Water → (R)-N-(thiazolo[5,4-b]pyridin-2-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amine

HRID 250109Notes

Reaction equation

HRID 250109 reaction equation
[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[S:3][C:2]=1[N:10]=[C:11](SC)SC.Cl.Cl.[NH2:18][CH2:19][C@@:20]1([OH:28])[CH:25]2[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]2)[CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[S:3][C:2]=1[NH:10][C:11]1[O:28][C@:20]2([CH2:19][N:18]=1)[CH:25]1[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]1)[CH2:21]2

Participants

6

Reactant 4

HCID 962WaterHCID 10796Cesium carbonateHCID 58088154Dimethyl thiazolo[5,4-b]pyridin-2-ylcarbonimidodithioateHCID 66724709(S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride

Product 1

HCID 58088019(R)-N-(thiazolo[5,4-b]pyridin-2-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amineYield 76.1%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of dimethyl thiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate (90 mg, 0.35 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (97 mg, 0.42 mmol) and cesium carbonate (230 mg, 0.71 mmol) in DMF (1 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-(thiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (84 mg, 76% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.30 (br. s., 1 H) 8.37 (dd, J=4.77, 1.51 Hz, 1 H) 7.82 (dd, J=8.03, 1.51 Hz, 1 H) 7.28 (dd, J=8.03, 4.77 Hz, 1 H) 4.05 (d, J=9.54 Hz, 1 H) 3.70 (d, J=9.54 Hz, 1 H) 3.42 (dd, J=15.06, 1.76 Hz, 1 H) 2.75-3.07 (m, 5 H) 2.14-2.26 (m, 2 H) 1.71-1.84 (m, J=13.99, 9.79, 4.17, 4.17 Hz, 1 H) 1.48-1.68 (m, 2 H). MS (LC/MS) R.T.=0.64; [M+H]+=316.15.

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-9554f7fc3e5147f88e8483ce1ab815be
Source dataset
uspto-grants-2011_01
Patent number
US07863291B2

Reaction notes

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