1,2-Dichloroethane → (2R,5R)-2,5-bis(4-fluorobenzyl)-6-oxo-6-((S)-2-oxo-1-phenylazepan-3-ylamino)hexanoic acid

HRID 529562Notes

Reaction equation

HRID 529562 reaction equation
C(Cl)CCl.[F:5][C:6]1[CH:30]=[CH:29][C:9]([CH2:10][C@@H:11]([CH2:15][CH2:16][C@H:17]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:18]([OH:20])=[O:19])[C:12](O)=[O:13])=[CH:8][CH:7]=1.[NH2:31][C@H:32]1[CH2:38][CH2:37][CH2:36][CH2:35][N:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]1=[O:45]>CN(C=O)C.C(Cl)Cl>[F:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C@@H:17]([CH2:16][CH2:15][C@H:11]([CH2:10][C:9]2[CH:29]=[CH:30][C:6]([F:5])=[CH:7][CH:8]=2)[C:12](=[O:13])[NH:31][C@H:32]2[CH2:38][CH2:37][CH2:36][CH2:35][N:34]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]2=[O:45])[C:18]([OH:20])=[O:19])=[CH:27][CH:26]=1

Participants

6

Reactant 3

HCID 111,2-DichloroethaneHCID 29926948HCID 29926948, compoundHCID 68292048HCID 68292048, compound

Product 1

HCID 68311028(2R,5R)-2,5-bis(4-fluorobenzyl)-6-oxo-6-((S)-2-oxo-1-phenylazepan-3-ylamino)hexanoic acidYield 71%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

EDC (16 mg, 0.083 mmol) was added to a 0° C. solution of (2R,5R)-2,5-Bis(4-fluorobenzyl)hexanedioic acid (30 mg, 0.083 mmol) in DMF (1 mL) and DCM (5 mL). The ice bath was removed and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated to remove most of the DCM. (S)-3-Amino-1-phenylazepan-2-one (21 mg, 0.085 mmol) was added followed by TEA (18.4 mg, 0.182 mmol). The reaction mixture was left to stir at rt for 3 hr. The reaction mixture was partitioned between EtOAc and 5% aqueous KHSO4. The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give (2R,5R)-2,5-bis(4-fluorobenzyl)-6-oxo-6-((S)-2-oxo-1-phenylazepan-3-ylamino)hexanoic acid (32 mg, 0.058 mmol, 71% yield) as a colorless syrup. Anal. Calcd. for C32H34F2N2O4 m/z 548.3. found: 549.1 (M+H)+.

Workup

  1. customThe ice bath was removed
  2. concentrationThe reaction mixture was concentrated
  3. customto remove most of the DCM
  4. waitThe reaction mixture was left
  5. stirringto stir at rt for 3 hr
  6. customThe reaction mixture was partitioned between EtOAc and 5% aqueous KHSO4
  7. customThe organic phase was isolated
  8. washwashed with saturated aqueous NaCl
  9. dry with materialdried over MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customThe crude product was purified
  13. washeluting with a gradient of 0-100% EtOAc/Hex

Sources & evidence

ORD record
ord-b926733c54b94d98a677b1326158f279
Source dataset
uspto-grants-2016_05
Patent number
US09346852B2

Reaction notes

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