Imidazole → 3-(2,8-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione

HRID 509514Notes

Reaction equation

HRID 509514 reaction equation
[NH2:1][C:2]1[C:10]([CH2:11]C)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.N1[CH:17]=[CH:16]N=C1.C(Cl)(=O)C.Cl.[NH2:23][CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(#N)C.CS(C)=O.O>[CH3:16][C:17]1[N:23]([CH:24]2[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]2=[O:31])[C:4](=[O:6])[C:3]2[C:2](=[C:10]([CH3:11])[CH:9]=[CH:8][CH:7]=2)[N:1]=1

Participants

9

Reactant 5

HCID 795Imidazole2×HCID 6367Acetyl chlorideHCID 7540Triphenyl phosphiteHCID 1345483-Aminopiperidine-2,6-dione hydrochlorideHCID 2260442-Amino-3-ethylbenzoic acid

Product 1

HCID 252359183-(2,8-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dioneYield 56.1%

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolventHCID 6342AcetonitrileSolvent

Procedure

To a stirred mixture of 2-amino-3-ethylbenzoic acid (3.0 g, 20 mmol) and imidazole (1.6 g, 24 mmol) in acetonitrile (30 mL), was added acetyl chloride (1.7 mL, 24 mmol) at room temperature. The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (3.3 g, 20 mmol), imidazole (3.0 g, 68 mmol) and triphenyl phosphite (6.2 mL, 24 mmol) and heated to reflux for 22 hours. To the mixture, was added water (60 mL). The suspension was filtered and washed with water (2×100 mL), ethyl acetate (2×100 mL), sodium hydrogen carbonate (sat, 100 mL) and water (100 mL) to give a white solid, which was stirred in DMSO (20 mL) at 65° C. The mixture was polished filtered and washed with DMSO (10 mL). To the filtrate, was added water (100 mL) to give a suspension. The suspension was filtered and washed with water (2×50 mL) to give 3-(2,8-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (3.2 g, 56% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 25/75 CH3CN/0.1% H3PO4, 5.85 min (99.6%); mp: 296-298° C.; 1H NMR (DMSO-d6) δ 2.12-2.24 (m, 1H, CHH), 2.51 (s, 3H, CH3), 2.48-2.74 (m, 2H, 2CHH), 2.66 (s, 3H, CH), 2.76-2.91 (m, 1H, CHH), 5.27 (dd, J=6, 11 Hz, 1H, NCH), 7.38 (t, J=8 Hz, 1H, Ar), 7.67 (d, J=7 Hz, 1H, Ar), 7.86 (dd, J=0.6, 8 Hz, 1H, Ar), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 16.91, 20.91, 23.80, 30.60, 56.51, 120.23, 123.59, 126.05, 134.72, 134.94, 145.25, 153.82, 160.71, 169.51, 172.62; LCMS: MH=286; Anal Calcd for C15H15N3O3+0.2H2O: C, 62.36; H, 5.37; N, 14.54. Found: C, 62.21; H, 5.31; N, 14.43.

Workup

  1. temperatureheated
  2. temperatureto reflux for 22 hours
  3. filtrationThe suspension was filtered
  4. washwashed with water (2×100 mL), ethyl acetate (2×100 mL), sodium hydrogen carbonate (sat, 100 mL) and water (100 mL)
  5. customto give a white solid, which
  6. filtrationThe mixture was polished filtered
  7. washwashed with DMSO (10 mL)
  8. additionTo the filtrate, was added water (100 mL)
  9. customto give a suspension
  10. filtrationThe suspension was filtered
  11. washwashed with water (2×50 mL)

Sources & evidence

ORD record
ord-97f48a143d9547158586166feed61003
Source dataset
uspto-grants-2015_08
Patent number
US09096573B2

Reaction notes

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