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 2108693노트

반응식

HRID 2108693 반응식
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

참가 물질

7

반응물 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

생성물 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

시약·촉매·용매 1

HCID 8471Triethylamine용매

실험 절차

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 (x2), aqueous citric acid (0.5M, x2) and brine (x1l), 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 (x3) and cyclohexane/ether (1:1, x2). 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, x2), saturated aqueous sodium bicarbonate solution (x1) and brine (x1). The liquors were then dried over magnesium sulphate and in vacuo and were then co-evaporated with cyclohexane: ether (1: 1, x2). 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)

후처리

  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 (x2), aqueous citric acid (0.5M, x2) and brine (x1l)
  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, x2), saturated aqueous sodium bicarbonate solution (x1) and brine (x1)
  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

출처 및 근거

ORD 기록
ord-c6739524ed7743c48e7bdf70ee42c8cb
출처 데이터셋
uspto-grants-2009_04
특허 번호
US07514437B2

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