1,2-Dichloroethane → 1-((2R)-3,3-dimethyl-2-hydroxybutanoyl)-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)-L-prolinamide

HRID 1058278Notes

Reaction equation

HRID 1058278 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].[CH3:26][C:27]([CH3:34])([CH3:33])[C@@H:28]([OH:32])[C:29](O)=[O:30].C1C=C2N=NN(O)C2=CC=1.O.C(Cl)CCl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:26][C:27]([CH3:34])([CH3:33])[C@@H:28]([OH:32])[C:29]([N:16]1[CH2:17][CH2:18][CH2:19][C@H:15]1[C:14]([NH:13][CH2:12][C:11]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:10]=1[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:20])=[O:30]

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 81531DiisopropylethylamineHCID 27960291-Hydroxybenzotriazole hydrateHCID 11344038(2R)-2-hydroxy-3,3-dimethylbutanoic acidHCID 11428605L-prolin-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)amide

Product 1

HCID 113061991-((2R)-3,3-dimethyl-2-hydroxybutanoyl)-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)-L-prolinamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a stirred solution of L-prolin-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)amide from step 2 (3.90 g, 10.6 mmol, HPLC RT=2.77 min), (2R)-3,3-dimethyl-R-hydroxybutyric acid from step 3 (1.40 g, 10.6 mmol), and HOBT hydrate (1.68 g, 11 mmol) in DMF (60 mL) was added EDC (2.65 g, 13.8 mmol). Diisopropylethylamine was then added slowly in portions (11.5 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 6 h, at which time HPLC analysis indicated complete consumption of the proline starting material. Water (10 mL) was added and the solvents were removed under reduced pressure. The residue was partitioned between EtOAc (300 mL) and saturated aqueous NaHCO3 (200 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 a gradient elution of 2:1, 4:1, and 1:0 EtOAc:hexanes. 1-((2R)-3,3-dimethyl-2-hydroxybutanoyl)-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)-L-prolinamide was obtained as a colorless gum (4.65 g, 91%; TLC Rf=0.7 (EtOAc); HPLC RT=3.35 min, method A; LC-MS m/z=482).

Workup

  1. customconsumption of the proline starting material
  2. additionWater (10 mL) was added
  3. customthe solvents were removed under reduced pressure
  4. customThe residue was partitioned between EtOAc (300 mL) and saturated aqueous NaHCO3 (200 mL)
  5. customThe EtOAc layer was separated
  6. dry with materialdried over anhydrous MgSO4
  7. filtrationfiltered
  8. customThe filtrate solvent was removed under reduced pressure
  9. customthe residue was purified by flash chromatography
  10. washa gradient elution of 2:1, 4:1, and 1:0 EtOAc

Sources & evidence

ORD record
ord-eaaab7d3860b46709e29a2f8f9e90a78
Source dataset
uspto-grants-2003_02
Patent number
US06515011B2

Reaction notes

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