Diisopropylethylamine → N2-(9-fluorenylmethoxycarbonyl)-N5-(bis(diallylphosphoryl)methyl)-L-glutamine

HRID 39271Notes

Reaction equation

HRID 39271 reaction equation
[NH:1]([C:15]([O:17][CH2:18][CH:19]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C@H:2]([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:3][CH2:4][C:5](=O)[OH:6].CCN([CH:38]([CH3:40])[CH3:39])C(C)C.CN(C(ON1N=NC2C=C[CH:54]=[CH:55][C:50]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:65][CH:66]([P:71](=[O:74])([O-])[O-])[P:67](=O)([O-])[O-:68]>CN(C=O)C.C(Cl)Cl>[CH:21]1[C:20]2[CH:19]([CH2:18][O:17][C:15]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[NH:65][CH:66]([P:71]([CH2:40][CH:38]=[CH2:39])([CH2:54][CH:55]=[CH2:50])=[O:74])[P:67]([CH2:20][CH:19]=[CH2:18])([CH2:8][CH:2]=[CH2:3])=[O:68])=[O:16])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 7017912(4S)-5-(tert-Butoxy)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-oxopentanoic acidHCID 224767091-Aminomethylenebisphosphonate

Product 1

HCID 86762030N2-(9-fluorenylmethoxycarbonyl)-N5-(bis(diallylphosphoryl)methyl)-L-glutamine

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of Fmoc-Glu-Ot-Bu (646 mg, 1.52 mmol) in DMF (5 mL) at 0° C. was added DIEA (529 μL, 3.04 mmol) and HBTU (576 mg, 1.52 mmol). After stirring for 15 min at 0° C., amino bisphosphonate 96 (533 mg, 1.52 mmol) in DMF (2.6 mL) was added and stirring was pursued for 5 h at 0° C. The reaction mixture was diluted with CH2Cl2, washed with H2O, 0.5 N HCl solution, saturated NaHCO3 solution and saturated NaCl solution. The organic layer was dried over MgSO4, filtered and concentrated to dryness. The crude product was purified by silica gel chromatography on a Biotage™ flash chromatography system using a gradient of 0-5% methanol in CH2Cl2. Compound 97 was obtained as a light yellow oil (898 mg, 78%). 1H NMR (400 MHz, CDCl3) δ 1.46 (s, 9H), 1.82-1.91 (m, 1H), 2.15-2.32 (m, 3H), 4.20-4.27 (m, 2H), 4.38-4.47 (m, 2H), 4.58-4.68 (m, 8H), 5.20-5.26 (m, 5H), 5.34-5.40 (m, 4H), 5.54 (d, J=7.9 Hz, 1H), 5.87-5.98 (m, 4H), 6.59 (bs, 1H), 7.30-7.34 (m, 2H), 7.41 (t, J=7.5 Hz, 2H), 7.61 (d, J=7.5 Hz, 2H), 7.77 (d, J=7.5 Hz, 2H).

Workup

  1. stirringstirring
  2. waitwas pursued for 5 h at 0° C
  3. washwashed with H2O, 0.5 N HCl solution, saturated NaHCO3 solution and saturated NaCl solution
  4. dry with materialThe organic layer was dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated to dryness
  7. customThe crude product was purified by silica gel chromatography on a Biotage™ flash chromatography system

Sources & evidence

ORD record
ord-42ba13ac53e944e2b9c3e23385d697ab
Source dataset
uspto-grants-2013_09
Patent number
US08524691B2

Reaction notes

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