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

HRID 473213Notes

Reaction equation

HRID 473213 reaction equation
[F:1][C:2]([F:26])([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=1)[C:3]1[N:12]=[C:11](SC)[C:10]2[C:5](=[C:6]([NH:15][C:16](=[O:18])[CH3:17])[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+].[CH3:50][C:51]1[NH:55][N:54]=[C:53]([NH2:56])[CH:52]=1>C(Cl)Cl.C1COCC1>[F:1][C:2]([F:26])([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=1)[C:3]1[N:12]=[C:11]([NH:56][C:53]2[CH:52]=[C:51]([CH3:50])[NH:55][N:54]=2)[C:10]2[C:5](=[C:6]([NH:15][C:16](=[O:18])[CH3:17])[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 66609059N-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazolin-8-yl)acetamide

Product 1

HCID 56848867N-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-8-yl)acetamideYield 36.1%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

To N-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazolin-8-yl)acetamide (90 mg, 0.24 mmol) in DCM (5 mL) at 0° C. was added 3-chloroperbenzoic acid (70%, 77 mg, 0.3 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 (3 mL) and 5-methyl-1H-pyrazol-3-amine (107 mg, 1.1 mmol) and the mixture was stirred at rt for 1 h. The mixture was concentrated under reduced pressure and purified by preparative HPLC (Varian diphenyl reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O) to afford N-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-8-yl)acetamide (37 mg, 36%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.17 (s, 3H) 2.24 (s, 3H) 5.93 (s, 1H) 7.59 (t, J=8.10 Hz, 1H) 7.92-8.12 (m, 2H) 8.34 (d, J=8.29 Hz, 1H) 8.57-8.75 (m, 2H) 9.52 (s, 1H) 10.76 (br s, 1H) 12.20 (br s, 1H); LC-MS (ESI) m/z 428 (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 1 h
  5. concentrationThe mixture was concentrated under reduced pressure
  6. custompurified by preparative HPLC (Varian diphenyl reverse phase column
  7. washeluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O)

Sources & evidence

ORD record
ord-4f816a20e9a24b62a7c999d6380eacb3
Source dataset
uspto-grants-2014_01
Patent number
US08633207B2

Reaction notes

Loading…