4-Methylmorpholine → (S)-tert-butyl 1-(6-fluoro-1-phenyl-1H-benzo[d]imidazol-2-yl)propylcarbamate

HRID 242864Notes

Reaction equation

HRID 242864 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH2:28][CH3:29])[C:25](O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:25]([C@@H:24]([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:28][CH3:29])[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 181649HOAtHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 2755934(S)-2-((tert)-Butoxycarbonyl)amino)butanoic acidHCID 214506204-Fluoro-2-phenylaminoaniline

Product 1

HCID 68158046(S)-tert-butyl 1-(6-fluoro-1-phenyl-1H-benzo[d]imidazol-2-yl)propylcarbamateYield 64.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A mixture of 4-fluoro-N2-phenylbenzene-1,2-diamine from Example 8 (199 mg, 0.984 mmol), (S)-2-tertbutoxycarbonylaminobutyric acid (219 mg, 1.08 mmol), HOAt (147 mg, 1.08 mmol), 4-methylmorpholine (0.238 mL, 2.16 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (207 mg, 1.08 mmol) in DCM (5 mL) was stirred at RT for 2 h. The reaction mixture was then partitioned between DCM (50 mL) and a saturated solution of NaHCO3. The organic layer was dried (Na2SO4) and concentrated in vacuo and the resulting residue was dissolved in AcOH (10 mL) and stirred for 18 h at 70° C. After cooling to RT, volatiles were evaporated in vacuo and the residue was partitioned between DCM (50 mL) and a saturated solution of NaHCO3. The organic layer was washed with brine, dried (Na2SO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane) affording (S)-tert-butyl 1-(6-fluoro-1-phenyl-1H-benzo[d]imidazol-2-yl)propylcarbamate as a beige solid (234 mg, 64%). LCMS: RT 3.82 min [M+H]+ 370.5

Workup

  1. customThe reaction mixture was then partitioned between DCM (50 mL)
  2. dry with materialThe organic layer was dried (Na2SO4)
  3. concentrationconcentrated in vacuo
  4. dissolutionthe resulting residue was dissolved in AcOH (10 mL)
  5. stirringstirred for 18 h at 70° C
  6. temperatureAfter cooling to RT
  7. customvolatiles were evaporated in vacuo
  8. customthe residue was partitioned between DCM (50 mL)
  9. washThe organic layer was washed with brine
  10. dry with materialdried (Na2SO4)
  11. concentrationconcentrated in vacuo
  12. customThe resulting residue was purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane)

Sources & evidence

ORD record
ord-587d4ae1700e43f18576078384f216b7
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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