4-Methylmorpholine → 1-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3,3-dimethyl-L-prolinamide

HRID 1014157Notes

Reaction equation

HRID 1014157 reaction equation
[CH3:1][C:2]1([CH3:10])[CH2:6][CH2:5][NH:4][C@@H:3]1[C:7]([NH2:9])=[O:8].[CH:11]1([CH2:16][C@H:17]([CH2:21][N:22]([CH:31]=[O:32])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:18](O)=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12]1.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH:11]1([CH2:16][C@H:17]([CH2:21][N:22]([CH:31]=[O:32])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:18]([N:4]2[CH2:5][CH2:6][C:2]([CH3:10])([CH3:1])[C@H:3]2[C:7]([NH2:9])=[O:8])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12]1

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 181649HOAtHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 21305218(R)-3-(Benzyloxy-formyl-amino)-2-cyclopentylmethyl-propionic acidHCID 54083353(S)-3,3-dimethylpyrrolidine-2-carboxamide

Product 1

HCID 578781031-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3,3-dimethyl-L-prolinamideYield 63.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

In an oven-dried 100 ml flask was dissolved 3,3-dimethyl-L-prolinamide (0.0174 mol, 2.46 g), (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (WO 2003101442, 0.0174 mol, 5.30 g), and 1-hydroxy-7-azabenzotriazole (0.0191 mol, 2.60 g) in 25 ml DMF with stirring under argon. To this solution was added N-methylmorpholine (0.0522 mol, 5.28 g) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.0191 mol, 3.67 g). The reaction was stirred at 20° C. for 16 hr after which time it was diluted with 300 ml water and extracted with ethylacetate (3×100 ml). The combined organics were washed with 100 ml 1M HCl followed by brine. The organics were dried over MgSO4, filtered and concentrated to a yellow oil and purified on 90 g silica (chloroform/methanol/water), yielding 4.72 g (63%) of 1-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3,3-dimethyl-L-prolinamide as a white solid. LCMS (ESI+)=430 m/z (MH+). 1H NMR (400 MHz, CDCl3)— rotomers δ 8.20-7.86 (m, 1H), 7.49-7.30 (m, 5H), 6.01-5.50 (m, 2H), 5.05-4.70 (m, 2H), 3.89-3.56 (m, 4H), 3.14-2.90 (m, 2H), 2.16-2.05 (m, 1H), 1.89-1.40 (m, 10H), 1.13-1.06 (m, 6H), 1.02-0.84 (m, 2H).

Workup

  1. stirringThe reaction was stirred at 20° C. for 16 hr after which time it
  2. extractionextracted with ethylacetate (3×100 ml)
  3. washThe combined organics were washed with 100 ml 1M HCl
  4. dry with materialThe organics were dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated to a yellow oil
  7. custompurified on 90 g silica (chloroform/methanol/water)

Sources & evidence

ORD record
ord-75e67f6cfde24d0f8570c4fb37bb5b09
Source dataset
uspto-grants-2011_07
Patent number
US07982053B2

Reaction notes

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