Imidazole → 3-(8-Fluoro-2-methyl-4-oxo-4h-quinazolin-3-yl)-piperidine-2,6-dione

HRID 509515Notes

Reaction equation

HRID 509515 reaction equation
[NH2:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][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.CS(C)=O.O>[F:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[N:1]=[C:15]([CH3:16])[N:22]([CH:23]1[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:24]1=[O:30])[C:4]2=[O:6]

Participants

9

Reactant 5

HCID 795Imidazole2×HCID 6367Acetyl chlorideHCID 7540Triphenyl phosphiteHCID 1345483-Aminopiperidine-2,6-dione hydrochlorideHCID 5864082-Amino-3-fluorobenzoic acid

Product 1

HCID 252352213-(8-Fluoro-2-methyl-4-oxo-4h-quinazolin-3-yl)-piperidine-2,6-dioneYield 67%

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent2×HCID 6342AcetonitrileSolvent

Procedure

To a stirred mixture of 2-amino-3-fluorobenzoic acid (3.0 g, 19 mmol) and imidazole (1.6 g, 23 mmol) in acetonitrile (30 mL), was added acetyl chloride (1.7 mL, 23 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 (3.2 g, 19 mmol), imidazole (2.9 g, 43 mmol) and triphenyl phosphite (6.1 mL, 23 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 purified with preparative HPLC (C 18 20/80 CH3CN/H2O) to give a white solid. The white solid in DMSO (20 mL) was heated at 60° C. for 30 minutes. To the solution, was added water (10 mL). The suspension was cooled to room temperature. The suspension was filtered and washed with DMSO (4 mL) and water (20 mL) to give 3-(8-fluoro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (3.11 g, 67% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 4.7 min (99.7%); mp: 305° C. (decomp); 1H NMR (DMSO-d6) δ 2.16-2.23 (m, 1H, CHH), 2.43-2.76 (m, 5H, CH3, 2CHH), 2.79-2.92 (m, 1H, CHH), 5.32 (dd, J=6, 11 Hz, 1H, NCH), 7.46-7.53 (m, 1H. Ar), 7.67-7.73 (m, 1H, Ar), 7.84-7.94 (m, 1H, Ar), 11.06 (s, 1H, NH); NMR (DMSO-d6) δ 20.80, 23.67, 30.58, 56.71, 120.04 (d, JC-F=19 Hz), 121.71 (d, JC-F=4 Hz), 122.31, 126.91 (d, JC-F=8 Hz), 136.04 (d, JC-F=12 Hz), 155.93 (d, JC-F=254 Hz), 155.93, 159.62 (d, JC-F=3 Hz), 169.32, 172.57; LCMS: MH=290; Anal Calcd for C14H12N3O3F: C, 58.13; H, 4.18; N, 14.53; F, 6.57. Found: C, 57.87; H, 3.94; N, 14.35; F, 6.91.

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. customwas purified with preparative HPLC (C 18 20/80 CH3CN/H2O)
  7. customto give a white solid
  8. temperatureThe suspension was cooled to room temperature
  9. filtrationThe suspension was filtered
  10. washwashed with DMSO (4 mL) and water (20 mL)

Sources & evidence

ORD record
ord-dd922fa33ecd420ebc3cc4d8aae63ab0
Source dataset
uspto-grants-2015_08
Patent number
US09096573B2

Reaction notes

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