Water → (RS)-1-[2-(4-Cyano-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]methanone

HRID 598593Notes

Reaction equation

HRID 598593 reaction equation
Br[C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18]([C:20]3[N:21]=[C:22]([CH3:32])[S:23][C:24]=3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:19])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cu][C:34]#[N:35].O>CN1CCCC1=O>[C:34]([C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18]([C:20]3[N:21]=[C:22]([CH3:32])[S:23][C:24]=3[C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)=[O:19])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:35]

Participants

5

Reactant 3

HCID 962WaterHCID 17973675HCID 17973675, compoundHCID 178418546HCID 178418546, compound

Product 1

HCID 17973695(RS)-1-[2-(4-Cyano-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]methanoneYield 3%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Procedure

A mixture of (RS)-1-[2-(4-bromo-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]methanone, E66 (216 mg, 0.42 mmol) and copper(I)cyanide (76 mg, 0.84 mmol) in N-methylpyrrolidinone (15 ml) was heated at reflux for 3 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate (2×). Solid sodium chloride was added to the aqueous layer which was further extracted with ethyl acetate (2×). The combined organic extracts were washed with brine, dried (Na2SO4) and the solvent removed in vacuo. The residue was Chromatographed (silica gel, 10-100% ethyl acetate-hexane then 1-20% methanol-ethyl acetate). Further purification by HPLC (Supercosil ABZ+, 5-95% acetonitrile containing 0.1% trifluoroacetic acid-water containing 0.1% trifluoroacetic acid) afforded the title compound as a pale brown amorphous solid (5.3 mg, 3%).

Workup

  1. temperaturewas heated
  2. temperatureat reflux for 3 h
  3. temperatureThe reaction mixture was cooled
  4. extractionextracted with ethyl acetate (2×)
  5. additionSolid sodium chloride was added to the aqueous layer which
  6. extractionwas further extracted with ethyl acetate (2×)
  7. washThe combined organic extracts were washed with brine
  8. dry with materialdried (Na2SO4)
  9. customthe solvent removed in vacuo
  10. customThe residue was Chromatographed (silica gel, 10-100% ethyl acetate-hexane
  11. customFurther purification by HPLC (Supercosil ABZ+, 5-95% acetonitrile containing 0.1% trifluoroacetic acid-water containing 0.1% trifluoroacetic acid)

Sources & evidence

ORD record
ord-e9145842c4c244d0bb55fcbbc3ac45fe
Source dataset
uspto-grants-2011_03
Patent number
US07897618B2

Reaction notes

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