Hydrogen chloride-ethyl acetate → 2-[(1R,3S,4S)-2-azabicyclo[2.2.1]hept-3-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-one

HRID 1409030Notes

Reaction equation

HRID 1409030 reaction equation
[CH3:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]1[S:15][C:14]2[C:13](=[O:16])[NH:12][C:11]([C@@H:17]3[C@@H:22]4[CH2:23][C@@H:19]([CH2:20][CH2:21]4)[N:18]3C(OC(C)(C)C)=O)=[N:10][C:9]=2[CH:8]=1.Cl.C(OCC)(=O)C>CO>[C@H:19]12[CH2:23][C@H:22]([CH2:21][CH2:20]1)[C@@H:17]([C:11]1[NH:12][C:13](=[O:16])[C:14]3[S:15][C:7]([C:3]4[CH:4]=[N:5][NH:6][C:2]=4[CH3:1])=[CH:8][C:9]=3[N:10]=1)[NH:18]2

Participants

4

Reactant 2

HCID 21866389Hydrogen chloride-ethyl acetateHCID 136333924tert-butyl (1R,3S,4S)-3-[6-(5-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylate

Product 1

HCID 1363339252-[(1R,3S,4S)-2-azabicyclo[2.2.1]hept-3-yl]-6-(5-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidin-4(3H)-oneYield 41.6%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To a solution of tert-butyl (1R,3S,4S)-3-[6-(5-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylate (690 mg) in methanol (10 mL) was added 4M hydrochloric acid/ethyl acetate solution (2.0 mL) with stirring at room temperature. The reaction system was stirred with heating at 50° C. for 30 min, and the mixture was concentrated under reduced pressure. The residue was neutralized with saturated aqueous sodium hydrogen carbonate. Insoluble material was removed by filtration. The mixture was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate), and the obtained colorless solid was crystallized from methanol/ethyl acetate to give the title compound (220 mg) as a colorless solid. The optical purity was 86% ee. The analysis was performed by high performance liquid chromatography (column: CHIRALPAK OD-H (4.6 mm i.d.×250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: methanol, flow rate: 0.5 mL/min, column temperature: 30° C., detection 254 nm).

Workup

  1. stirringThe reaction system was stirred
  2. temperaturewith heating at 50° C. for 30 min
  3. concentrationthe mixture was concentrated under reduced pressure
  4. customInsoluble material was removed by filtration
  5. extractionThe mixture was extracted with ethyl acetate
  6. dry with materialdried over anhydrous sodium sulfate
  7. customInsoluble material was removed by filtration
  8. concentrationthe filtrate was concentrated under reduced pressure
  9. customThe residue was purified by basic silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate)
  10. customthe obtained colorless solid was crystallized from methanol/ethyl acetate

Sources & evidence

ORD record
ord-b0f6d74fbd4b4da0bd11952a41af34ff
Source dataset
uspto-grants-2014_12
Patent number
US08921354B2

Reaction notes

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