Sodium Hydroxide → 2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-azetidine-1-sulfonyl}-ethanol

HRID 1849316Notes

Reaction equation

HRID 1849316 reaction equation
[NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[S:13][C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)=[N:11][C:10]=4[C:9]=3[CH:26]=2)[CH2:2]1.Cl[CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31].[OH-:34].[Na+]>C1COCC1>[CH:23]([N:19]1[C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[CH:6][C:5]([CH:3]5[CH2:4][N:1]([S:30]([CH2:29][CH2:28][OH:34])(=[O:32])=[O:31])[CH2:2]5)=[CH:26][C:9]=4[C:10]=3[N:11]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]

Participants

5

Reactant 3

HCID 14798Sodium HydroxideHCID 15385Ethanesulfonylchloride, 2-chloro-2×HCID 670505299-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

Product 1

HCID 582041062-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-9-yl]-azetidine-1-sulfonyl}-ethanolYield 23%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.20 g, 0.54 mmol) in dry THF (20 mL) at 0° C. was added 2-chloroethanesulfonyl chloride (65 μL, 0.6 mmol) and the reaction mixture was stirred at RT for 18 hours. The reaction mixture was cooled to 0° C. and a further 2-chloroethanesulfonyl chloride (130 μL) was added and the reaction mixture was stirred at RT for 18 hours. An aqueous sodium hydroxide solution (8M, 3.38 mL, 27 mmol) was added and the mixture was heated at 40° C. for 18 hours then concentrated in vacuo. The resultant residue was extracted several times with 10% MeOH in DCM and the combined extracts concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 0-20% MeOH in DCM) followed by preparative HPLC (Gemini C18 column, gradient 5-95% MeOH in H2O+0.1% HCO2H) to give 394 (58 mg, 23%). LCMS: RT=8.45 min, [M+H]+=476. 1H NMR δ (ppm) (DMSO-d6, 80° C.): 8.22 (1 H, d, J=2.31 Hz), 8.01 (1 H, s), 7.33 (1 H, dd, J=8.34, 2.39 Hz), 7.08 (1 H, d, J=8.32 Hz), 5.81-5.73 (1 H, m), 4.53 (2 H, s), 4.37 (2 H, t, J=5.09 Hz), 4.22 (3 H, s), 3.57 (2 H, t, J=6.26 Hz), 3.43 (2 H, t, J=5.09 Hz), 2.79 (2 H, t, J=6.37 Hz), 1.59 (6 H, d, J=6.61 Hz). 1 Exchangeable proton not observed

Workup

  1. temperatureThe reaction mixture was cooled to 0° C.
  2. stirringthe reaction mixture was stirred at RT for 18 hours
  3. temperaturethe mixture was heated at 40° C. for 18 hours
  4. concentrationthen concentrated in vacuo
  5. extractionThe resultant residue was extracted several times with 10% MeOH in DCM
  6. concentrationthe combined extracts concentrated in vacuo
  7. customThe residue was purified by flash chromatography (SiO2, 0-20% MeOH in DCM)

Sources & evidence

ORD record
ord-dcf89e6b36a447dfbc9d686042b921a6
Source dataset
uspto-grants-2015_02
Patent number
US08952043B2

Reaction notes

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