Acetonitrile → 5-Bromo-N-[[2-[(3S)-3-methyl-2,6-dioxopiperidin-3-YL]-1,3-dioxoisoindolin-5-YL]methyl]picolinamide

HRID 63408

Reaktionsgleichung

Reaktionsgleichung von HRID 63408
[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:24][CH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[C:31](=[O:35])[N:30]([C@@:36]1([CH3:44])[CH2:41][CH2:40][C:39](=[O:42])[NH:38][C:37]1=[O:43])[C:29]2=[O:45].CC#N>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:24][CH2:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[C:31](=[O:35])[N:30]([C@@:36]2([CH3:44])[CH2:41][CH2:40][C:39](=[O:42])[NH:38][C:37]2=[O:43])[C:29]3=[O:45])=[O:10])=[N:6][CH:7]=1

Komponenten

6

Edukt 4

HCID 6342AcetonitrileHCID 682631,1'-CarbonyldiimidazoleHCID 6085445-Bromopyridine-2-carboxylic acidHCID 670196915-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidin-3-yl]-isoindole-1,3-dione hydrochloride

Produkt 1

HCID 247883085-Bromo-N-[[2-[(3S)-3-methyl-2,6-dioxopiperidin-3-YL]-1,3-dioxoisoindolin-5-YL]methyl]picolinamideAusbeute 57 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6228DimethylformamideLösungsmittel

Reaktionsbedingungen

Temperatur
40 °C

Versuchsvorschrift

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.

Aufarbeitung

  1. stirringthe mixture was stirred at this temperature for an additional 2 hours
  2. temperatureThe mixture was cooled to room temperature
  3. customthe solvent was evaporated under vacuum
  4. dissolutionThe residue was dissolved in ethyl acetate (100 mL)
  5. washwashed with saturated aqueous sodium bicarbonate solution (2×100 mL)
  6. customThe organic phase was evaporated
  7. customThe residue was chromatographed on silica gel
  8. customA pale red solid was obtained
  9. customthis material was triturated in 10 mL of acetonitrile for 16 hours
  10. filtrationThe solid was filtered
  11. washwashed with an additional 7 mL of acetonitrile
  12. customThe product was dried under vacuum
  13. customproviding 0.55 g (57% yield) as a white solid

Quellen und Nachweise

ORD-Eintrag
ord-e75b2731b7334b1b808a0290bf69e7b8
Quelldatensatz
uspto-grants-2016_09
Patentnummer
US09447070B2

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