4-Fluorobenzylamine → tert-butyl (2R,5S)-5-({[(4-fluorobenzyl)carbamoyl]oxy}methyl)-2-[2-(2-{[N-(methoxycarbonyl)-beta-phenyl-L-phenylalanyl]amino}pyridin-3-yl)ethyl]morpholine-4-carboxylate

HRID 629709Notes

Reaction equation

HRID 629709 reaction equation
[OH:1][CH2:2][C@H:3]1[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][C@@H:6]([CH2:16][CH2:17][C:18]2[C:19]([NH:24][C:25](=[O:45])[C@H:26]([CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[NH:27][C:28]([O:30][CH3:31])=[O:29])=[N:20][CH:21]=[CH:22][CH:23]=2)[O:5][CH2:4]1.C1N=CN([C:51]([N:53]2C=N[CH:55]=[CH:54]2)=[O:52])C=1.[F:58][C:59]1[CH:66]=[CH:65]C(CN)=[CH:61][CH:60]=1>N1C=CC=CC=1.CCOC(C)=O>[F:58][C:59]1[CH:66]=[CH:65][C:55]([CH2:54][NH:53][C:51]([O:1][CH2:2][C@H:3]2[N:8]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:7][C@@H:6]([CH2:16][CH2:17][C:18]3[C:19]([NH:24][C:25](=[O:45])[C@H:26]([CH:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[NH:27][C:28]([O:30][CH3:31])=[O:29])=[N:20][CH:21]=[CH:22][CH:23]=3)[O:5][CH2:4]2)=[O:52])=[CH:61][CH:60]=1

Participants

6

Reactant 3

HCID 673264-FluorobenzylamineHCID 682631,1'-CarbonyldiimidazoleHCID 86726315tert-butyl (2R,5R)-5-(hydroxymethyl)-2-[2-(2-{[N-(methoxycarbonyl)-beta-phenyl-L-phenylalanyl]amino}pyridin-3-yl)ethyl]morpholine-4-carboxylate

Product 1

HCID 86726316tert-butyl (2R,5S)-5-({[(4-fluorobenzyl)carbamoyl]oxy}methyl)-2-[2-(2-{[N-(methoxycarbonyl)-beta-phenyl-L-phenylalanyl]amino}pyridin-3-yl)ethyl]morpholine-4-carboxylate

Reagents, catalysts & solvents 2

HCID 1049PyridineSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of tert-butyl (2R,5R)-5-(hydroxymethyl)-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}pyridin-3-yl)ethyl]morpholine-4-carboxylate (1 eq) and CDI (2.05 eq.) was dissolved in dry Pyridine (0.04 M) and the resulting solution stirred under N2 at rt for 5 h and then at 49° C. for 0.5 h; then neat 4-fluorobenzylamine (6 eq.) was added and the resulting mixture further stirred at the same temperature for 12 h. The crude reaction mixture was diluted with EtOAc, washed with 5% aq. KHSO4 then sat. NaHCO3, dried over Na2SO4, filtered and concentrated. The residue was purified by automated silicagel flash chromatography system eluted with a gradient 0% to 5% MeOH in DCM, to afford title compound.

Workup

  1. waitat 49° C. for 0.5 h
  2. stirringthe resulting mixture further stirred at the same temperature for 12 h
  3. customThe crude reaction mixture
  4. washwashed with 5% aq. KHSO4
  5. dry with materialsat. NaHCO3, dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was purified by automated silicagel flash chromatography system
  9. washeluted with a gradient 0% to 5% MeOH in DCM

Sources & evidence

ORD record
ord-bad6f00254814ab89c1bca3aeb999080
Source dataset
uspto-grants-2016_04
Patent number
US09315475B2

Reaction notes

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