Nitrogen → Cyclopentyl(S)-2-{4-[6-Amino-5-(4-fluorobenzoyl)-2-oxo-2H-pyridin-1-yl]cyclohexyl amino}-3-phenylpropionate

HRID 1667374Notes

Reaction equation

HRID 1667374 reaction equation
[NH2:1][C:2]1[N:7]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[C:6](=[O:15])[CH:5]=[CH:4][C:3]=1[C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.[CH:25]1([O:30][C:31](=[O:41])[C@H:32]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[NH2:33])[CH2:29][CH2:28][CH2:27][CH2:26]1.N#N.[BH3-]C#N.[Na+]>CO.CC(O)=O>[NH2:1][C:2]1[N:7]([CH:8]2[CH2:13][CH2:12][CH:11]([NH:33][C@@H:32]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:31]([O:30][CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29]3)=[O:41])[CH2:10][CH2:9]2)[C:6](=[O:15])[CH:5]=[CH:4][C:3]=1[C:16](=[O:24])[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1

Participants

7

Reactant 4

HCID 947NitrogenHCID 5003444Sodium cyanoborohydrideHCID 53840847Cyclopentyl (2S)-2-amino-3-phenylpropanoateHCID 576584256-Amino-5-(4-fluorobenzoyl)-1-(4-oxo-cyclohexyl)-1H-pyridin-2-one

Product 1

HCID 57658387Cyclopentyl(S)-2-{4-[6-Amino-5-(4-fluorobenzoyl)-2-oxo-2H-pyridin-1-yl]cyclohexyl amino}-3-phenylpropionate

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 887MethanolSolvent

Procedure

Intermediate 6 (50 mg, 0.15 mmol) was added to a colourless solution of L-phenylalanine cyclopentyl ester (89 mg, 0.38 mmol) in MeOH (10 ml) at RT/N2 and stirred at RT for 1 h. AcOH glacial was added dropwise to adjust the pH to 6 followed by the NaCNBH3 (38 mg, 0.61 mmol). The resultant colourless solution was stirred at RT overnight and then carefully quenched with sat. NaHCO3 (20 ml) and extracted into CH2Cl2 (3×15 ml). The combined organic phases were washed with 2M HCl (2×20 ml), brine (20 ml), dried (Na2SO4), filtered and concentrated in vacuo giving a cream coloured solid. Purification by flash column chromatography (silica, gradient elution 40-100% EtOAc/heptane) gave the desired material, separable as two isomers, isomer 1 (Example 34) as a white solid (Yield=39 mg, 47%) LCMS purity 100%, m/z 546 [M+H]+, 1H NMR (400 MHz, CD3OD), δ: 1.40-2.05 (16H, m), 2.85-3.10 (3H, m), 3.60-3.70 (1H, m), 4.55-4.65 (1H, m), 5.10-5.20 (1H, m), 5.70 (1H, d), 7.15-7.40 (7H, m), 7.45-7.50 (1H, m), 7.50-7.60 (2H, m) and isomer 2 (Example 35) LCMS purity 97%, m/z 546 [M+H]+, 1H NMR (400 MHz, CD3OD), δ: 1.25-1.85 (12H, m), 1.95-2.20 (2H, m), 2.45-2.95 (4H, m), 3.00-3.10 (1H, m), 3.65-3.75 (1H, m), 4.55-4.65 (1H, m), 5.05-5.15 (1H, m), 5.65 (1H, d), 7.20-7.35 (7H, m), 7.40-7.50 (1H, m), 7.50-7.60 (2H, m) as a colourless film (Yield=15 mg, 18%).

Workup

  1. stirringThe resultant colourless solution was stirred at RT overnight
  2. customcarefully quenched with sat. NaHCO3 (20 ml)
  3. extractionextracted into CH2Cl2 (3×15 ml)
  4. washThe combined organic phases were washed with 2M HCl (2×20 ml), brine (20 ml)
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customgiving a cream
  9. customPurification
  10. washby flash column chromatography (silica, gradient elution 40-100% EtOAc/heptane)

Sources & evidence

ORD record
ord-8b786c1b1b494c1185d0dc3996cb081e
Source dataset
uspto-grants-2011_10
Patent number
US08044211B2

Reaction notes

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