4-Methylmorpholine → (1S)-1-(4-Fluoro-1-phenyl-1H-benzimidazol-2-yl)ethan-1-amine

HRID 242817Notes

Reaction equation

HRID 242817 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[NH2:15].C(OC([NH:23][C@@H:24]([CH3:28])[C:25](O)=O)=O)(C)(C)C.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C(Cl)Cl>[F:1][C:2]1[C:3]2[N:15]=[C:25]([C@@H:24]([NH2:23])[CH3:28])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4]=2[CH:5]=[CH:6][CH:7]=1

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 85082Tert-butoxycarbonylalanineHCID 181649HOAtHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 44254861HCID 44254861, compound

Product 1

HCID 68156990(1S)-1-(4-Fluoro-1-phenyl-1H-benzimidazol-2-yl)ethan-1-amineYield 71.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A mixture of 3-fluoro-N1-phenylbenzene-1,2-diamine (440 mg, 2.18 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (454 mg, 2.40 mmol), HOAt (327 mg, 2.40 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (460 mg, 2.40 mmol) and 4-methylmorpholine (0.527 mL, 4.79 mmol) in anhydrous DCM (20 mL) was stirred at RT for 2 h. The reaction mixture was diluted with DCM (100 mL) and washed with a saturated solution of NaHCO3. The organic layer was then dried and concentrated in vacuo. The resulting residue was dissolved in AcOH (10 mL) and heated to 70° C. for 2 h and then to 80° C. for 20 h. After cooling to RT, TFA (20 mL) was added and the mixture was stirred at RT for 1 h and 20 min. Volatiles were then removed in vacuo and the residue was dissolved in DCM (100 mL) and washed with a saturated solution of NaHCO3. The organic layer was then washed with brine, dried (Na2SO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in TBME) affording (S)-1-(4-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine as a brown oil (396 mg, 71%). LCMS: RT 2.01 min [M−NH2]+ 239.1.

Workup

  1. washwashed with a saturated solution of NaHCO3
  2. customThe organic layer was then dried
  3. concentrationconcentrated in vacuo
  4. dissolutionThe resulting residue was dissolved in AcOH (10 mL)
  5. temperatureheated to 70° C. for 2 h
  6. waitto 80° C. for 20 h
  7. temperatureAfter cooling to RT
  8. additionTFA (20 mL) was added
  9. stirringthe mixture was stirred at RT for 1 h and 20 min
  10. customVolatiles were then removed in vacuo
  11. dissolutionthe residue was dissolved in DCM (100 mL)
  12. washwashed with a saturated solution of NaHCO3
  13. washThe organic layer was then washed with brine
  14. dry with materialdried (Na2SO4)
  15. concentrationconcentrated in vacuo
  16. customThe resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in TBME)

Sources & evidence

ORD record
ord-3cd03a71ec8f42d98a99b3d83abe8ce9
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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