3-Fluorophenylacetic acid → HCID 58827347, compound

HRID 448474Notes

Reaction equation

HRID 448474 reaction equation
Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.[F:34][C:35]1[CH:36]=[C:37]([CH2:41][C:42](O)=[O:43])[CH:38]=[CH:39][CH:40]=1.Cl.CN(C)CCCN=C=NCC>CC#N>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:42](=[O:43])[CH2:41][C:37]3[CH:38]=[CH:39][CH:40]=[C:35]([F:34])[CH:36]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1

Participants

6

Reactant 4

HCID 676173-Fluorophenylacetic acidHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 219885254-(aminomethyl)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione hydrochloride

Product 1

HCID 58827347HCID 58827347, compoundYield 69%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.70 g, 2.2 mmol) in CH3CN (60 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.82 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.35 g, 2.6 mmol) and 3-fluorophenylacetic acid (0.37 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.62 g, 3.2 mmol). After stirring at room temperature overnight, the mixture was concentrated in vacuo, and the residue was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was then washed with water (2×30 mL) and brine (30 mL), and dried over MgSO4. Solvent was removed in vacuo, and the resulting oil was purified by ISCO silica gel flash chromatography (eluent: 40% EtOAc in CH2Cl2 for 5 min then increase to 80% EtOAc in CH2Cl2 over 20 min.) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(3-fluoro-phenyl)-acetamide as a white solid (0.63 g, 69%): mp, 192-194° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.0 min (98%); 1H NMR (DMSO-d6): δ 2.03-2.08 (m, 1H), 2.52-2.63 (m, 2H), 2.84-2.91 (m, 1H), 3.57 (s, 2H), 4.73 (d, J=5.9 Hz, 2H), 5.12-5.18 (dd, J=5, 12 Hz, 1H), 7.03-7.14 (m, 3H), 7.31-7.39 (m, 1H), 7.63-7.67 (m, 1H), 7.78-7.81 (m, 2H), 8.69 (t, J=6.0 Hz, 1H), 11.14 (s, 1H). 13C NMR (DMSO-d6) δ: 21.94, 30.90, 37.86, 41.67, 48.82, 113.08, 113.35, 115.69, 115.98, 121.91, 125.19, 125.22, 127.13, 129.98, 130.09, 131.51, 133.22, 134.67, 138.77, 138.87, 139.03, 160.38, 163.60, 166.88, 167.41, 169.78, 170.06, 172.73. Anal Calcd for C22H18FN3O5: C, 62.41; H, 4.29; N, 9.92; F, 4.49. Found: C, 62.55; H, 4.04; N, 9.80; F, 4.36.

Workup

  1. stirringAfter stirring at room temperature overnight
  2. concentrationthe mixture was concentrated in vacuo
  3. dissolutionthe residue was dissolved in CH2Cl2 (50 mL)
  4. washThe CH2Cl2 solution was then washed with water (2×30 mL) and brine (30 mL)
  5. dry with materialdried over MgSO4
  6. customSolvent was removed in vacuo
  7. customthe resulting oil was purified by ISCO silica gel flash chromatography (eluent
  8. temperature40% EtOAc in CH2Cl2 for 5 min then increase to 80% EtOAc in CH2Cl2 over 20 min.)

Sources & evidence

ORD record
ord-f5c9ccbc4ec14b2fa52e6361f452c766
Source dataset
uspto-grants-2013_07
Patent number
US08481568B2

Reaction notes

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