Methanol → (2R)-2-(4-fluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide

HRID 45606Notes

Reaction equation

HRID 45606 reaction equation
Cl.CO[C:4](=[O:11])[C@@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C(OC([NH:28][C@H:29]([CH:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34]1)[C:30]([OH:32])=O)=O)(C)(C)C.[CH:42]([N+:45]#[C-:46])([CH3:44])[CH3:43].C[OH:48]>C(N(CC)CC)C>[F:12][C:13]1[CH:20]=[CH:19][C:16]([C@@H:17]([N:6]2[C@H:5]([CH2:7][CH:8]([CH3:9])[CH3:10])[C:4](=[O:11])[NH:28][C@H:29]([CH:33]3[CH2:34][C:35]4[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:41]3)[C:30]2=[O:32])[C:46]([NH:45][CH:42]([CH3:44])[CH3:43])=[O:48])=[CH:15][CH:14]=1

Participants

7

Reactant 5

HCID 887MethanolHCID 680234-FluorobenzaldehydeHCID 150783Isopropyl isocyanideHCID 11208543(R)-2-((tert-Butoxycarbonyl)amino)-2-(2,3-dihydro-1H-inden-2-yl)acetic acidHCID 11600782D-Leucine Methyl Ester Hydrochloride

Product 1

HCID 11569194(2R)-2-(4-fluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide

Reagents, catalysts & solvents 1

HCID 8471TriethylamineSolvent

Procedure

To a solution of (D)-leucine methyl ester hydrochloride (300 mg) in methanol (4 ml) was added triethylamine (230 μl) and 4-fluorobenzaldehyde (177 μl). The mixture was stirred for 2.5 hours before (2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoic acid (481 mg) and isopropylisocyanide (225 μl) were sequentially added. After stirring for 16 hr, the solvent was removed in vacuo and the residue was dissolved in chloroform. This solution was washed with a saturated aqueous sodium carbonate solution (×2), aqueous citric acid (0.5M, ×2) and brine (×1), dried over magnesium sulphate and evaporated in vacuo. The residue was dissolved in dichloromethane (2 ml) and trifluoroacetic acid (5 ml) and stirred for 3 hours at ambient temperature. After this time, the solvent was removed in vacuo and the residue co-evaporation with toluene (×3) and cyclohexane/ether (1:1, ×2). The residue was treated with a solution of triethylamine in dioxane (2% solution, 10 ml) and was left to stir overnight. After this time, the dioxane was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with citric acid solution (0.5M, ×2), saturated aqueous sodium bicarbonate solution (×1) and brine (×1). The liquors were then dried over magnesium sulphate and in vacuo and were then co-evaporated with cyclohexane:ether (1:1, ×2). This crude material was purified by Biotage™ (90 g, silica) eluting with toluene:ethyl acetate:cyclohexane (5:3:2) with 5% triethylamine to give (2R)-2-(4-fluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide (149 mg)

Workup

  1. additionwere sequentially added
  2. customthe solvent was removed in vacuo
  3. dissolutionthe residue was dissolved in chloroform
  4. washThis solution was washed with a saturated aqueous sodium carbonate solution (×2), aqueous citric acid (0.5M, ×2) and brine (×1)
  5. dry with materialdried over magnesium sulphate
  6. customevaporated in vacuo
  7. dissolutionThe residue was dissolved in dichloromethane (2 ml)
  8. stirringtrifluoroacetic acid (5 ml) and stirred for 3 hours at ambient temperature
  9. customAfter this time, the solvent was removed in vacuo
  10. additionThe residue was treated with a solution of triethylamine in dioxane (2% solution, 10 ml)
  11. waitwas left
  12. stirringto stir overnight
  13. customAfter this time, the dioxane was removed in vacuo
  14. dissolutionthe residue was dissolved in ethyl acetate
  15. washThe solution was washed with citric acid solution (0.5M, ×2), saturated aqueous sodium bicarbonate solution (×1) and brine (×1)
  16. dry with materialThe liquors were then dried over magnesium sulphate and in vacuo
  17. customThis crude material was purified by Biotage™ (90 g, silica)
  18. washeluting with toluene:ethyl acetate:cyclohexane (5:3:2) with 5% triethylamine

Sources & evidence

ORD record
ord-7a9cab20522146bbb4ad22ea07b9f9e1
Source dataset
uspto-grants-2013_09
Patent number
US08541579B2

Reaction notes

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