Sodium Thiosulfate → N-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-8-yl)formamide

HRID 473205Notes

Reaction equation

HRID 473205 reaction equation
[F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[N:12]=[C:11](SC)[C:10]2[C:5](=[C:6]([NH:15][CH:16]=[O:17])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.ClC1C=CC=C(C(OO)=O)C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+].[CH3:49][C:50]1[NH:54][N:53]=[C:52]([NH2:55])[CH:51]=1>C(Cl)Cl.C1COCC1>[F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[N:12]=[C:11]([NH:55][C:52]2[CH:51]=[C:50]([CH3:49])[NH:54][N:53]=2)[C:10]2[C:5](=[C:6]([NH:15][CH:16]=[O:17])[CH:7]=[CH:8][CH:9]=2)[N:4]=1

Participants

8

Reactant 5

HCID 24477Sodium ThiosulfateHCID 70297m-Chloroperbenzoic acidHCID 931461H-Pyrazol-3-amine, 5-methyl-HCID 516892Sodium BicarbonateHCID 86662704N-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazolin-8-yl)formamide

Product 1

HCID 56848813N-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-8-yl)formamideYield 35%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

To N-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazolin-8-yl)formamide (168 mg, 0.462 mmol) in DCM (5 mL) at 0° C. was added 3-chloroperbenzoic acid (70%, 171 mg, 0.69 mmol) and the mixture stirred for 40 min. The mixture was diluted with DCM and then aq sodium thiosulfate and saturated aq sodium bicarbonate were added. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. To the residue were added THF (4 mL) and 5-methyl-1H-pyrazol-3-amine (135 mg, 1.38 mmol) and the mixture was stirred at rt for 20 min. The mixture was concentrated under reduced pressure and purified by preparative HPLC (Varian C-18 reverse phase column, eluted with gradient of solvent B=0.05% formic acid/ACN and solvent A=5% ACN/0.05% formic acid/H2O) to afford N-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-8-yl)formamide (66 mg, 35%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.17 (s, 3H) 5.89 (s, 1H) 7.61 (t, J=8.10 Hz, 1H) 7.96-8.11 (m, 2H) 8.37 (d, J=8.29 Hz, 1H) 8.66 (d, J=11.87 Hz, 2H) 8.79 (d, J=7.72 Hz, 1H) 10.24 (s, 1H) 10.77 (br s, 1H) 11.81-12.73 (m, 1H); LC-MS (ESI) m/z 414 (M+H)+.

Workup

  1. customThe organic layer was separated
  2. dry with materialdried over sodium sulfate
  3. concentrationconcentrated under reduced pressure
  4. stirringthe mixture was stirred at rt for 20 min
  5. concentrationThe mixture was concentrated under reduced pressure
  6. custompurified by preparative HPLC (Varian C-18 reverse phase column
  7. washeluted with gradient of solvent B=0.05% formic acid/ACN and solvent A=5% ACN/0.05% formic acid/H2O)

Sources & evidence

ORD record
ord-42a890da7ac54129afbc5e6367f2f5b7
Source dataset
uspto-grants-2014_01
Patent number
US08633207B2

Reaction notes

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