1,2-Dichloroethane → (2S,4S)-tert-butyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidine-1-carboxylate

HRID 339236Notes

Reaction equation

HRID 339236 reaction equation
[CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:12]([C:13](O)=[O:14])[CH2:11][C@H:10]([NH:16][C:17]([O:19][CH2:20][CH:21]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:9]1)=[O:7])([CH3:4])[CH3:3].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.[C@H:55]1([NH2:65])[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH2:58][CH2:57][CH2:56]1>CN(C=O)C.O>[CH:23]1[C:22]2[CH:21]([CH2:20][O:19][C:17]([NH:16][C@@H:10]3[CH2:9][N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:4])[CH3:3])=[O:7])[C@H:12]([C:13](=[O:14])[NH:65][C@H:55]4[C:64]5[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=5)[CH2:58][CH2:57][CH2:56]4)[CH2:11]3)=[O:18])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1

Participants

8

Reactant 5

HCID 111,2-DichloroethaneHCID 79724-MethylmorpholineHCID 181649HOAtHCID 2756134(4S)-4-N-Fmoc-amino-1-Boc-L-prolineHCID 70580721-Aminotetralin, (R)-

Product 1

HCID 57806828(2S,4S)-tert-butyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidine-1-carboxylateYield 87%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent2×

Procedure

To a solution of (2S,4S)-Boc-gamma-(Fmoc-amino)-proline (Chem-Impex, 6.00 g, 13.3 mmol) in DMF (20 mL) at 0° C. were added EDC (3.05 g, 15.9 mmol), HOAt (2.17 g, 15.9 mmol) and NMM (4.38 mL, 39.8 mmol). The reaction mixture was stirred at ice bath temperature for 20 min then treated with a solution of (R)-1,2,3,4-tetrahydronaphthalen-1-amine (Alfa Aesar, 2.15 g, 14.6 mmol) in DMF (2 mL). The reaction mixture was stirred at rt for 1 h and cold water (100 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) and the organic solution was washed with 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 30% EtOAc in CH2Cl2) provided the title compound (6.70 g, 87%) as a light tan solid. 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=7.5 Hz, 2H), 7.67 (d, J=7.3 Hz, 2H), 7.42 (td, J=7.2, 4.0 Hz, 2H), 7.37-7.03 (m, 6H), 5.22 (br. s., 1H), 4.57-4.23 (m, 5H), 3.68-3.49 (m, 2H), 2.91-2.74 (m, 2H), 2.52 (d, J=13.4 Hz, 1H), 2.35-2.21 (m, 1H), 2.14 (d, J=5.1 Hz, 1H), 1.97-1.80 (m, 3H), 1.44 (s, 9H); MS (ESI+) m/z 582.2 (M+H)+.

Workup

  1. stirringThe reaction mixture was stirred at rt for 1 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 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 30% EtOAc in CH2Cl2)

Sources & evidence

ORD record
ord-eb54401381fb4314a4c979bbf85e6697
Source dataset
uspto-grants-2014_11
Patent number
US08889712B2

Reaction notes

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