Imidazole → 3-(2-Methyl-4-oxo-7-trifluoromethyl-4h-quinazolin-3-yl)-piperidine-2,6-dione

HRID 453039Notes

Reaction equation

HRID 453039 reaction equation
[NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.N1[CH:19]=[CH:18]N=C1.C(Cl)(=O)C.Cl.[NH2:25][CH:26]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:27]1=[O:33].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(#N)C.CS(C)=O.O>[CH3:18][C:19]1[N:25]([CH:26]2[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:27]2=[O:33])[C:4](=[O:6])[C:3]2[C:2](=[CH:10][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:7]=2)[N:1]=1

Participants

9

Reactant 5

HCID 795Imidazole2×HCID 6367Acetyl chlorideHCID 7540Triphenyl phosphiteHCID 678694-(Trifluoromethyl)anthranilic acidHCID 1345483-Aminopiperidine-2,6-dione hydrochloride

Product 1

HCID 252359123-(2-Methyl-4-oxo-7-trifluoromethyl-4h-quinazolin-3-yl)-piperidine-2,6-dioneYield 24%

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent3×HCID 6342AcetonitrileSolvent

Procedure

To a stirred mixture of 2-amino-4-(trifluoromethyl)benzoic acid (3.0 g, 15 mmol) and imidazole (1.2 g, 18 mmol) in acetonitrile (30 mL), was added acetyl chloride (1.3 mL, 18 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 (2.4 g, 15 mmol), imidazole (2.2 g, 32 mmol) and triphenyl phosphite (4.6 mL, 18 mmol) and heated to reflux for 22 hours. To the mixture, was added water (100 mL). The suspension was filtered and washed with water (2×50 mL), ethyl acetate (2×50 mL), sodium hydrogen carbonate (sat, 50 mL) and water (50 mL) to give a white solid, which was dissolved in DMSO (10 mL). To the solution, was added water (3 mL) to give a suspension. The suspension was filtered and washed with DMSO (2 mL) to give a white solid. The solid was stirred in water (50 mL) at 60° C. for 2 hours, then at room temperature overnight. The suspension was filtered and washed with water (2×50 mL) to give 3-(2-methyl-4-oxo-7-trifluoromethyl-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (1.17 g, 24% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 8.14 min (99.9%); mp: 277-279° C.; 1H NMR (DMSO-d6) δ 2.18-2.25 (m, 1H, CHH), 2.59-2.74 (m, 5H, CH3, 2CH—H), 2.81-2.88 (m, 1H, CHH), 5.34 (dd, J=6, 11 Hz, 1H, NCH), 7.80 (dd, J=2, 8 Hz, 1H, Ar), 7.96 (s, 1H, Ar), 8.24 (d, J=8 Hz, 1H, Ar), 11.09 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.73, 23.54, 30.57, 56.82, 122.30 (q, JC-F=3 Hz), 122.99, 123.45 (q, JC-F=273 Hz), 123.74 (q, JC-F=4 Hz), 127.85, 134.22 (q, JC-F=32 Hz), 146.84, 156.98, 159.80, 169.24, 172.56; LCMS: MH=340; Anal Calcd for C15H12N3O3F3: C, 53.10; H, 3.57; N, 12.39; F, 16.80. Found: C, 52.55; H, 3.42; N, 12.21; F, 17.18.

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), sodium hydrogen carbonate (sat, 50 mL) and water (50 mL)
  5. customto give a white solid, which
  6. customto give a suspension
  7. filtrationThe suspension was filtered
  8. washwashed with DMSO (2 mL)
  9. customto give a white solid
  10. customat room temperature
  11. customovernight
  12. filtrationThe suspension was filtered
  13. washwashed with water (2×50 mL)

Sources & evidence

ORD record
ord-3afa6c48f35c4610958c8b62a5003510
Source dataset
uspto-grants-2013_07
Patent number
US08492395B2

Reaction notes

Loading…