Triethylamine → 2-((1S)-5-{[(hydroxyamino)carbonyl]amino}-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}pentyl)-5-(2-naphthyl)-1H-imidazol-3-ium trifluoroacetate

HRID 659716Notes

Reaction equation

HRID 659716 reaction equation
[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:22][C:23](=[O:37])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=2)[NH:27][C:26]=1[CH3:36])[C:7]1[NH:8][C:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)=[CH:10][N:11]=1.CCN(CC)CC.ClC(Cl)(O[C:49](=[O:55])OC(Cl)(Cl)Cl)Cl.[Si]([O:64][NH2:65])(C(C)(C)C)(C)C.[C:66]([OH:72])([C:68]([F:71])([F:70])[F:69])=[O:67].O>C(Cl)Cl.CN(C=O)C>[F:69][C:68]([F:71])([F:70])[C:66]([O-:72])=[O:67].[OH:64][NH:65][C:49]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([C:7]1[NH:8][C:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)=[CH:10][NH+:11]=1)[NH:22][C:23](=[O:37])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=2)[NH:27][C:26]=1[CH3:36])=[O:55]

Participants

7

Reactant 5

HCID 8471TriethylamineHCID 94429TriphosgeneHCID 4691350O-(tert-Butyldimethylsilyl)hydroxylamineHCID 16061501N-{(1S)-5-amino-1-[5-(2-naphthyl)-1H-imidazol-2-yl]pentyl}-2-(5-methoxy-2-methyl-1H-indol-3-yl)acetamideHCID 22392675Trifluoroacetic acid water

Product 1

HCID 866315422-((1S)-5-{[(hydroxyamino)carbonyl]amino}-1-{[(5-methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}pentyl)-5-(2-naphthyl)-1H-imidazol-3-ium trifluoroacetateYield 40%

Reagents, catalysts & solvents 1

HCID 22350042dichloromethane N,N-dimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

To a stirred solution (0.04 M) of the product from example 1 step 4 and Et3N (1 eq.) in DCM/DMF (3:1) at 0° C., triphosgene (0.33 eq.) was added. The reaction mixture was stirred at 0° C. for 1 h., then, O-(tert-butyldimethylsilyl)hydroxylamine (large excess) was added and the resulting reaction mixture was stirred at RT overnight. After addition of TFA/water (1:1) and stirring of the mixture for another 4 h, the solvent was concentrated to give a crude product which was purified by RP-HPLC (Waters Symetry Prep C18, 7 micron, 19×300 mm; flow: 20 mL/min; Gradient: A: H2O+0.1% TFA; B: MeCN+0.1% TFA; 80% A isocratic for 2 min, linear to 20% A in 14 min) to yield (40%) the title compound as a solid. 1H NMR (400 MHz, DMSO-d6, 300K) δ 1H NMR (400 MHz, DMSO d6, 300K) δ 10.61 (s, 1H), 8.60 (bs, 1H), 8.51 (bs, 1H), 8.33 (s, 1H), 8.25 (bs, 1H), 8.07 (d, J=9.2 Hz, 1H), 7.97 (t, J=9.2 Hz, 2H), 7.88 (dd, J=8.4 Hz J=1.6 Hz, 1H), 7.64-7.56 (m, 2H), 7.10 (d, J=8.4 Hz, 1H), 6.69 (d, J=6.0 Hz, 1H), 6.60 (t, J=8.4 Hz, 1H), 6.59 (dd, J=8A Hz J=2.4 Hz, 1H), 5.06-4.97 (m, 1H), 3.67 (s, 3H), 3.59 (d, J=15.6 Hz, 1H), 3.51 (d, J=15.6 Hz, 1H), 3.02 (q, J=6.4 Hz, 2H), 2.31 (s, 3H), 2.06-1.90 (m, 2H), 1.50-1.16 (m, 4H). MS (ES+) C31H34N6O4 requires: 554, found. 555 (M+H)+.

Workup

  1. customthe resulting reaction mixture
  2. stirringwas stirred at RT overnight
  3. stirringstirring of the mixture for another 4 h
  4. concentrationthe solvent was concentrated
  5. customto give a crude product which
  6. customwas purified by RP-HPLC (Waters Symetry Prep C18, 7 micron, 19×300 mm
  7. wait80% A isocratic for 2 min

Sources & evidence

ORD record
ord-ec117037c56c454786b32cfef6ef9d1e
Source dataset
uspto-grants-2011_12
Patent number
US08080573B2

Reaction notes

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