4-Methylmorpholine → N-hydroxy-2-[(1-methyl-1H-pyrrol-2-yl)carbonyl]isoindoline-5-carboxamide

To a mixture of N-methylpyrrole-2-carboxylic acid (25.7 mg, 0.21 mmol) and methyl 2,3-dihydro-1H-isoindole-5-carboxylate hydrochloride (40 mg, 0.19 mmol) in DCM was added HATU (78.2 mg, 0.21 mmol) and N-methylmorpholine (0.1 mL, 0.91 mmol). The heterogenous mixture was stirred overnight at room temperature during which time the mixture became a homogenous solution. The reaction solution was washed with saturated aqueous NaHCO3 (2 mL) and the layers separated. The aqueous layer was washed with additional methylene chloride (3 mL) and the combined organic layers were concentrated. The residue obtained was dissolved in methanol (3 mL), and to the solution was added hydroxylamine hydrochloride (39 mg, 0.56 mmol) and potassium hydroxide (0.1 g, 1.8 mmol). The resulting mixture was heated to 80° C. for 30 minutes. Upon cooling to room temperature, the solvent was removed in vacuo. The residue was dissolved in DMSO (1 mL), the insolubles removed via filtration and purified by reverse phase prep-HPLC to afford the title compound as a white solid (27.1 mg, 50%). LCMS: (FA) ES+ 286; 1H NMR (d6-DMSO, 400 MHz) δ 7.80-7.71 (m, 1H), 7.84 (s, 1H), 7.62 (d, J=7.7 Hz, 1H), 7.43 (br d, J=10.2 Hz, 1H), 6.95 (t, J=2.1 Hz, 1H), 6.76 (dd, J=3.8, 1.6 Hz, 1H), 6.10 (dd, J=3.8, 2.5 Hz, 1H), 5.05 (br s, 2H), 4.87 (br s, 2H), 3.77 (s, 3H).

1. washThe reaction solution was washed with saturated aqueous NaHCO3 (2 mL)
2. customthe layers separated
3. washThe aqueous layer was washed with additional methylene chloride (3 mL)
4. concentrationthe combined organic layers were concentrated
5. customThe residue obtained
6. temperatureThe resulting mixture was heated to 80° C. for 30 minutes
7. temperatureUpon cooling to room temperature
8. customthe solvent was removed in vacuo
9. dissolutionThe residue was dissolved in DMSO (1 mL)
10. customthe insolubles removed via filtration
11. custompurified by reverse phase prep-HPLC

ORD record

ord-0d76d612818c4e4fb28d7b49340aa786

Source dataset

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09096518B2