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

HRID 629704Notes

Reaction equation

HRID 629704 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[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][C:25](=[O:45])[C@H:26]([CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:27][C:28]([O:30][CH3:31])=[O:29])[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]1C=[CH:65][CH:64]=[CH:63][C:60]=1CN>N1C=CC=CC=1.CCOC(C)=O>[F:58][C:59]1[CH:60]=[CH:63][CH:64]=[CH:65][C:55]=1[CH2:54][NH:53][C:51]([O:1][CH2:2][C@H:3]1[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]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][C:25](=[O:45])[C@H:26]([CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:27][C:28]([O:30][CH3:31])=[O:29])[O:5][CH2:4]1)=[O:52]

Participants

6

Reactant 3

HCID 666492-FluorobenzylamineHCID 682631,1'-CarbonyldiimidazoleHCID 86726307(2R,5R)-5-hydroxymethyl-2-{2-[2-((S)-2-methoxycarbonylamino-3,3-diphenyl-propionylamino)-phenyl]-ethyl}-morpholine-4-carboxylic acid tert-butyl ester

Product 1

HCID 86726310tert-butyl (2R,5S)-5-({[(2-fluorobenzyl)carbamoyl]oxy}methyl)-2-[2-(2-{[N-(methoxycarbonyl)-beta-phenyl-L-phenylalanyl]amino}phenyl)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}phenyl)ethyl]morpholine-4-carboxylate (Example 1, step 10) (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 2-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-f74c5d6ed94f4d859d402b78cd2fc2bd
Source dataset
uspto-grants-2016_04
Patent number
US09315475B2

Reaction notes

Loading…