4-Methylmorpholine → [(S)-1-(7-chloro-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester

HRID 242932Notes

Reaction equation

HRID 242932 reaction equation
[Cl: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:17]([O:21][C:22]([NH:24][C@@H:25]([CH3:29])[C:26](O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:17]([O:21][C:22](=[O:23])[NH:24][C@H:25]([C:26]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]2[C:2]([Cl:1])=[C:7]([F:8])[CH:6]=[CH:5][C:4]=2[N:9]=1)[CH3:29])([CH3:20])([CH3:19])[CH3:18]

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 85082Tert-butoxycarbonylalanineHCID 181649HOAtHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 681577133-Chloro-4-fluoro-N2-phenylbenzene-1,2-diamine

Product 1

HCID 68157284[(S)-1-(7-chloro-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 516892Sodium BicarbonateSolvent

Procedure

A mixture of 3-chloro-4-fluoro-N2-phenylbenzene-1,2-diamine (300 mg, 1.26 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (264 mg, 1.39 mmol), HOAt (190 mg, 1.39 mmol), 4-methylmorpholine (0.31 mL, 2.79 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (270 mg, 1.39 mmol) in DCM (5 mL) was stirred at RT for 18 h. The reaction mixture was diluted with a saturated aqueous solution of NaHCO3 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 AcOH (5 mL) and the solution heated at 70° C. for 36 h. The volatiles were removed in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in cyclohexane) to afford impure [(S)-1-(7-chloro-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester. The product thus obtained was dissolved in 4N HCl in dioxane (7 mL) and heated at 70° C. for 2 h. The volatiles were removed in vacuo to afford (S)-1-(7-chloro-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride as an off-white foam (368 mg, 80% over three steps). LCMS (Method C): RT 2.28 min [M+H]+ 290.2.

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 AcOH (5 mL)
  6. temperaturethe solution heated at 70° C. for 36 h
  7. customThe volatiles were removed in vacuo
  8. customthe resulting residue purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in cyclohexane)

Sources & evidence

ORD record
ord-02b1f396a5f04676b9b50ac937c67ad8
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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