4-Methylmorpholine → 2-(6-bromo-1H-benzimidazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 71732

Reaction equation

HRID 71732 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:10]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19](O)=O)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:13]([O:12][C:10]([N:17]1[CH2:24][CH2:23][CH2:22][CH:18]1[C:19]1[NH:9][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=2[N:8]=1)=[O:11])([CH3:16])([CH3:14])[CH3:15]

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 850831,2-Pyrrolidinedicarboxylic acid, 1-(1,1-dimethylethyl) ester, (2S)-HCID 3235934-Bromobenzene-1,2-diamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)

Product 1

HCID 581852752-(6-bromo-1H-benzimidazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl esterYield 66.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
120 °C

Procedure

To a mixture of 4-Bromo-benzene-1,2-diamine (5.0 g), Boc-L-proline (6.0 g), and 4-methylmorpholine (5.88 mL) in DMF (100 mL) was added HATU (10.7 g). Reaction mixture was stirred for 16 hours and then concentrated. Residue was dissolved in ethyl acetate and washed with 5% lithium chloride solution (2×), brine and dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 30 to 60% ethyl acetate/hexanes) to a dark brown foam. Brown foam was dissolved in ethanol (100 mL) and heated in a sealed tube at 110-130° C. for 2 days. Reaction mixture was cooled and concentrated. Residue was dissolved in ethyl acetate and extracted with 1N HCl (3×). Aqueous layer was basified with 50% NaOH solution to pH 10 and extracted with ethyl acetate (2×). The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 0 to 10% isopropanol/hexanes) to give 2-(6-Bromo-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (6.5 g) as an off-white foam: LCMS-ESI+: calc'd for C16H21BrN3O2: 367.26 (M+H+). Found: 365.8, 367.8 (M+H+).

Workup

  1. customReaction mixture
  2. concentrationconcentrated
  3. dissolutionResidue was dissolved in ethyl acetate
  4. washwashed with 5% lithium chloride solution (2×), brine
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated
  7. custompurified by flash column chromatography (silica gel, 30 to 60% ethyl acetate/hexanes) to a dark brown foam
  8. dissolutionBrown foam was dissolved in ethanol (100 mL)
  9. customReaction mixture
  10. temperaturewas cooled
  11. concentrationconcentrated
  12. dissolutionResidue was dissolved in ethyl acetate
  13. extractionextracted with 1N HCl (3×)
  14. extractionextracted with ethyl acetate (2×)
  15. dry with materialThe organic layer was dried (MgSO4)
  16. concentrationconcentrated
  17. custompurified by flash column chromatography (silica gel, 0 to 10% isopropanol/hexanes)

Sources & evidence

ORD record
ord-7886092102bb4928a54ce3a4693016be
Source dataset
uspto-grants-2014_09
Patent number
US08822430B2

Linked notes

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