p-Toluenesulfonic acid → 1'-methyl-6'-(1H-pyrazol-4-yl)-1'H-spiro [cyclohexane-1,2'-thieno[3,2-d]pyrimidin]-4'(3'H)-one

HRID 2364025Notes

Reaction equation

HRID 2364025 reaction equation
Cl.Cl.[CH3:3][NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][NH:13][CH:14]=2)[S:7][C:6]=1[C:15]([NH2:17])=[O:16].C([O-])(O)=O.[Na+].[C:23]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.CC1C=CC(S(O)(=O)=O)=CC=1.[O-]S([O-])(=O)=O.[Mg+2]>CN(C=O)C.CCOC(C)=O>[CH3:3][N:4]1[C:5]2[CH:9]=[C:8]([C:10]3[CH:14]=[N:13][NH:12][CH:11]=3)[S:7][C:6]=2[C:15](=[O:16])[NH:17][C:23]21[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2

Participants

8

Reactant 5

HCID 6101p-Toluenesulfonic acidHCID 7967CyclohexanoneHCID 24083Sulfuric acid magnesium salt (1:1)HCID 516892Sodium Bicarbonate2×HCID 667434043-(methylamino)-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide dihydrochloride

Product 1

HCID 667437791'-methyl-6'-(1H-pyrazol-4-yl)-1'H-spiro [cyclohexane-1,2'-thieno[3,2-d]pyrimidin]-4'(3'H)-oneYield 16.5%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of 3-(methylamino)-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide dihydrochloride (145 mg, 0.491 mmol), saturated aqueous NaHCO3 (50 mL) and EtOAc (50 mL) was shaken well. The organic layer was collected, dried over MgSO4, filtered and concentrated under reduced pressure. This residue was mixed with cyclohexanone (2 mL, 19.3 mmol), PTSA (93 mg, 0.491 mmol), MgSO4 (118 mg, 0.982 mmol) and DMF (2 mL). This mixture was stirred at 80° C. overnight. The mixture was poured into saturated aqueous NaHCO3 and extracted with 3:1 EtOAc/THF (100 mL), and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc then to 90:10 EtOAc/MeOH) to afford a yellow solid. This solid was triturated with EtOAc/hexane, and the precipitate was collected by filtration to afford the title compound (24.5 mg, 16%) as a yellow solid:

Workup

  1. customThe organic layer was collected
  2. dry with materialdried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated under reduced pressure
  5. stirringThis mixture was stirred at 80° C. overnight
  6. extractionextracted with 3:1 EtOAc/THF (100 mL)
  7. dry with materialthe extract was dried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customThe residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc
  11. customto 90:10 EtOAc/MeOH) to afford a yellow solid
  12. customThis solid was triturated with EtOAc/hexane
  13. filtrationthe precipitate was collected by filtration

Sources & evidence

ORD record
ord-30e67fdc653d4af8a5b9459dba9a41cf
Source dataset
uspto-grants-2014_04
Patent number
US08691828B2

Reaction notes

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