Trifluoroacetic acid → 2-{4-Fluoro-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidin-1-yl}-N,N-dimethyl-acetamide

HRID 708278Notes

Reaction equation

HRID 708278 reaction equation
C(OC([N:8]1[CH2:13][CH2:12][C:11]([F:36])([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:19]=[C:20]([C:26]5[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=5)[S:21][C:22]=4[CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(N(CC)CC)C.[I-].Cl[CH2:53][C:54]([N:56]([CH3:58])[CH3:57])=[O:55]>C(Cl)Cl>[F:36][C:11]1([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:19]=[C:20]([C:26]5[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=5)[S:21][C:22]=4[CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH2:12][CH2:13][N:8]([CH2:53][C:54]([N:56]([CH3:58])[CH3:57])=[O:55])[CH2:9][CH2:10]1

Participants

7

Reactant 5

HCID 6422Trifluoroacetic acidHCID 8471TriethylamineHCID 30165Iodide IonHCID 758862-chloro-N,N-dimethylacetamideHCID 58203893HCID 58203893, compound

Product 1

HCID 582042582-{4-Fluoro-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidin-1-yl}-N,N-dimethyl-acetamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

To a solution of 4-fluoro-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (45 mg, 88 μmol) in DCM (2.5 mL) was added TFA (0.8 mL) and the reaction mixture stirred at RT for 1 h before being concentrated in vacuo. The residue was dissolved in DCM (2 mL) and triethylamine (88 μL, 0.61 mmol), tetrabutylammonimum iodide (8 mg, 21 μmol) and 2-chloro-N,N-dimethyl-acetamide (14 μL, 0.1 mmol) added. The reaction mixture was stirred at RT for 16 h then diluted with DCM (20 mL) and washed with saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with DCM (3×5 mL) and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2 20% ethyl acetate in DCM then 2% MeOH in DCM) producing impure material. The material was subjected to flash chromatography (Si—NH2 eluting with DCM) to yield 523. LCMS: RT=3.43 min, [M+H]+=499 [ad823805] 1H NMR 400 MHz (d6-DMSO) δ: 8.37 (1H, d, J=8.4 Hz), 7.96 (1H, s), 7.18 (1H, dd, J=1.8, 8.4 Hz), 7.09 (1H, d, J=1.8 Hz), 5.93 (1H, sept, J=6.6 Hz), 4.37 (2H, t, J=5.1 Hz), 3.42 (2H, t, J=5.1 Hz), 3.30 (2H, s), 3.09 (3H, s), 2.93 (3H, s), 2.92-2.85 (2H, m), 2.55-2.46 (2H, m), 2.31-2.11 (2H, m), 1.97-1.87 (2H, m), 1.59 (6H, d, J=6.6 Hz)

Workup

  1. concentrationbefore being concentrated in vacuo
  2. dissolutionThe residue was dissolved in DCM (2 mL)
  3. stirringThe reaction mixture was stirred at RT for 16 h
  4. washwashed with saturated aqueous sodium bicarbonate solution
  5. extractionThe aqueous layer was extracted with DCM (3×5 mL)
  6. dry with materialthe combined organic extracts were dried (MgSO4)
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. custom2% MeOH in DCM) producing impure material

Sources & evidence

ORD record
ord-8798ea0bc1984bd8a2f22a36a2c65fd1
Source dataset
uspto-grants-2015_11
Patent number
US09175009B2

Reaction notes

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