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

HRID 453053

반응식

HRID 453053 반응식
[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]

참가 물질

9

반응물 5

HCID 795Imidazole2회HCID 6367Acetyl chlorideHCID 7540Triphenyl phosphiteHCID 1345483-Aminopiperidine-2,6-dione hydrochlorideHCID 5864082-Amino-3-fluorobenzoic acid

생성물 1

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

시약·촉매·용매 3

HCID 679Dimethyl Sulfoxide용매HCID 962Water용매2회HCID 6342Acetonitrile용매

실험 절차

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 (C18 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); 13C 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.

후처리

  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 (C18 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)

출처 및 근거

ORD 기록
ord-64f6ee35643446629ca2619965b48575
출처 데이터셋
uspto-grants-2013_07
특허 번호
US08492395B2

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