1,2-Dichloroethane → tert-Butyl ((S)-1-(((S)-1-((2S,4S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

HRID 339238ノート

反応式

HRID 339238 の反応式
[C:1]([O:5][C:6]([N:8]([CH3:14])[C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15](Cl)CCl.C1C=N[C:22]2N(O)N=N[C:21]=2[CH:20]=1.C[N:30]1[CH2:35][CH2:34][O:33]CC1.[C@H:36]1([NH:46][C:47]([C@H:49]2[NH:53][CH2:52][C@@H:51]([NH:54][C:55](=[O:71])[O:56][CH2:57][CH:58]3[C:70]4[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=4[C:64]4[C:59]3=[CH:60][CH:61]=[CH:62][CH:63]=4)[CH2:50]2)=[O:48])[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH2:38][CH2:37]1>CN(C=O)C.O>[CH:60]1[C:59]2[CH:58]([CH2:57][O:56][C:55]([NH:54][C@@H:51]3[CH2:52][N:53]([C:34](=[O:33])[C@@H:35]([NH:30][C:10](=[O:12])[C@@H:9]([N:8]([CH3:14])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:13])[C:21]([CH3:20])([CH3:22])[CH3:15])[C@H:49]([C:47](=[O:48])[NH:46][C@H:36]4[C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[CH2:39][CH2:38][CH2:37]4)[CH2:50]3)=[O:71])[C:70]3[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=3)[C:64]=2[CH:63]=[CH:62][CH:61]=1

参加物

8

反応物 5

HCID 111,2-DichloroethaneHCID 79724-MethylmorpholineHCID 181649HOAtHCID 7009590(2S)-2-(((tert-butoxy)carbonyl)(methyl)amino)propanoic acidHCID 57806891(9H-fluoren-9-yl)methyl ((3S,5S)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)carbamate

生成物 1

HCID 57806842tert-Butyl ((S)-1-(((S)-1-((2S,4S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate収率 77.2%

試薬・触媒・溶媒 2

HCID 962Water溶媒HCID 6228Dimethylformamide溶媒2 回

実験手順

To a solution of (S)-2-((tert-butoxycarbonyl)(methyl)amino)propanoic acid (Chem-Impex, 2.49 g, 12.3 mmol) in DMF (20 mL) at 0° C. were added EDC (2.94 g, 15.3 mmol), HOAt (2.09 g, 15.3 mmol) and NMM (2.81 mL, 25.6 mmol). The reaction mixture was stirred at ice bath temperature for 20 min, and then treated with a solution of (9H-fluoren-9-yl)methyl ((3S,5S)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)carbamate (6.45 g, 10.2 mmol) in DMF (5 mL). The reaction mixture was stirred at rt for 2 h and then cold water (200 mL) was added to the reaction mixture. The solid that formed was collected by filtration and washed with cold water (100 mL). The solid was dissolved in CH2Cl2 (200 mL). The organic solution was washed with sat. aq. NaHCO3 solution, 5% aq. citric acid solution and brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo. The residue was dissolved in CH2Cl2 and purified by flash column chromatography (gradient elution from 10 to 40% EtOAc in CH2Cl2) provided the title compound (6.14 g, 77%) as a light tan solid. MS (ESI+) m/z 780.5 (M+H)+.

後処理

  1. stirringThe reaction mixture was stirred at rt for 2 h
  2. customThe solid that formed
  3. filtrationwas collected by filtration
  4. washwashed with cold water (100 mL)
  5. dissolutionThe solid was dissolved in CH2Cl2 (200 mL)
  6. washThe organic solution was washed with sat. aq. NaHCO3 solution, 5% aq. citric acid solution and brine
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. concentrationThe filtrate was concentrated in vacuo
  10. dissolutionThe residue was dissolved in CH2Cl2
  11. custompurified by flash column chromatography (gradient elution from 10 to 40% EtOAc in CH2Cl2)

出典と根拠

ORDレコード
ord-2b058af762c84736b47c3e635c185773
出典データセット
uspto-grants-2014_11
特許番号
US08889712B2

反応ノート

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