1-Hydroxybenzotriazole → n-Hydroxy-2-[2-phenyl-5-(2-phenyl-1h-indole-6-carbonyl)thiophene-3-yl]acetamide

HRID 453614Notes

Reaction equation

HRID 453614 reaction equation
C1([C:7]2[S:8][C:9]([C:16]([C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[C:23](C5C=CC=CC=5)[NH:24]4)=[CH:20][CH:19]=3)=[O:17])=[CH:10][C:11]=2[CH2:12][C:13]([OH:15])=O)C=CC=CC=1.F[P-](F)(F)(F)(F)F.[N:40]1([O:49]C(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH:57]1[CH:58]=[CH:59][C:60]2N(O)N=N[C:61]=2[CH:62]=1.CCN(C(C)C)C(C)C.C(ON)(C1C=CC=CC=1)(C1C=CC=CC=1)[C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1.CC(O)=O.FC(F)(F)CO>C(Cl)Cl>[OH:49][NH:40][C:13](=[O:15])[CH2:12][C:11]1[CH:10]=[C:9]([C:16]([C:18]2[CH:26]=[C:25]3[C:21]([CH:22]=[C:23]([C:77]4[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=4)[NH:24]3)=[CH:20][CH:19]=2)=[O:17])[S:8][C:7]=1[C:62]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1

Participants

8

Reactant 6

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 3015602O-(triphenylmethyl)hydroxylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 25221754[2-Phenyl-5-(2-phenyl-1H-indole-6-carbonyl)thiophene-3-yl]acetic acidHCID 85816740AcOH 2,2,2-trifluoroethanol

Product 1

HCID 25221753n-Hydroxy-2-[2-phenyl-5-(2-phenyl-1h-indole-6-carbonyl)thiophene-3-yl]acetamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a stirred solution of 40.1 mg (0.09 mmol) of 8 in 5 mL of dry CH2Cl2 was added sequentially 140 mg (0.37 mmol) of O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), 49.5 mg (0.37 mmol) of HOBt, and 91 uL (0.55 mmol) of DIEA. The resulting solution was stirred at room temperature for 10 min followed by adding 50.5 mg (0.18 mmol) of O-tritylhydroxylamine. After stirring at the same temperature for 30 min, the solvent was removed in vacuo and the residue was purified by flash chromatography (EtOAc/Hex 1:4) to give O-trityl hydroxyamic acid of 8 in a quantitative yield. The resulting oily product was treated with 5 mL of 1:2 mixture of AcOH/2,2,2-trifluoroethanol at room temperature for 24 h. After evaporation of the solvent in vacuo, the residue was dissolved in CH2Cl2 and washed with 10 mL of a saturated NaHCO3 solution. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (MeOH/EtOAc 1:9) to give 12.7 mg (54% over two steps) of 9 as a bright yellow powder: mp˜150° C. (decomp); 1H NMR (400 MHz, DMSO-d6) δ 12.1 (s, 1H), 11.68 (brs, 1H), 8.95 (brs, 1H), 7.99 (s, 1H), 7.93 (d, J=7.8 Hz, 2H), 7.81 (s, 1H), 7.70 (m, 3H), 7.66-7.48 (m, 6H), 7.38 (t, J=7.0 Hz, 1H), 7.08 (s, 1H), 3.41 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 187.4, 167.1, 147.9, 142.3, 141.6, 138.1, 136.9, 133.3, 133.2, 132.8, 132.1, 131.4, 131.0, 129.8, 129.7, 129.0, 127.7, 126.2, 121.1, 120.7, 113.9, 99.9, 33.2; IR (KBr) cm−1 3422-3241, 2902, 1596, 1433, 1322.

Workup

  1. stirringAfter stirring at the same temperature for 30 min
  2. customthe solvent was removed in vacuo
  3. customthe residue was purified by flash chromatography (EtOAc/Hex 1:4)
  4. customto give O-trityl hydroxyamic acid of 8 in a quantitative yield
  5. customAfter evaporation of the solvent in vacuo
  6. dissolutionthe residue was dissolved in CH2Cl2
  7. washwashed with 10 mL of a saturated NaHCO3 solution
  8. dry with materialThe organic layer was dried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customThe residue was purified by flash chromatography (MeOH/EtOAc 1:9)

Sources & evidence

ORD record
ord-0f6e0d9d99334d36b23e1be080270ddf
Source dataset
uspto-grants-2013_07
Patent number
US08492428B2

Reaction notes

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