Triethylamine → 2-{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]-pyrazol-1-yl}-N-(1-methyl-azetidin-3-yl)-isobutyramide

HRID 708196Notes

Reaction equation

HRID 708196 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]([C:23]5[CH:24]=[N:25][N:26]([C:28]([CH3:33])([CH3:32])[C:29](O)=[O:30])[CH:27]=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(Cl)(=O)C(Cl)=O.[CH3:40][N:41]1[CH2:44][CH:43]([NH2:45])[CH2:42]1.C(N(CC)CC)C>CN(C)C=O.[Cl-].[Na+].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]([C:23]5[CH:24]=[N:25][N:26]([C:28]([CH3:33])([CH3:32])[C:29]([NH:45][CH:43]6[CH2:44][N:41]([CH3:40])[CH2:42]6)=[O:30])[CH:27]=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

8

Reactant 4

HCID 8471TriethylamineHCID 65578Oxalyl chlorideHCID 187126621-Methylazetidin-3-amineHCID 670505692-{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]-pyrazol-1-yl}-2-methyl-propionic acid

Product 1

HCID 582040872-{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]-pyrazol-1-yl}-N-(1-methyl-azetidin-3-yl)-isobutyramideYield 22.5%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent4×HCID 57417360Sodium chloride; waterSolvent

Procedure

To a solution of 2-{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]-pyrazol-1-yl}-2-methyl-propionic acid (0.350 g, 0.000753 mol) and oxalyl chloride (2M in methylene chloride, 0.38 mL, 0.0007534 mol) in dry methylene chloride (2.415 mL, 0.03767 mol) was added 1 drop of N,N-dimethylformamide (0.02917 mL, 0.0003767 mol). The solution was stirred for 1 h at room temperature and concentrated in vacuo. The acid chloride was re-dissolved in methylene chloride (1.739 mL, 0.02712 mol) and added dropwise to a solution of 1-methyl-azetidin-3-ylamine (0.1198 g, 0.0007534 mol) and triethylamine (0.3255 mL, 0.002336 mol) in methylene chloride (1.739 mL, 0.02712 mol). The reaction was stirred at room temperature for 3 h. Brine and methylene chloride were added and the aqueous layer was extracted 3× with methylene chloride. The organic layers were combined, dried with MgSO4, and concentrated. The crude was purified by reverse-phase HPLC to give 453 (90.1 mg) as a beige solid. MS(ESI+) 533.2. 1H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 8.32 (d, J=8.3, 1H), 8.10 (s, 1H), 8.02 (s, 1H), 7.76 (d, J=6.9, 1H), 7.51 (dd, J=8.3, 1.8, 1H), 7.40 (d, J=1.7, 1H), 5.84 (sept, J=6.4, 1H), 4.39 (t, J=5.0, 2H), 4.25-4.15 (m, 1H), 3.46 (m, 4H), 2.89 (t, J=7.3, 2H), 2.22 (s, 3H), 1.73 (s, 6H), 1.56 (d, J=6.6, 6H)

Workup

  1. concentrationconcentrated in vacuo
  2. stirringThe reaction was stirred at room temperature for 3 h
  3. extractionthe aqueous layer was extracted 3× with methylene chloride
  4. dry with materialdried with MgSO4
  5. concentrationconcentrated
  6. customThe crude was purified by reverse-phase HPLC

Sources & evidence

ORD record
ord-1b0076fb0739475aa1d30192edef7200
Source dataset
uspto-grants-2015_11
Patent number
US09175009B2

Reaction notes

Loading…