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 1399127ノート

反応式

HRID 1399127 の反応式
[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

参加物

6

反応物 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、化合物

生成物 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

試薬・触媒・溶媒 3

HCID 178418745HCID 178418745、化合物触媒HCID 962Water溶媒HCID 8028Tetrahydrofuran溶媒

実験手順

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%)

後処理

  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

出典と根拠

ORDレコード
ord-7b2d1847bb4a468788f76fe0dc97b9f5
出典データセット
uspto-grants-2014_12
特許番号
US08901141B2

反応ノート

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