4-Methylmorpholine → (S)-1-(7-bromo-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine

HRID 242928Notes

Reaction equation

HRID 242928 reaction equation
[Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OC([NH:24][C@@H:25]([CH3:29])[C:26](O)=O)=O)(C)(C)C.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.O>[Br:1][C:2]1[C:3]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:26]([C@@H:25]([NH2:24])[CH3:29])=[N:9][C:4]=2[CH:5]=[CH:6][C:7]=1[F:8]

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 85082Tert-butoxycarbonylalanineHCID 181649HOAtHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 68157124HCID 68157124, compound

Product 1

HCID 68157744(S)-1-(7-bromo-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamineYield 17.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

A mixture of 3-bromo-4-fluoro-N2-phenylbenzene-1,2-diamine (500 mg, 1.79 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (370 mg, 1.95 mmol), HOAt (266 mg, 1.95 mmol), 4-methylmorpholine (0.43 mL, 3.91 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (376 mg, 1.95 mmol) in DCM (5 mL) was stirred at RT for 2 h. The reaction mixture was diluted with water and extracted with DCM (×3). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was dissolved in dioxane (10 mL) and HCl (12N, 1.5 mL) added. The reaction mixture was stirred at RT for 18 h then made basic by addition of 1N NaOH. The aqueous phase was extracted with EtOAc (×3) and the combined organic fractions washed with brine, dried (MgSO4) and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford (S)-1-(7-bromo-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine (102 mg, 17%). LCMS (Method C): RT 2.28 min [M+H]+ 334.1/336.1. Chromatography purification afforded also (S)-2-amino-N-(3-bromo-4-fluoro-2-phenylaminophenyl)propionamide (384 mg) which was dissolved in 4N HCl in dioxane (10 mL) and heated at 70° C. for 3 h. The volatiles were removed in vacuo to afford (S)-1-(7-bromo-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride salt (434 mg, 60%). 1H NMR (DMSO-d6, 400 MHz): δ 8.84 (2H, s), 7.83 (1H, dd, J=8.80, 4.57 Hz), 7.71-7.58 (5H, m), 7.38 (1H, dd, J=9.65, 8.80 Hz), 4.17-4.07 (1H, m), 3.56 (2H, s), 1.42 (3H, d, J=6.80 Hz)

Workup

  1. extractionextracted with DCM (×3)
  2. washThe combined organic fractions were washed with brine
  3. dry with materialdried (MgSO4)
  4. concentrationconcentrated in vacuo
  5. dissolutionThe resulting residue was dissolved in dioxane (10 mL)
  6. additionHCl (12N, 1.5 mL) added
  7. stirringThe reaction mixture was stirred at RT for 18 h
  8. additionthen made basic by addition of 1N NaOH
  9. extractionThe aqueous phase was extracted with EtOAc (×3)
  10. washthe combined organic fractions washed with brine
  11. dry with materialdried (MgSO4)
  12. concentrationconcentrated under reduced pressure
  13. customThe resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM)

Sources & evidence

ORD record
ord-43f63e7b7e1242f395af19e7d65a3497
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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