, 129.3, 128.7, 127.1, 120.6, 116.7, 79.9, 51.0, 49.3, 49.1, 45.5, 41.9, 40.6, 28.4.
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Reference:
Article; Chan, A. W. Edith; Greenwood, Simon O. R.; Hansen, D. Flemming; Marson, Charles M.; Bioorganic and medicinal chemistry letters; (2020);,
Indoline – Wikipedia,
Indoline | C8H9N – PubChem