Imidazole → 2,6-Piperidinedione, 3-(5-fluoro-2-methyl-4-oxo-3(4H)-quinazolinyl)-

HRID 1409603Notes

Reaction equation

HRID 1409603 reaction equation
[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.N1[CH:16]=[CH:15]N=C1.C(Cl)(=O)C.Cl.[NH2:22][CH:23]1[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:24]1=[O:30].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(#N)C.CO.O>[F:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]2[C:3]=1[C:4](=[O:6])[N:22]([CH:23]1[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:24]1=[O:30])[C:15]([CH3:16])=[N:1]2

Participants

9

Reactant 5

HCID 795Imidazole2×HCID 6367Acetyl chlorideHCID 7540Triphenyl phosphiteHCID 1345483-Aminopiperidine-2,6-dione hydrochlorideHCID 5211422-Amino-6-fluorobenzoic acid

Product 1

HCID 249672322,6-Piperidinedione, 3-(5-fluoro-2-methyl-4-oxo-3(4H)-quinazolinyl)-Yield 78%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 6342AcetonitrileSolvent

Procedure

To a stirred mixture of 2-amino-6-fluorobenzoic acid (5.3 g, 34 mmol) and imidazole (2.8 g, 41 mmol) in acetonitrile (60 mL), was added acetyl chloride (2.9 mL, 41 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 (6.1 g, 37 mmol), imidazole (5.1 g, 75 mmol) and triphenyl phosphite (10.6 mL, 41 mmol) and heated to reflux for 22 hours. To the mixture, was added water (60 mL). The suspension was filtered and washed with water (2×50 mL), ethyl acetate (2×50 mL), and water (50 mL) to give a white solid, which was stirred in methanol (50 mL) overnight. The suspension was washed with methanol (30 mL) and water (30 mL) to give 3-(5-fluoro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (7.6 g, 78% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 3.8 min (99.6%); mp: 275-277° C.; 1H NMR (DMSO-d6) δ 2.13-2.20 (m, 1H, CHH), 2.57-2.69 (m, 5H, CH3, 2CHH), 2.77-2.90 (m, 1H, CHH), 5.25 (dd, J=6, 11 Hz, 1H, NCH), 7.26 (ddd, J=0.6, 8, 11 Hz, 1H, Ar), 7.44 (d, J=8 Hz, 1H, Ar), 7.80 (dt, J=5, 8 Hz 1H, Ar), 11.04 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.73, 23.45, 30.57, 56.45, 109.79 (d, JC-F=6 Hz), 112.89 (d, JC-F=21 Hz), 122.64 (d, JC-F=4 Hz), 135.39 (d, JC-F=11 Hz), 148.86, 156.22, 157.46, 160.15 (d, JC-F=264 Hz), 169.38, 172.57; LCMS: MH=290; Anal Calcd for C14H12N3O3F: C, 58.13; H, 4.18; N, 14.53; F, 6.57. Found: C, 57.98; H, 4.00; N, 14.45; F, 6.73.

Workup

  1. temperatureheated
  2. temperatureto reflux for 22 hours
  3. filtrationThe suspension was filtered
  4. washwashed with water (2×50 mL), ethyl acetate (2×50 mL), and water (50 mL)
  5. customto give a white solid, which
  6. washThe suspension was washed with methanol (30 mL) and water (30 mL)

Sources & evidence

ORD record
ord-74e9c3feaf9944858c77575f7a211363
Source dataset
uspto-grants-2014_12
Patent number
US08921385B2

Reaction notes

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