Water → HCID 58204187, compound

HRID 708139Notes

Reaction equation

HRID 708139 reaction equation
[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:28][CH2:27][N:26]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:25][CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]

Participants

6

Reactant 4

HCID 962WaterHCID 8471Triethylamine2×HCID 31297Methanesulfonyl chloride2×HCID 582037792-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

Product 1

HCID 58204187HCID 58204187, compoundYield 50%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

To a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 375 hydrochloride salt (141 mg, 0.33 mmol) in DCM (3.3 mL) was added triethylamine (0.16 mL, 1.14 mmol). The reaction mixture was cooled to 0° C. then methanesulfonyl chloride (30 μL, 0.39 mmol) was added and the reaction mixture was stirred at RT for 18 hours. The reaction mixture was cooled to 0° C. and a further triethylamine (45 μL) and methanesulfonyl chloride (30 μL) were added and the reaction mixture was stirred at 0° C. for 30 minutes. Water was added and the phases were separated. The aqueous layer was extracted with DCM (×2) and the combined organic extracts were washed with an aqueous 10% citric acid solution, followed by an aqueous saturated sodium bicarbonate solution and then brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 0-20% EtOAc in DCM). The resulting solid was suspended in cyclohexane and collected by filtration to give 395 as a white solid (78 mg, 50%). LCMS: RT=11.69 min, [M+H]+=474. 1H NMR δ (ppm) (CDCl3): 8.31 (1H, d, J=8.19 Hz), 7.90 (1H, s), 7.01 (1H, dd, J=8.23, 1.88 Hz), 6.90 (1H, d, J=1.84 Hz), 5.93-5.85 (1H, m), 4.39 (2H, t, J=5.03 Hz), 3.93 (2H, d, J=11.84 Hz), 3.39 (2H, t, J=5.04 Hz), 2.81-2.70 (5H, m), 2.60 (1H, tt, J=12.04, 3.68 Hz), 1.97 (2H, d, J=13.31 Hz), 1.89-1.76 (2H, m), 1.61 (6H, d, J=6.63 Hz)

Workup

  1. temperatureThe reaction mixture was cooled to 0° C.
  2. stirringthe reaction mixture was stirred at 0° C. for 30 minutes
  3. customthe phases were separated
  4. extractionThe aqueous layer was extracted with DCM (×2)
  5. washthe combined organic extracts were washed with an aqueous 10% citric acid solution
  6. dry with materialbrine, dried (Na2SO4)
  7. concentrationconcentrated in vacuo
  8. customThe resultant residue was purified by flash chromatography (SiO2, 0-20% EtOAc in DCM)
  9. filtrationcollected by filtration

Sources & evidence

ORD record
ord-0c246cd3def944a4a41e84188343749d
Source dataset
uspto-grants-2015_11
Patent number
US09175009B2

Reaction notes

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