Tert-butoxycarbonylalanine → 2-((S)-1-tert-Butoxycarbonylaminoethyl)-3-cyclopropyl-5-fluoro-3H-benzoimidazole-4-carboxylic acid methyl ester

HRID 243110Notes

Reaction equation

HRID 243110 reaction equation
[CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=1[NH:12][CH:13]1[CH2:15][CH2:14]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.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:12]([CH:13]3[CH2:14][CH2:15]3)[C:29]([C@@H:25]([NH:24][C:22]([O:21][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:23])[CH3:26])=[N:11][C:6]=2[CH:7]=[CH:8][C:9]=1[F:10])=[O:16]

Participants

6

Reactant 4

HCID 85082Tert-butoxycarbonylalanineHCID 181649HOAtHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 681570823-Amino-2-cyclopropylamino-6-fluorobenzoic acid methyl ester

Product 1

HCID 681572452-((S)-1-tert-Butoxycarbonylaminoethyl)-3-cyclopropyl-5-fluoro-3H-benzoimidazole-4-carboxylic acid methyl esterYield 55%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

A mixture of 3-amino-2-cyclopropylamino-6-fluorobenzoic acid methyl ester (756 mg, 3.37 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (702 mg, 3.71 mmol), HOAt (505 mg, 3.71 mmol) and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (711 mg, 3.71 mmol) in DCM (20 mL) was stirred at 0° C. for 1 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic fraction was dried and concentrated in vacuo. The resulting residue was taken up in AcOH (20 mL) and heated at 70° C. for 21 h. After cooling to RT, the volatiles were evaporated in vacuo and the residue partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The aqueous phase was extracted with EtOAc and the combined organic fractions washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in DCM) to afford the title compound (700 mg, 55% over 2 steps). LCMS (Method C): RT 3.27 min [M+H]+ 378.18

Workup

  1. customThe reaction mixture was partitioned between DCM
  2. customThe organic fraction was dried
  3. concentrationconcentrated in vacuo
  4. temperatureheated at 70° C. for 21 h
  5. temperatureAfter cooling to RT
  6. customthe volatiles were evaporated in vacuo
  7. customthe residue partitioned between EtOAc
  8. extractionThe aqueous phase was extracted with EtOAc
  9. washthe combined organic fractions washed with brine
  10. dry with materialdried (Na2SO4)
  11. concentrationconcentrated in vacuo
  12. customThe resulting residue was purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in DCM)

Sources & evidence

ORD record
ord-3de53bc0af724abc989f3130f53403a2
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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