1,2-Dichloroethane → 1-((2R)-2-Cyclohexyl-2-hydroxyethanoyl)-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)-L-prolinamide

HRID 1058280Notes

Reaction equation

HRID 1058280 reaction equation
[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:11]=1[CH2:12][NH:13][C:14](=[O:20])[C@@H:15]1[CH2:19][CH2:18][CH2:17][NH:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:26]1[CH:31]=[C:30]2N=NN(O)[C:29]2=[CH:28][CH:27]=1.[OH2:36].[CH2:37](Cl)[CH2:38]Cl.C(N(C(C)C)CC)(C)C.CN(C=[O:54])C>>[CH:30]1([C@@H:37]([OH:54])[C:38]([N:16]2[CH2:17][CH2:18][CH2:19][C@H:15]2[C:14]([NH:13][CH2:12][C:11]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:10]=2[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:20])=[O:36])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:31]1

Participants

6

Reactant 5

HCID 111,2-DichloroethaneHCID 6228DimethylformamideHCID 81531DiisopropylethylamineHCID 27960291-Hydroxybenzotriazole hydrateHCID 11428605L-prolin-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)amide

Product 1

HCID 699394781-((2R)-2-Cyclohexyl-2-hydroxyethanoyl)-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)-L-prolinamide

Procedure

To a stirred solution of L-prolin-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)amide (1.23 g, 3.32 mmol, 1.0 equiv, HPLC RT=2.77 min), R-hexahydromandelic acid (0.552 g, 3.49 mmol, 1.05 equiv), and HOBT hydrate (0.524 g, 3.32 mmol, 1.0 equiv) in DMF (20 mL) was added EDC (0.855 g, 4.32 mmol, 1.3 equiv). Diisopropylethylamine was then added in portions (0.5 mL total) to bring the pH of the solution to 6-7 as measured on wetted E. Merck pH indicator strips. The mixture was stirred at ambient temperature for 2 h, at which time HPLC analysis indicated complete consumption of the proline starting material. The DMF was removed under reduced pressure and the residue was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (50 mL). The EtOAc layer was separated, dried over anhydrous MgSO4, and filtered. The filtrate solvent was removed under reduced pressure and the residue was purified by flash chromatography using EtOAc as eluant. 1-((2R)-2-Cyclohexyl-2-hydroxyethanoyl)-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)-L-prolinamide was obtained as a colorless gum (1.87 g, 90%; TLC Rf=0.7 (EtOAc); HPLC RT=3.45 min, method A; LC-MS m/z=508).

Workup

  1. customconsumption of the proline starting material
  2. customThe DMF was removed under reduced pressure
  3. customthe residue was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (50 mL)
  4. customThe EtOAc layer was separated
  5. dry with materialdried over anhydrous MgSO4
  6. filtrationfiltered
  7. customThe filtrate solvent was removed under reduced pressure
  8. customthe residue was purified by flash chromatography

Sources & evidence

ORD record
ord-cee872273cdc4972880f802db3be5c56
Source dataset
uspto-grants-2003_02
Patent number
US06515011B2

Reaction notes

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