1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → morpholine-4-carboxylic acid [(S)-3,3-difluoro-1-((S)-1-hydroxymethyl-1-methyl-butylcarbamoyl)-4-phenyl-butyl]-amide

HRID 1455603Notes

Reaction equation

HRID 1455603 reaction equation
Cl.[NH2:2][C@@:3]([CH3:9])([CH2:6][CH2:7][CH3:8])[CH2:4][OH:5].[F:10][C:11]([F:33])([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:12][C@H:13]([NH:17][C:18]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:19])[C:14](O)=[O:15].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[F:33][C:11]([F:10])([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:12][C@H:13]([NH:17][C:18]([N:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1)=[O:19])[C:14](=[O:15])[NH:2][C@@:3]([CH2:4][OH:5])([CH3:9])[CH2:6][CH2:7][CH3:8]

Participants

8

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 57535341(S)-4,4-Difluoro-2-[(morpholine-4-carbonyl)-amino]-5-phenyl-pentanoic acidHCID 86607351(S)-2-amino-2-methyl-pentan-1-ol hydrochloride

Product 1

HCID 86607350morpholine-4-carboxylic acid [(S)-3,3-difluoro-1-((S)-1-hydroxymethyl-1-methyl-butylcarbamoyl)-4-phenyl-butyl]-amideYield 75.4%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of (S)-2-amino-2-methyl-pentan-1-ol hydrochloride (104.4 mg, 0.67 mmol), (S)-4,4-difluoro-2-[(morpholine-4-carbonyl)-amino]-5-phenyl-pentanoic acid (231 mg, 0.67 mmol), EDCI (154 mg, 0.8 mmol), HOBT (108 mg, 0.8 mmol) and Diisopropyl ethylamine (0.23 mL) in DMF (2 mL) is stirred at room temperature overnight. The reaction mixture is diluted with ethyl acetate, washed with cold 1N HCl, saturated NaHCO3 and then saturated NaCl solution. The organic phase is dried over MgSO4 and solvent evaporated under reduced pressure to give the crude product. Purification by Silica gel column chromatography, eluting with ethyl acetate and heptane mixture gives morpholine-4-carboxylic acid [(S)-3,3-difluoro-1-((S)-1-hydroxymethyl-1-methyl-butylcarbamoyl)-4-phenyl-butyl]-amide (223 mg, 75%).

Workup

  1. washwashed with cold 1N HCl, saturated NaHCO3
  2. dry with materialThe organic phase is dried over MgSO4 and solvent
  3. customevaporated under reduced pressure
  4. customto give the crude product
  5. customPurification by Silica gel column chromatography
  6. washeluting with ethyl acetate and heptane mixture

Sources & evidence

ORD record
ord-b0cdd4d63746428d83aef298ac799755
Source dataset
uspto-grants-2009_01
Patent number
US07482448B2

Reaction notes

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