تفاعل #91686

معادلة التفاعل

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

المردود 57.0%

المذيبات

DMF

ظروف التفاعل

المعالجة

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

الإجراء التجريبي

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.

المصدر