2,4,6-Trimethylpyridine → HCID 178502496, compound

HRID 1625510Notes

Reaction equation

HRID 1625510 reaction equation
[I:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH3:10][O:11][C:12]([NH:14][C@@H:15]([CH:27]([CH3:29])[CH3:28])[C:16]([N:18]1[C@@H:22]([CH3:23])[CH2:21][CH2:20][C@H:19]1[C:24](O)=O)=[O:17])=[O:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC(C)=CC=1C>CN(C=O)C.O.C(O)(=O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:23]([C@@H:22]3[CH2:21][CH2:20][C@H:19]([CH3:24])[N:18]3[C:16]([C@@H:15]([NH:14][C:12](=[O:13])[O:11][CH3:10])[CH:27]([CH3:28])[CH3:29])=[O:17])=[N:9][C:4]=2[CH:3]=1

Participants

8

Reactant 4

HCID 79532,4,6-TrimethylpyridineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 112070494-Iodobenzene-1,2-diamineHCID 67412687L-Proline, N-(methoxycarbonyl)-L-valyl-5-methyl-, (5S)-

Product 1

HCID 178502496HCID 178502496, compoundYield 92%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a cold (0-4° C.) stirred solution of 4-iodobenzene-1,2-diamine (1.3 g, 5.3 mmol) and (2S,5S)-1-[(2S)-2-(methoxycarbonylamino)-3-methyl-butanoyl]-5-methyl-pyrrolidine-2-carboxylic acid (1.52 g, 4.99 mmol) in DMF (23.8 ml) is sequentially added HATU (2.321 g, 6.103 mmol) and 2,4,6-collidine (1.052 ml, 7.964 mmol). The reaction mixture is stirred at rt overnight, diluted with water, extracted with ethyl acetate. Combined extracts are washed with water, saturated bicarbonate solution, brine, dried (Na2SO4), concentrated and dried under high vacuum to afford crude amide. The resulting residue dissolved in acetic acid (28 ml) is heated at 60° C. for 8 hours. Acetic acid is removed, the residue neutralized with sat. NaHCO3 solution, and diluted with ethyl acetate (20 ml). The aqueous solution is extracted with ethyl acetate, combined organic extracts are washed with aq. NaHCO3 solution, brine, dried (Na2SO4), and concentrated. The concentrate is purified by flash column chromatography on silica gel using ethyl acetate-hexanes (1:1 to 7:3) as eluent afforded methyl N-[(1S)-1-[(2S,5S)-2-(5-iodo-1H-benzimidazol-2-yl)-5-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl]carbamate (2.3 g, 2.28 mmol, 92%).

Workup

  1. extractionextracted with ethyl acetate
  2. washCombined extracts are washed with water, saturated bicarbonate solution, brine
  3. dry with materialdried (Na2SO4)
  4. concentrationconcentrated
  5. customdried under high vacuum
  6. customto afford crude amide
  7. temperatureis heated at 60° C. for 8 hours
  8. customAcetic acid is removed
  9. additiondiluted with ethyl acetate (20 ml)
  10. extractionThe aqueous solution is extracted with ethyl acetate
  11. washare washed with aq. NaHCO3 solution, brine
  12. dry with materialdried (Na2SO4)
  13. concentrationconcentrated
  14. customThe concentrate is purified by flash column chromatography on silica gel

Sources & evidence

ORD record
ord-46ca794ab26b44b2b794a3614574fd2b
Source dataset
uspto-grants-2014_07
Patent number
US08779156B2

Reaction notes

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