4-Methylmorpholine → 2-((S)-1-aminoethyl)-5-fluoro-3-phenyl-3H-benzoimidazole-4-carbonitrile hydrochloride

HRID 243363Notes

Reaction equation

HRID 243363 reaction equation
[NH2:1][C:2]1[C:3]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[C:5]#[N:6].C(OC([NH:25][C@@H:26]([CH3:30])[C:27](O)=O)=O)(C)(C)C.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.[ClH:48].CN(C)CCCN=C=NCC>C(Cl)Cl.O>[ClH:48].[NH2:25][C@H:26]([C:30]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:3]2[C:4]([C:5]#[N:6])=[C:7]([F:10])[CH:8]=[CH:9][C:2]=2[N:1]=1)[CH3:27]

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 85082Tert-butoxycarbonylalanineHCID 181649HOAtHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 681579663-Amino-6-fluoro-2-phenylaminobenzonitrile

Product 1

HCID 681571202-((S)-1-aminoethyl)-5-fluoro-3-phenyl-3H-benzoimidazole-4-carbonitrile hydrochloride

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

A mixture of 3-amino-6-fluoro-2-phenylaminobenzonitrile (960 mg, 4.22 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (879 mg, 4.6 mmol), HOAt (633 mg, 4.6 mmol), 4-methylmorpholine (1.02 mL, 9.29 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (892 mg, 4.6 mmol) in DCM (5 mL) was stirred at RT for 1 h. The reaction mixture was diluted with water and extracted with DCM (×3). The combined organic fractions were washed with brine, then dried (MgSO4) and concentrated in vacuo. A solution of the resulting residue in AcOH (5 mL) was heated at 70° C. for 18 h and then concentrated under reduced pressure. The resulting residue was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The aqueous phase was extracted with EtOAc (×3) and the combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was dissolved in 4N HCl in dioxane (5 mL) and stirred at RT for 1 h. The volatiles were removed under reduced pressure to afford 2-((S)-1-aminoethyl)-5-fluoro-3-phenyl-3H-benzoimidazole-4-carbonitrile hydrochloride as a brown solid which was used in the following step without further purification.

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. temperatureA solution of the resulting residue in AcOH (5 mL) was heated at 70° C. for 18 h
  6. concentrationconcentrated under reduced pressure
  7. customThe resulting residue was partitioned between EtOAc
  8. extractionThe aqueous phase was extracted with EtOAc (×3)
  9. washthe combined organic fractions were washed with brine
  10. dry with materialdried (MgSO4)
  11. concentrationconcentrated in vacuo
  12. dissolutionThe resulting residue was dissolved in 4N HCl in dioxane (5 mL)
  13. stirringstirred at RT for 1 h
  14. customThe volatiles were removed under reduced pressure

Sources & evidence

ORD record
ord-1a7af0c256d143d8af3e10c817d3f991
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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