Potassium Carbonate → 10-Chloro-1-(2,6-dimethoxypyridin-3-yl)-7-(1-ethylpropyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole

HRID 1398983Notes

Reaction equation

HRID 1398983 reaction equation
[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:13]([O:20][CH3:21])=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[N:7]([CH2:22][CH2:23][CH2:24][CH2:25]O)[C:6]=2[C:5]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:12]4[C:13]([O:20][CH3:21])=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=4)[CH2:25][CH2:24][CH2:23][CH2:22][N:7]3[C:6]=2[C:5]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 31297Methanesulfonyl chlorideHCID 516892Sodium BicarbonateHCID 687627314-[4-Chloro-2-[(2,6-dimethoxypyridin-3-yl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butan-1-ol

Product 1

HCID 5778584810-Chloro-1-(2,6-dimethoxypyridin-3-yl)-7-(1-ethylpropyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazoleYield 19.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 1049PyridineSolvent

Procedure

To a solution of 4-[4-chloro-2-[(2,6-dimethoxypyridin-3-yl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butan-1-ol (Reference Example 44; 80 mg, 0.18 mmol) in pyridine (1.8 mL) was added methanesulfonyl chloride (0.070 mL, 0.89 mmol) dropwise at 0° C. The mixture was warmed to room temperature and stirred for 16 hr. Aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The resulting crude mesylate was dissolved in N,N-dimethylformamide (3.6 mL) and potassium carbonate (123 mg, 0.89 mmol) was added. The mixture was stirred at 80° C. for 16 hr. Water was added and the mixture was extracted with ethyl acetate. Organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 5-20% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give a solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound (15 mg, 0.035 mmol, 19%) as a colorless solid.

Workup

  1. extractionthe mixture was extracted with ethyl acetate
  2. washOrganic layer was washed with brine
  3. dry with materialdried over sodium sulfate
  4. concentrationconcentrated in vacuo
  5. dissolutionThe resulting crude mesylate was dissolved in N,N-dimethylformamide (3.6 mL)
  6. stirringThe mixture was stirred at 80° C. for 16 hr
  7. extractionthe mixture was extracted with ethyl acetate
  8. washOrganic layer was washed with water and brine
  9. dry with materialdried over anhydrous sodium sulfate
  10. concentrationconcentrated in vacuo
  11. customThe residue was purified by flash chromatography on silica gel eluting with a 5-20% ethyl acetate/n-hexane gradient mixture
  12. concentrationThe filtrate was concentrated in vacuo
  13. customto give a solid, which
  14. customwas recrystallized from ethyl acetate/n-hexane

Sources & evidence

ORD record
ord-d3d48477f2394ef39af9e704bd0b2d0b
Source dataset
uspto-grants-2014_12
Patent number
US08901141B2

Reaction notes

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