Ethanamine, 2,2,2-trifluoro- → tert-butyl (2S,5S)-2-[(2-{[N-(tert-butoxycarbonyl)-4-fluoro-beta-(4-fluorophenyl)-L-phenylalanyl]amino}-6-fluorophenoxy)methyl]-5-[({[(2,2,2-trifluoroethyl)amino]carbonyl}oxy)methyl]morpholine-4-carboxylate

HRID 629747Notes

Reaction equation

HRID 629747 reaction equation
[C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([NH:27][C:28]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:29]=1[O:30][CH2:31][C@H:32]1[O:37][CH2:36][C@@H:35]([CH2:38][OH:39])[N:34]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:33]1)=[O:26])[CH:10]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:57](N2C=NC=C2)=[O:58])C=1.[F:64][C:65]([F:69])([F:68])[CH2:66][NH2:67]>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([NH:27][C:28]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:29]=1[O:30][CH2:31][C@H:32]1[O:37][CH2:36][C@@H:35]([CH2:38][O:39][C:57]([NH:67][CH2:66][C:65]([F:69])([F:68])[F:64])=[O:58])[N:34]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH2:33]1)=[O:26])[CH:10]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

5

Reactant 3

HCID 9773Ethanamine, 2,2,2-trifluoro-HCID 682631,1'-CarbonyldiimidazoleHCID 86726346tert-butyl (2S,5R)-2-[(2-{[N-(tert-butoxycarbonyl)-4-fluoro-beta-(4-fluorophenyl)-L-phenylalanyl]amino}-6-fluorophenoxy)methyl]-5-(hydroxymethyl)morpholine-4-carboxylate

Product 1

HCID 86726347tert-butyl (2S,5S)-2-[(2-{[N-(tert-butoxycarbonyl)-4-fluoro-beta-(4-fluorophenyl)-L-phenylalanyl]amino}-6-fluorophenoxy)methyl]-5-[({[(2,2,2-trifluoroethyl)amino]carbonyl}oxy)methyl]morpholine-4-carboxylateYield 74%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Conditions

Temperature
60 °C

Procedure

tert-butyl (2S,5R)-2-[(2-{[N-(tert-butoxycarbonyl)-4-fluoro-β-(4-fluorophenyl)-L-phenylalanyl]amino}-6-fluorophenoxy)methyl]-5-(hydroxymethyl)morpholine-4-carboxylate (350 mg, 0.489 mmol) and CDI (159 mg, 0.978 mmol) in pyridine (4.89 mL) were heated to 60° C. for 30 min, LC/MS shows formation of desired intermediate. 2,2,2-trifluoroethylamine (1153 μl, 14.67 mmol) was then added and the reaction heated at 60° C. overnight (18 hours). LCMS shows complete conversion the next morning. The solvent was removed in vacuo and the residue was purified on silica gel (120 g), eluting with a gradient of 10-100% EtOAc/hexanes to afford the title compound (310 mg, 0.361 mmol, 74% yield) as a white foam, MS (ESI): m/z=841.4 (M+H); 98% pure by LC/MS.

Workup

  1. customThe solvent was removed in vacuo
  2. customthe residue was purified on silica gel (120 g)
  3. washeluting with a gradient of 10-100% EtOAc/hexanes

Sources & evidence

ORD record
ord-695a4b9ac0cb4754bd78bcea56af3d3e
Source dataset
uspto-grants-2016_04
Patent number
US09315475B2

Reaction notes

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