Ethanethiol → N-methyl-4-(2-(methylthio)quinazolin-6-yloxy)picolinamide

HRID 639358Notes

Reaction equation

HRID 639358 reaction equation
ClC1N=CC2C(=CC=C(OC)C=2)N=1.C[S-].[Na+].C(S)C.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:24][S:25][C:26]1[N:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([OH:36])[CH:32]=2)[N:27]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:48]1[CH:53]=[CH:52][N:51]=[C:50]([C:54]([NH:56][CH3:57])=[O:55])[CH:49]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(Cl)Cl.CN(C=O)C.C(OCC)(=O)C>[CH3:57][NH:56][C:54]([C:50]1[CH:49]=[C:48]([O:36][C:31]2[CH:32]=[C:33]3[C:28](=[CH:29][CH:30]=2)[N:27]=[C:26]([S:25][CH3:24])[N:35]=[CH:34]3)[CH:53]=[CH:52][N:51]=1)=[O:55]

Participants

13

Reactant 8

HCID 6343EthanethiolHCID 11430Potassium CarbonateHCID 14768144-Chloro-N-methylpicolinamideHCID 3251421Potassium bis(trimethylsilyl)amideHCID 4378561Sodium methanethiolateHCID 6451240Aluminum(III) ChlorideHCID 592548522-Chloro-6-methoxyquinazolineHCID 592548632-(Methylthio)quinazolin-6-ol

Product 1

HCID 59254845N-methyl-4-(2-(methylthio)quinazolin-6-yloxy)picolinamideYield 75%

Reagents, catalysts & solvents 4

HCID 702EthanolSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

The mixture of 2-chloro-6-methoxyquinazoline (1 eq) and sodiumthiomethoxide (2 eq) in ethanol (0.5 M) was refluxed for 3 hours. The reaction was cooled down to room temperature and evaporated. The mixture was taken in ethyl acetate and washed with water and brine, dried in sodium sulfate and concentrated. The resulting crude was treated with dry methylene chloride and ethane thiol (5 eq) was added to it at room temperature. Aluminium chloride (5 eq) was added carefully at 0° C. The reaction was warmed to room temperature and stirred vigorously over night. The reaction was diluted with methylene chloride and saturated Rochelles's salt solution was added and stirred for about 3 hours until 2 layers separated. The organic layer was separated, washed with Rochelle's salt solution (2×), followed by water and brine, dried and evaporated. The crude 2-methylthioquinazolin-6-ol (1 eq) was taken in DMF (0.5 M) and Potassiumbis(trimethylsilyl)amide (2 eq) was added and stirred for 10 min at room temperature. 4-chloro(2-pyridyl)-N-methylcarboxamide (1.1 eq) was added followed by potassium carbonate (1 eq) and stirred at 85-90° C. for 16 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried and evaporated. The crude was subjected to column chromatography (4:1 Hexanes in ethyl acetate followed by 2:1 and 1:1 Hexanes in ethyl acetate) to afford the product in 75-85% yield.

Workup

  1. temperaturewas refluxed for 3 hours
  2. customevaporated
  3. washwashed with water and brine
  4. dry with materialdried in sodium sulfate
  5. concentrationconcentrated
  6. additionwas added to it at room temperature
  7. temperatureThe reaction was warmed to room temperature
  8. additionwas added
  9. stirringstirred for about 3 hours until 2 layers
  10. customseparated
  11. customThe organic layer was separated
  12. washwashed with Rochelle's salt solution (2×)
  13. customdried
  14. customevaporated
  15. stirringstirred for 10 min at room temperature
  16. stirringstirred at 85-90° C. for 16 hours
  17. washwashed with water and brine
  18. customdried
  19. customevaporated
  20. customto afford the product in 75-85% yield

Sources & evidence

ORD record
ord-33aa2468fb1c464e90db692cdba77dc4
Source dataset
uspto-grants-2010_04
Patent number
US07691866B2

Reaction notes

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