Hydrochloric Acid → 4,4-difluoro-1'-methyl-6'-(1H-pyrazol-4-yl)-1'H-spiro[cyclohexane-1,2'-thieno[3,2-d]pyrimidin]-4'(3'H)-one

HRID 2364020Notes

Reaction equation

HRID 2364020 reaction equation
[CH3:1][N:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][NH:14][CH:15]=3)[S:10][C:6]=2[C:5](=[O:16])[NH:4][C:3]1([CH3:18])[CH3:17].Cl.C([O-])(O)=O.[Na+].[F:25][C:26]1([F:33])[CH2:31]CC(=O)C[CH2:27]1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[O-]S([O-])(=O)=O.[Mg+2]>CCOC(C)=O.CC(N(C)C)=O.CO>[F:25][C:26]1([F:33])[CH2:31][CH2:18][C:3]2([N:2]([CH3:1])[C:7]3[CH:8]=[C:9]([C:11]4[CH:15]=[N:14][NH:13][CH:12]=4)[S:10][C:6]=3[C:5](=[O:16])[NH:4]2)[CH2:17][CH2:27]1

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 18462Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)-HCID 24083Sulfuric acid magnesium salt (1:1)HCID 516892Sodium Bicarbonate2×HCID 157890924,4-DifluorocyclohexanoneHCID 667433581,2,2-trimethyl-6-(1H-pyrazol-4-yl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one

Product 1

HCID 667442414,4-difluoro-1'-methyl-6'-(1H-pyrazol-4-yl)-1'H-spiro[cyclohexane-1,2'-thieno[3,2-d]pyrimidin]-4'(3'H)-oneYield 72%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 8857Ethyl AcetateSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
50 °C

Procedure

A mixture of 1,2,2-trimethyl-6-(1H-pyrazol-4-yl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (131 mg, 0.50 mmol), 1 M aqueous HCl (2.5 mL, 2.5 mmol) and MeOH (2.5 mL) was stirred at 50° C. for 1 h. After addition of saturated aqueous NaHCO3, the organic materials were extracted with EtOAc. After removal of the solvent at reduced pressure, the residue was mixed with 4,4-difluorocyclohexanone (335 mg, 2.5 mmol), CSA (12 mg, 0.050 mmol), MgSO4 (96 mg, 1.0 mmol) and DMA (1 mL). After stirred at 80° C. for 1.5 h, saturated aqueous NaHCO3 and EtOAc were added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 90:10 hexane/EtOAc to EtOAc), then crystallized from MeOH/EtOAc/hexane to give the title compound (121 mg, 72%) as a yellow solid:

Workup

  1. extractionthe organic materials were extracted with EtOAc
  2. customAfter removal of the solvent at reduced pressure
  3. stirringAfter stirred at 80° C. for 1.5 h
  4. customto quench
  5. customthe reaction
  6. extractionThe organic materials were extracted with EtOAc
  7. washThe combined extracts were washed with water and brine
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. customAfter removal of the solvent at reduced pressure
  11. customthe residue was purified by column chromatography (Purif, silica gel, 90:10 hexane/EtOAc to EtOAc)
  12. customcrystallized from MeOH/EtOAc/hexane

Sources & evidence

ORD record
ord-9440d595b6394b94ad67f8af5d9708cc
Source dataset
uspto-grants-2014_04
Patent number
US08691828B2

Reaction notes

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