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

HRID 63408

반응식

HRID 63408 반응식
[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

참가 물질

6

반응물 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

생성물 1

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

시약·촉매·용매 1

HCID 6228Dimethylformamide용매

반응 조건

온도
40 °C

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.

후처리

  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

출처 및 근거

ORD 기록
ord-e75b2731b7334b1b808a0290bf69e7b8
출처 데이터셋
uspto-grants-2016_09
특허 번호
US09447070B2

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