Morpholine → 2-[4-(3-chloropyridin-2-yl)phenyl]-6-morpholin-4-yl-1H-benzoimidazole

HRID 1497487Notes

Reaction equation

HRID 1497487 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:23]=1.CN(C(C(C)C)C)C.C[Si](C)(C)CCOCCl.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>ClCCl.C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:22][C:21]1[C:16]([C:13]2[CH:14]=[CH:15][C:10]([C:8]3[NH:7][C:6]4[CH:23]=[C:2]([N:41]5[CH2:46][CH2:45][O:44][CH2:43][CH2:42]5)[CH:3]=[CH:4][C:5]=4[N:9]=3)=[CH:11][CH:12]=2)=[N:17][CH:18]=[CH:19][CH:20]=1

Participants

9

Reactant 5

HCID 8083MorpholineHCID 27242712-Chloromethyl 2-(trimethylsilyl)ethyl etherHCID 27342152-(Di-tert-butylphosphino)biphenylHCID 117179436-bromo-2-(4-(3-chloropyridin-2-yl)phenyl)-1H-benzoimidazoleHCID 22949790N,N,3-Trimethylbutan-2-amine

Product 1

HCID 116682682-[4-(3-chloropyridin-2-yl)phenyl]-6-morpholin-4-yl-1H-benzoimidazoleYield 98.1%

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 162 mg (0.42 mmol) 6-bromo-2-(4-(3-chloropyridin-2-yl)phenyl)-1H-benzoimidazole in 6 mL dichloromethane were added 0.2 mL (1.15 mmol) N,N-dimethylisopropylethylamine and 0.1 mL (0.57 mmol) 2-(trimethylsilyl)ethoxymethyl chloride, followed by stirring at room temperature for 16 hours. After vacuum concentration, 26 μL (0.30 mmol) morpholine, 56.3 mg (0.013 mmol) tris(dibenzylidine acetone)dipalladium(0), 10 mg (0.038 mmol) 2-(di-t-butylphosphino)biphenyl, and 38.8 mg (0.41 mmol) sodium-t-botoxide were added to the concentrate, which was then dissolved in 2.5 mL toluene and allowed to react at 90° C. for 10 min in a microwave reactor. After being cooled to room temperature, the product was dissolved in 5 mL ethyl acetate and filtered with diatomite. The filtrate was dried over magnesium sulfate and vacuum concentrated. The concentrate was dissolved in 3 mL of a mixture of trifluoro fluoroacetic acid and methylene:chloride (1:1) and stirred for 12 hours. Neutralization with 10% NaOH, extraction with ethyl acetate, drying with magnesium sulfate and vacuum concentration were sequentially conducted in that order. The residue thus obtained was separated using column chromatography (developing solvent: hexane/ethyl acetate=1/1) to produce 115 mg of 2-[4-(3-chloropyridin-2-yl)phenyl]-6-morpholin-4-yl-1H-benzoimidazole (yield 70%).

Workup

  1. additionwere added to the concentrate, which
  2. customto react at 90° C. for 10 min in a microwave reactor
  3. temperatureAfter being cooled to room temperature
  4. filtrationfiltered with diatomite
  5. dry with materialThe filtrate was dried over magnesium sulfate and vacuum
  6. concentrationconcentrated
  7. dissolutionThe concentrate was dissolved in 3 mL of a mixture of trifluoro fluoroacetic acid and methylene:chloride (1:1)
  8. stirringstirred for 12 hours
  9. extractionNeutralization with 10% NaOH, extraction with ethyl acetate
  10. dry with materialdrying with magnesium sulfate and vacuum concentration
  11. customThe residue thus obtained
  12. customwas separated

Sources & evidence

ORD record
ord-eec35884170744d585395b6ecd011ee2
Source dataset
uspto-grants-2015_12
Patent number
US09199965B2

Reaction notes

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