Ethanamine, 2,2,2-trifluoro- → (2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(4-fluorophenyl)-N-(2,2,2-trifluoroethyl)ethanamide

HRID 45607Notes

Reaction equation

HRID 45607 reaction equation
C(O[C:6]([NH:8][C@H:9]([CH:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34]1)[C:10]([N:12]([C@H:22]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:23](O)=[O:24])[C@@H:13](C(OC)=O)[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])=[O:7])(C)(C)C.C(N(C(C)C)CC)(C)C.[F:51][C:52]([F:56])([F:55])[CH2:53][NH2:54]>CN(C)C=O>[CH2:41]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH:33]1[C@H:9]1[NH:8][C:6](=[O:7])[C@@H:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:12]([C@H:22]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[C:23]([NH:54][CH2:53][C:52]([F:56])([F:55])[F:51])=[O:24])[C:10]1=[O:11]

Participants

5

Reactant 3

HCID 9773Ethanamine, 2,2,2-trifluoro-HCID 81531DiisopropylethylamineHCID 57439045(2R)-{[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl][(1R)-1-(methoxycarbonyl)-3-methylbutyl]amino}(4-fluorophenyl)ethanoic acid

Product 1

HCID 11375822(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(4-fluorophenyl)-N-(2,2,2-trifluoroethyl)ethanamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A solution of (2R)-{[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)ethanoyl][(1R)-1-(methoxycarbonyl)-3-methylbutyl]amino}(4-fluorophenyl)ethanoic acid (73 mg) in N,N-dimethylformamide (2 ml) was sequentially treated with diisopropylethylamine (51 μl), phosphorusI (1-hydroxy-1H-benzotriazolato-O)tri-1-pyrrolidinyl-(T-4)-hexafluorophosphate (80 mg) and then after 2 minutes, 2,2,2-trifluoroethylamine (25 μl). This reaction mixture was stirred for 2 hours before being partitioned between 2M aqueous hydrochloric acid and ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine before being dried over magnesium sulphate and evaporated in vacuo. The residue was dissolved in 4M hydrogen chloride in dioxane and stirred for 7 hours at room temperature. The reagent was removed in vacuo and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The separated organic fraction was washed with brine before being dried over magnesium sulphate and evaporated in vacuo. The crude material was purified by column chromatography (silica) eluting with methanol:dichloromethane (1% to 3%) to furnish ((2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-2-(4-fluorophenyl)-N-(2,2,2-trifluoroethyl)ethanamide (10 mg)

Workup

  1. custombefore being partitioned between 2M aqueous hydrochloric acid and ethyl acetate
  2. washThe organic layer was washed with saturated aqueous sodium bicarbonate solution and brine
  3. dry with materialbefore being dried over magnesium sulphate
  4. customevaporated in vacuo
  5. dissolutionThe residue was dissolved in 4M hydrogen chloride in dioxane
  6. stirringstirred for 7 hours at room temperature
  7. customThe reagent was removed in vacuo
  8. customthe residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution
  9. washThe separated organic fraction was washed with brine
  10. dry with materialbefore being dried over magnesium sulphate
  11. customevaporated in vacuo
  12. customThe crude material was purified by column chromatography (silica)
  13. washeluting with methanol

Sources & evidence

ORD record
ord-d2c49389091e4e5e99cd75694aff8b82
Source dataset
uspto-grants-2013_09
Patent number
US08541579B2

Reaction notes

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