4-Methylmorpholine → [(S)-1-(6-Fluoro-1-isopropyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester

HRID 243123Notes

Reaction equation

HRID 243123 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([CH3:12])[CH3:11])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:13]([O:17][C:18]([NH:20][C@@H:21]([CH3:25])[C:22](O)=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.CN(C)CCCN=C=NCC>C(Cl)Cl.C(O)(=O)C>[C:13]([O:17][C:18](=[O:19])[NH:20][C@H:21]([C:22]1[N:9]([CH:10]([CH3:12])[CH3:11])[C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[N:8]=1)[CH3:25])([CH3:16])([CH3:15])[CH3:14]

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 85082Tert-butoxycarbonylalanineHCID 181649HOAtHCID 104873045-fluoro-N1-(propan-2-yl)benzene-1,2-diamine

Product 1

HCID 68179453[(S)-1-(6-Fluoro-1-isopropyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl esterYield 88%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 6344DichloromethaneSolvent2×

Procedure

4-Fluoro-N2-isopropylbenzene-1,2-diamine (0.7 g, 5.07 mmol) was dissolved in DCM (10 mL) and (S)-2-tert-butoxycarbonylaminopropionic acid (1.06 g, 5.58 mmol) added. To the resultant dark red solution was added HOAt (0.76 g, 5.58 mmol), followed by N-methyl morpholine (1.23 mL, 11.15 mmol) and N-(3-dimethylaminopropyl)-N′ ethylcarbodiimide (1.07 g, 5.58 mmol). The resultant blue/black solution was stirred at RT overnight, under an atmosphere of nitrogen. The mixture was diluted with DCM (40 mL) and washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL). The organic fraction was dried (MgSO4), filtered and concentrated in vacuo to afford a dark red oil. This was purified by column chromatography (silica gel, gradient 0-20% EtOAc in DCM) to afford a red oil which solidified on standing. This was dissolved in acetic acid (20 mL) and heated at 70° C. overnight. The resultant mixture was allowed to cool to RT and was concentrated in vacuo to afford the title compound as a dark red gum (1.0 g, 88%). This material was used in the next step without any purification. LCMS (Method B): RT 2.78 min [M+H]+ 322.2

Workup

  1. washwashed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL)
  2. dry with materialThe organic fraction was dried (MgSO4)
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. customto afford a dark red oil
  6. customThis was purified by column chromatography (silica gel, gradient 0-20% EtOAc in DCM)
  7. customto afford a red oil which
  8. temperatureheated at 70° C. overnight
  9. temperatureto cool to RT
  10. concentrationwas concentrated in vacuo

Sources & evidence

ORD record
ord-79c19910458947938e1f2dc122490460
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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