1,2-Dichloroethane → N-(3-fluoro-4-(2-(3-methyl-1,2,4-oxadiazol-5-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide

HRID 2359689Notes

Reaction equation

HRID 2359689 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[N:19]=3)[S:17][C:10]=12.[OH:25][C:26]([CH3:45])([CH3:44])[CH2:27][N:28]1[C:32]([CH3:33])=[C:31]([C:34](O)=[O:35])[C:30](=[O:37])[N:29]1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:34]([C:31]2[C:30](=[O:37])[N:29]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:28]([CH2:27][C:26]([OH:25])([CH3:45])[CH3:44])[C:32]=2[CH3:33])=[O:35])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[N:19]=3)[S:17][C:10]=12

Participants

8

Reactant 5

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 533934301-(2-Hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydropyrazole-4-carboxylic Acid2×HCID 595983463-Fluoro-4-(2-(3-methyl-1,2,4-oxadiazol-5-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine2×

Product 1

HCID 11963145N-(3-fluoro-4-(2-(3-methyl-1,2,4-oxadiazol-5-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamideYield 26%

Reagents, catalysts & solvents 2

HCID 6212ChloroformSolventHCID 6228DimethylformamideSolvent

Procedure

A 16 mm sealed tube was charged with 3-fluoro-4-(2-(3-methyl-1,2,4-oxadiazol-5-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine (0.0740 g, 0.22 mmol), 1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (0.094 g, 0.32 mmol), EDC (0.062 g, 0.32 mmol), HOBT (0.033 g, 0.22 mmol), Hunig's Base (0.13 ml, 0.76 mmol), and DMF (1.00 ml), sealed, and stirred at room temperature for 18 hours. LC/MS analysis indicated the presence of remaining 3-fluoro-4-(2-(3-methyl-1,2,4-oxadiazol-5-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine, so additional 1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (0.031 g, 0.11 mmol) was added and the reaction mixture was stirred at 50° C. for 8 hours. The flask was allowed to cool to room temperature, the mixture was diluted with chloroform (25 mL), then washed with water (25 mL), sat. aq. NaHCO3 (25 mL), and brine (25 mL). The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield a tan oil. The product was purified by silica gel chromatography eluting with 3% methanol in methylene chloride. The isolated yellow solid was triturated with EtOAc to yield N-(3-fluoro-4-(2-(3-methyl-1,2,4-oxadiazol-5-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (0.035 g, 26% yield). MS (ESI pos. ion) m/z: 615 (MH+). Calc'd exact mass for C8H4ClNO2S: 614. 1H NMR (400 MHz, DMSO-d6) 11.00 (s, 1H), 8.68 (d, J=5.31 Hz, 1H), 8.49 (s, 1H), 7.96-8.04 (m, 1H), 7.43-7.60 (m, 4H), 7.35 (d, J=8.21 Hz, 3H), 6.89 (d, J=5.31 Hz, 1H), 4.84 (s, 1H), 3.87 (s, 2H), 2.80 (s, 3H), 2.46 (s, 3H), 0.96 (s, 6H).

Workup

  1. customA 16 mm sealed tube
  2. customsealed
  3. additionwas added
  4. stirringthe reaction mixture was stirred at 50° C. for 8 hours
  5. temperatureto cool to room temperature
  6. washwashed with water (25 mL), sat. aq. NaHCO3 (25 mL), and brine (25 mL)
  7. dry with materialThe organic layer was dried with MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customto yield a tan oil
  11. customThe product was purified by silica gel chromatography
  12. washeluting with 3% methanol in methylene chloride
  13. customThe isolated yellow solid was triturated with EtOAc

Sources & evidence

ORD record
ord-e3281bf8348e421ab92f449bc87c45f2
Source dataset
uspto-grants-2014_04
Patent number
US08685983B2

Reaction notes

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