Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)- → 1-ethyl-6'-(5-methyl-1H-pyrazol-4-yl)-1'H-spiro [piperidine-4,2'-thieno[3,2-d]pyrimidin]-4'(3'H)-one

HRID 2364074Notes

Reaction equation

HRID 2364074 reaction equation
[NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH3:12])[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[CH2:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)[CH3:17].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[O-]S([O-])(=O)=O.[Mg+2].C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[CH2:16]([N:18]1[CH2:23][CH2:22][C:21]2([NH:1][C:2]3[CH:6]=[C:5]([C:7]4[CH:8]=[N:9][NH:10][C:11]=4[CH3:12])[S:4][C:3]=3[C:13](=[O:14])[NH:15]2)[CH2:20][CH2:19]1)[CH3:17]

Participants

7

Reactant 5

HCID 18462Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)-HCID 24083Sulfuric acid magnesium salt (1:1)HCID 771591-Ethylpiperidin-4-oneHCID 516892Sodium BicarbonateHCID 667430133-amino-5-(5-methyl-1H-pyrazol-4-yl)thiophene-2-carboxamide

Product 1

HCID 667440431-ethyl-6'-(5-methyl-1H-pyrazol-4-yl)-1'H-spiro [piperidine-4,2'-thieno[3,2-d]pyrimidin]-4'(3'H)-oneYield 64%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 3-amino-5-(5-methyl-1H-pyrazol-4-yl)thiophene -2-carboxamide (100 mg, 0.45 mmol), 1-ethylpiperidin-4-one (0.067 mL, 0.50 mmol), CSA (125 mg, 0.54 mmol), MgSO4 (108 mg, 0.90 mmol) and DMA (2.0 mL) was stirred at 100° C. for 4 h. Then, the mixture was poured into saturated aqueous NaHCO3. The organic materials were extracted with EtOAc. To the aqueous layer, NaCl was added. The organic materials were extracted again with EtOAc/THF. The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography (Purif, NH, 80:20 hexane/EtOAc to EtOAc then to 90:10 EtOAc/MeOH), then crystallized from MeOH/EtOAc/hexane to give the title compound (89 mg, 64%) as yellow solid:

Workup

  1. extractionThe organic materials were extracted with EtOAc
  2. additionTo the aqueous layer, NaCl was added
  3. extractionThe organic materials were extracted again with EtOAc/THF
  4. concentrationThe combined organic layers were concentrated under reduced pressure
  5. customThe residue was purified by column chromatography (Purif, NH, 80:20 hexane/EtOAc to EtOAc
  6. customto 90:10 EtOAc/MeOH), then crystallized from MeOH/EtOAc/hexane

Sources & evidence

ORD record
ord-7336ee1bb92c4d4eaf2f6d92bb36abff
Source dataset
uspto-grants-2014_04
Patent number
US08691828B2

Reaction notes

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