Cyclopropanecarbonyl chloride → (S)-N-(2-(1-(3,4-dihydroxyphenyl)-2-(methylsulfonyl)ethyl)-3-oxoisoindolin-4-yl)cyclopropanecarboxamide

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Reaction Conditions

Reaction Steps

A mixture of (S)-7-amino-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl)isoindolin-1-one (5 g, 12.4 mmol) and neat TMSI (25 g, 125 mmol) was heated at 80° C. for 16 hours. The mixture was cooled to room temperature and quenched with 5% aq. sodium sulfite. Ethyl acetate was added and the layers were separated. The organic layer was washed with water, brine and then dried over Na2SO4. The organic layer was concentrated, followed by a solvent swap to THF. To the THF solution, was added cyclopropanecarbonyl chloride (1.2 mL, 13.2 mmol). The mixture was heated to 40° C. for 0.5 hour then cooled to room temperature. The mixture was quenched with 1 N aq. NaHCO3 then extracted with ethyl acetate. The organic was washed with 1 N aq. NaHCO3, water, then brine. The solvent was removed and the crude was suspended in ACN at 40° C. for 1 hour. The product was collected by filtration to give 1 g of crude, 19% yield. Further purification by prep-HPLC followed by treatment with 2 N aq. HCl gave (S)—N-(2-(1-(3,4-dihydroxyphenyl)-2-(methylsulfonyl)ethyl)-3-oxoisoindolin-4-yl)cyclopropanecarboxamide as a white solid (0.25 g, 5% yield). HPLC: HPLC: Hypersil DBS C8 column, 250×4.6 mm, 5 μm; 99/1 to 85/15 over 15 minutes Gradient CH3CN/10 mM aq. KH2PO4, 1.0 mL/min, 35° C., run time 20 minutes: tR 10.91 minutes. 1H-NMR (DMSO-d6): 10.51 (1H, s), 9.02-9.07 (2H, d), 8.22-8.25 (1H, d), 7.48-7.53 (1H, t), 7.18-7.20 (1H, d), 6.70-6.78 (3H, m), 5.77-5.81 (1H, m), 4.59-4.65 (1H, d), 3.86-4.26 (3H, m), 3.02 (3H, s), 1.76-1.83 (1H, m), 0.88-0.90 (4H, m). LC-MS ES+ (M+1) 431.

Provenance & Evidence