Methyl iodide → HCID 66780292, compound

HRID 1958060Notes

Reaction equation

HRID 1958060 reaction equation
[H-].[Na+].[Cl:3][C:4]1[C:5]([CH3:26])=[C:6]([CH2:10][NH:11][C:12]2[N:13]=[C:14]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:15][C:16]=2[C:17]([NH2:19])=[O:18])[CH:7]=[CH:8][CH:9]=1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[S:28].IC.[C:41](=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CN(C)C=O>[Cl:3][C:4]1[C:5]([CH3:26])=[C:6]([CH2:10][N:11]2[C:12]3[N:13]=[C:14]([N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:15][C:16]=3[C:17](=[O:18])[N:19]=[C:41]2[S:28][CH3:27])[CH:7]=[CH:8][CH:9]=1

Participants

9

Reactant 6

HCID 6328Methyl iodide5×HCID 10340Sodium Carbonate3×HCID 11430Potassium CarbonateHCID 24758Sodium hydrideHCID 802641,1'-ThiocarbonyldiimidazoleHCID 66779830HCID 66779830, compound

Product 1

HCID 66780292HCID 66780292, compoundYield 65.6%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

Sodium hydride (2.62 g, 65.4 mmol) was added portionwise to a suspension of 4-{[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (3 g, 8.18 mmol) and 1,1′-thiocarbonyldiimidazole (4.37 g, 24.53 mmol) in Tetrahydrofuran (THF) (80 mL). The mixture was stirred at rt for 21 h, then quenched by the dropwise addition of water. The solvent was evaporated and the residue was suspended in water. The pH was adjusted to about 7 by the addition of 6 N HCl, while cooling in an ice bath. The yellow solid was collected by filtration, washed with water, then hexanes and dried. The solid obtained was suspended in Tetrahydrofuran (THF) (80 mL) and treated with iodomethane (0.562 mL, 9.00 mmol). After few hours minimal conversion was observed by LC/MS. Sodium carbonate (1.300 g, 12.27 mmol) and additional iodomethane (0.562 mL, 9.00 mmol) were added and stirring was continued overnight. LC/MS analysis showed that the reaction was still not complete. Additional sodium carbonate (1.300 g, 12.27 mmol) and iodomethane (0.562 mL, 9.00 mmol) were added and the mix was warmed at 45° C. for 4 h (an additional aliquot of sodium carbonate and iodomethane were added during this time). The reaction has stalled and only reached about 40% conversion. It was then cooled to rt, the solvent was evaporated and the residue was suspended in water. The pH was neutralized by the addition of 6 N HCl. The solid was collected, washed with water and dried. The dry solid obtained was suspended in N,N-Dimethylformamide (DMF) (35 mL). Potassium carbonate (3.96 g, 28.6 mmol) and iodomethane (1.534 mL, 24.53 mmol) were added and the mixture was stirred at 50° C. for 1.5 h. After cooling, it was poured into ice/water and the precipitate formed was collected, washed with water and dried to afford 4-[(3-chloro-2-methylphenyl)methyl]-5-(methylthio)-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (2.27 g, 5.37 mmol, 65.6% yield) which was used in the next step without further purification. LC/MS (ES+): [M+H]+=422.9 (80% pure). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.37 (d, J=7.83 Hz, 1H), 7.15 (t, J=7.83 Hz, 1H), 6.60 (d, J=7.33 Hz, 1H), 5.49 (s, 2H), 3.63-3.72 (m, 4H), 3.52 (d, J=4.55 Hz, 4H), 2.46 (s, 3H), 2.43 (s, 3H).

Workup

  1. customquenched by the dropwise addition of water
  2. customThe solvent was evaporated
  3. additionThe pH was adjusted to about 7 by the addition of 6 N HCl
  4. temperaturewhile cooling in an ice bath
  5. filtrationThe yellow solid was collected by filtration
  6. washwashed with water
  7. dry with materialhexanes and dried
  8. customThe solid obtained
  9. waitAfter few hours minimal conversion was observed by LC/MS
  10. stirringstirring
  11. waitwas continued overnight
  12. additionwere added during this time)
  13. temperatureIt was then cooled to rt
  14. customthe solvent was evaporated
  15. additionThe pH was neutralized by the addition of 6 N HCl
  16. customThe solid was collected
  17. washwashed with water
  18. customdried
  19. customThe dry solid obtained
  20. stirringthe mixture was stirred at 50° C. for 1.5 h
  21. temperatureAfter cooling
  22. customthe precipitate formed
  23. customwas collected
  24. washwashed with water
  25. customdried

Sources & evidence

ORD record
ord-916342d24c1c4f96a249ad990e0d4667
Source dataset
uspto-grants-2013_04
Patent number
US08410095B2

Reaction notes

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