Triethylamine → 2-(4-Isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylic acid isoxazol-3-ylamide

HRID 1190352Notes

Reaction equation

HRID 1190352 reaction equation
[CH:1]([N:4]1[CH:8]=[N:7][N:6]=[C:5]1[C:9]1[S:10][C:11]2[CH2:12][CH2:13][O:14][C:15]3[CH:22]=[C:21]([C:23](O)=[O:24])[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:32][C:33]1[CH:37]=[CH:36][O:35][N:34]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C=O)C>[O:35]1[CH:36]=[CH:37][C:33]([NH:32][C:23]([C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:18]=[C:9]([C:5]5[N:4]([CH:1]([CH3:3])[CH3:2])[CH:8]=[N:7][N:6]=5)[S:10][C:11]=4[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)=[O:24])=[N:34]1

Participants

8

Reactant 5

HCID 8471TriethylamineHCID 65578Oxalyl chlorideHCID 516892Sodium BicarbonateHCID 18102163-IsoxazolamineHCID 582037112-(4-Isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylic acid

Product 1

HCID 582040252-(4-Isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylic acid isoxazol-3-ylamideYield 47.3%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent

Procedure

To a suspension of 2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylic acid (226 mg, 0.63 mmol) in DCM (5 mL) at 0° C. was added DMF (4 drops, catalytic) then oxalyl chloride (115 μL, 1.32 mmol) dropwise. The reaction mixture was stirred at room temperature for 18 hours. 3-Amino-isoxazole (233 μL, 3.15 mmol) was added followed by triethylamine (176 μL, 1.26 mmol) and the reaction mixture was stirred for 4 hours. Aqueous saturated sodium bicarbonate solution was added and then ether and the mixture was filtered. The filtrate was concentrated in vacuo to remove the organics and the resulting aqueous phase was extracted with DCM (×3). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 0-5% MeOH in EtOAc) then trituration with EtOAc to give 140 as an off-white solid (126 mg, 47%). LCMS: RT=9.86 min, [M+H]+=423. 1H NMR δ (ppm) (DMSO-d6): 11.39 (1H, s), 8.94 (1H, s), 8.81 (1H, d, J=1.76 Hz), 8.39 (1H, d, J=8.33 Hz), 7.79 (1H, dd, J=8.34, 1.90 Hz), 7.70 (1H, d, J=1.87 Hz), 7.00 (1H, d, J=1.76 Hz), 5.51-5.41 (1H, m), 4.41-4.35 (2H, m), 3.47-3.41 (2H, m), 1.54 (6H, d, J=6.70 Hz)

Workup

  1. stirringthe reaction mixture was stirred for 4 hours
  2. filtrationether and the mixture was filtered
  3. concentrationThe filtrate was concentrated in vacuo
  4. customto remove the organics and the resulting aqueous phase
  5. extractionwas extracted with DCM (×3)
  6. dry with materialThe combined organic extracts were dried (Na2SO4)
  7. concentrationconcentrated in vacuo
  8. customThe resultant residue was purified by flash chromatography (SiO2, 0-5% MeOH in EtOAc)

Sources & evidence

ORD record
ord-64b7279e74bb49d3b7e9c46d7fa2f4a1
Source dataset
uspto-grants-2014_03
Patent number
US08673952B2

Reaction notes

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