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 2385912Notes

Reaction equation

HRID 2385912 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-aaa0149426ec44dfa2a42e90228237d3
Source dataset
uspto-grants-2012_09
Patent number
US08263633B2

Reaction notes

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