4-Methylmorpholine → 1-(2-ethyl-2-hydroxybutanoyl)-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)-L-prolinamide

HRID 1058288Notes

Reaction equation

HRID 1058288 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].[CH2:26]([C:28]([OH:34])([CH2:32][CH3:33])[C:29](O)=[O:30])[CH3:27].CN1CCOCC1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:26]([C:28]([OH:34])([CH2:32][CH3:33])[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])[CH3:27]

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 771992-Ethyl-2-hydroxybutanoic acidHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 11428605L-prolin-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)amide

Product 1

HCID 699380721-(2-ethyl-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 (100 mg, 0.27 mmol), 2-ethyl-2-hydroxybutanoic acid (36 mg, 0.27 mmol), and NMM (30 μL, 0.27 mmol) in DMF (5 mL) at ambient temperature under nitrogen atmosphere was added BOP reagent (144 mg, 0.326 mmol). The mixture was stirred at ambient temperature for 72 h. The solvent was removed under reduced pressure. The residue was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (100 mL). The EtOAc layer was separated, dried over anhydrous Na2SO4, and filtered. The filtrate solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using a gradient of 95:5 to 0:100 (water:CH3CN, 0.1% TFA) over 30 min with a flow rate of 18 mL/min. After concentration of desired fractions in vacuo, 1-(2-ethyl-2-hydroxybutanoyl)-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)-L-prolinamide was obtained an amorphous solid (55 mg; HPLC RT=3.32 min, method A; LC-MS m/z=482.2; 1H NMR, 400 MHz, CDCl3, 7.25 ppm (m, 3H), 7.2 ppm (m, 1H), 7.1 ppm (br s, 1H), 5.45 ppm (br s, 1H), 4.55 ppm (m, 2H), 4.3 ppm (m, 3H), 3.7 ppm (m, 2H), 2.2 ppm (m, 2H), 2.0 ppm (m, 2H), 1.8 ppm (m, 2H), 1.7 ppm (m, 2H), 1.4 ppm (s, 9H), 0.8 ppm (m, 6H)).

Workup

  1. customThe solvent was removed under reduced pressure
  2. customThe residue was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (100 mL)
  3. customThe EtOAc layer was separated
  4. dry with materialdried over anhydrous Na2SO4
  5. filtrationfiltered
  6. customThe filtrate solvent was removed under reduced pressure
  7. customthe residue was purified by preparative reverse phase HPLC
  8. customover 30 min

Sources & evidence

ORD record
ord-7b387fc4c8ca48cb9d1c51db16db2229
Source dataset
uspto-grants-2003_02
Patent number
US06515011B2

Reaction notes

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