9-Chloro-1-(2-chloro-4,6-dimethylpyrimidin-5-yl)-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole → 9-Chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(2,4,6-trimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole

HRID 1628776노트

반응식

HRID 1628776 반응식
[CH3:1][Mg]Br.[Cl:4][C:5]1[C:13]2[N:12]=[C:11]3[N:14]([C:18]4[C:19]([CH3:26])=[N:20][C:21](Cl)=[N:22][C:23]=4[CH3:24])[CH2:15][CH2:16][CH2:17][N:10]3[C:9]=2[C:8]([CH:27]([O:32][CH:33]([F:35])[F:34])[C:28]([F:31])([F:30])[F:29])=[CH:7][CH:6]=1>O1CCCC1.O.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:4][C:5]1[C:13]2[N:12]=[C:11]3[N:14]([C:18]4[C:23]([CH3:24])=[N:22][C:21]([CH3:1])=[N:20][C:19]=4[CH3:26])[CH2:15][CH2:16][CH2:17][N:10]3[C:9]=2[C:8]([CH:27]([O:32][CH:33]([F:34])[F:35])[C:28]([F:30])([F:31])[F:29])=[CH:7][CH:6]=1

참가 물질

6

반응물 2

HCID 577862249-Chloro-1-(2-chloro-4,6-dimethylpyrimidin-5-yl)-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazoleHCID 178418573HCID 178418573, 화합물

생성물 1

HCID 577860969-Chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(2,4,6-trimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole

시약·촉매·용매 3

HCID 178418745HCID 178418745, 화합물촉매HCID 962Water용매HCID 8028Tetrahydrofuran용매

실험 절차

Methylmagnesium bromide (1.0 M solution in tetrahydrofuran, 0.49 mL, 0.490 mmol) was added dropwise to a stirred suspension of 9-chloro-1-(2-chloro-4,6-dimethylpyrimidin-5-yl)-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (163 mg, 0.328 mmol) and [1,3-bis(diphenylphosphino)propane]dichloronickel (17.8 mg, 0.0328 mmol) in tetrahydrofuran (1.3 mL) at 0° C., and the mixture was stirred at room temperature for 7 hr. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 30-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was purified by preparative HPLC to give a mixture contained an intermediate of the title compound as the trifluoroacetic acid salt. The mixture was washed with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (49.8 mg, 0.105 mmol, 32%).

후처리

  1. extractionextracted with ethyl acetate
  2. washThe combined organic layer was washed with brine
  3. dry with materialdried over anhydrous magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by flash column chromatography on silica gel eluting with a 30-100% ethyl acetate/n-hexane gradient mixture
  7. concentrationThe filtrate was concentrated in vacuo
  8. customto give the solid, which
  9. customwas purified by preparative HPLC
  10. customto give a mixture

출처 및 근거

ORD 기록
ord-b3b8d4cc86264801a88844fe063f968e
출처 데이터셋
uspto-grants-2014_07
특허 번호
US08785460B2

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