Water → (3R)-N-(7-Methoxythiazolo[5,4-d]pyrimidin-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,5′(4′H)-oxazol]-2′-amine

HRID 1875979Notes

Reaction equation

HRID 1875979 reaction equation
[CH3:1][O:2][C:3]1[C:4]2[N:11]=[C:10]([N:12]=[C:13](SC)SC)[S:9][C:5]=2[N:6]=[CH:7][N:8]=1.Cl.Cl.[NH2:20][CH2:21][C@@:22]1([OH:30])[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]2[N:11]=[C:10]([NH:12][C:13]3[O:30][C@:22]4([CH2:21][N:20]=3)[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]4)[S:9][C:5]=2[N:6]=[CH:7][N:8]=1

Participants

6

Reactant 4

HCID 962WaterHCID 10796Cesium carbonateHCID 66724709(S)-3-(aminomethyl)quinuclidin-3-ol dihydrochlorideHCID 86635292HCID 86635292, compound

Product 1

HCID 58088223(3R)-N-(7-Methoxythiazolo[5,4-d]pyrimidin-2-yl)spiro[1-azabicyclo[2.2.2]octane-3,5′(4′H)-oxazol]-2′-amineYield 52.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of dimethyl 7-methoxythiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate (150 mg, 0.52 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (132 mg, 0.58 mmol) and cesium carbonate (427 mg, 1.31 mmol) in DMF (3 mL) was heated to 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature, poured into water and extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The mixture was purified by silica gel chromatography (2-40% [9:1 methanol:ammonium hydroxide]-chloroform). The product fractions were combined and concentrated in vacuo to afford (R)—N-(7-methoxythiazolo[5,4-d]pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (95 mg, 51% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.12 (br. s., 1H) 8.52 (s, 1H) 4.16 (s, 3H) 4.05 (d, J=9.54 Hz, 1H) 3.70 (d, J=9.54 Hz, 1H) 3.40 (dd, J=14.93, 1.88 Hz, 1H) 2.70-3.07 (m, 5H) 2.08-2.27 (m, 2H) 1.68-1.85 (m, 1H) 1.48-1.66 (m, 2H). MS (LC/MS) R.T.=0.90; [M+H]+=347.34.

Workup

  1. temperatureThe reaction mixture was cooled to ambient temperature
  2. extractionextracted with chloroform (4×)
  3. washThe combined organics were washed with brine
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe mixture was purified by silica gel chromatography (2-40% [9:1 methanol:ammonium hydroxide]-chloroform)
  8. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-fb900b7665fc46cd8706997f62e8fdc9
Source dataset
uspto-grants-2012_11
Patent number
US08309577B2

Reaction notes

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