Sodium Thiosulfate → 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazoline-8-carboxamide

HRID 473194Notes

Reaction equation

HRID 473194 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]([C:15]([NH2:17])=[O:16])[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]([C:15]([NH2:17])=[O:16])[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 666100452-(Difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline-8-carboxamide

Product 1

HCID 568487582-(difluoro(5-fluoropyridin-2-yl)methyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazoline-8-carboxamideYield 50.2%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline-8-carboxamide (191 mg, 0.52 mmol) in DCM (8 mL) at 0° C. was added 3-chloroperbenzoic acid (70%, 192 mg, 0.78 mmol) and the mixture was stirred for 90 min. The mixture was diluted with DCM and then aq sodium thiosulfate was added, followed by addition of saturated aq sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. To the residue were added THF (5 mL) and 5-methyl-1H-pyrazol-3-amine (153 mg, 1.58 mmol) and the mixture was stirred at rt for 15 min. The mixture was concentrated under reduced pressure and purified by preparative HPLC (Varian diphenyl reverse phase column, eluted with gradient of solvent B=0.05% AcOH/ACN and solvent A=5% ACN/0.05% AcOH/H2O) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazoline-8-carboxamide (108 mg, 50%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.20 (s, 3H) 6.08 (s, 1H) 7.76 (t, J=7.82 Hz, 1H) 7.92 (d, J=3.39 Hz, 1H) 7.98-8.11 (m, 2H) 8.58-8.75 (m, 2H) 8.89 (d, J=7.54 Hz, 1H) 9.91 (d, J=3.20 Hz, 1H) 10.80-11.38 (m, 1H) 12.17 (br s, 1H); LC-MS (ESI) m/z 414 (M+H)+.

Workup

  1. dry with materialThe organic layer was dried over sodium sulfate
  2. concentrationconcentrated under reduced pressure
  3. stirringthe mixture was stirred at rt for 15 min
  4. concentrationThe mixture was concentrated under reduced pressure
  5. custompurified by preparative HPLC (Varian diphenyl reverse phase column
  6. washeluted with gradient of solvent B=0.05% AcOH/ACN and solvent A=5% ACN/0.05% AcOH/H2O)

Sources & evidence

ORD record
ord-7c6cdb46b99e44feb5053a5627e6e03f
Source dataset
uspto-grants-2014_01
Patent number
US08633207B2

Reaction notes

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