반응 #91686

반응 방정식

CH3CN

5-bromopicolinic acid

CDI

5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidin-3-yl]-isoindole-1,3-dione hydrochloride

→

5-bromo-N-[[2-[(3S)-3-methyl-2,6-dioxopiperidin-3-yl]-1,3-dioxoisoindolin-5-yl]methyl]picolinamide

수율 57.0%

용매

DMF

반응 조건

후처리

1. 1
   workup.STIRRINGthe mixture was stirred at this temperature for an additional 2 hours
2. 2
   온도The mixture was cooled to room temperature
3. 3
   기타the solvent was evaporated under vacuum
4. 4
   workup.DISSOLUTIONThe residue was dissolved in ethyl acetate (100 mL)
5. 5
   세척washed with saturated aqueous sodium bicarbonate solution (2×100 mL)
6. 6
   기타The organic phase was evaporated
7. 7
   기타The residue was chromatographed on silica gel
8. 8
   기타A pale red solid was obtained
9. 9
   기타this material was triturated in 10 mL of acetonitrile for 16 hours
10. 10
    여과The solid was filtered
11. 11
    세척washed with an additional 7 mL of acetonitrile
12. 12
    기타The product was dried under vacuum
13. 13
    기타providing 0.55 g (57% yield) as a white solid

실험 절차

A mixture of 5-bromopicolinic acid (0.40 g, 2.0 mmol) and CDI (0.36 g, 2.2 mmol) in DMF (20 mL) was stirred under nitrogen at 40° C. for 2 hours. Then, 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidin-3-yl]-isoindole-1,3-dione hydrochloride (0.67 g, 2.0 mmol) was added, and the mixture was stirred at this temperature for an additional 2 hours. The mixture was cooled to room temperature, and the solvent was evaporated under vacuum. The residue was dissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (2×100 mL). The organic phase was evaporated. The residue was chromatographed on silica gel using methylene chloride as the mobile phase. A pale red solid was obtained; this material was triturated in 10 mL of acetonitrile for 16 hours. The solid was filtered and washed with an additional 7 mL of acetonitrile. The product was dried under vacuum, providing 0.55 g (57% yield) as a white solid; mp 260-262° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 45/55 CH3CN/0.1% H3PO4, 3.61 (96.62%); 1H NMR (DMSO-d6) δ 1.88 (s, 3H), 2.00-2.08 (m, 1H), 2.49-2.62 (m, 2H), 2.65-2.73 (m, 1H), 4.62 (d, J=6.3 Hz, 2H), 7.76-7.82 (m, 3H), 7.97 (dd, J=8.4 Hz, J=0.6 Hz, 1H), 8.26 (dd, J=8.4 Hz, J=2.3 Hz, 1H), 8.81 (dd, J=2.3 Hz, J=0.6 Hz, 1H), 9.63 (t, J=6.3 Hz, 1H), 11.00 (s, 1H); 13C NMR (DMSO-d6) δ 21.0, 28.5, 29.1, 42.4, 58.7, 121.8, 123.1, 123.5, 123.9, 129.6, 131.3, 133.6, 140.5, 147.1, 148.5, 149.3, 163.5, 167.7, 167.8, 172.0, 172.1; Anal. Calcd for C21H17BrN4O5: C, 51.97; H, 3.53; N, 11.55. Found: C, 52.05; H, 3.44; N, 11.39.

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