Cesium carbonate → (R)-N-(6-bromothiazolo[5,4-b]pyrazin-2-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amine

HRID 1875964Notes

Reaction equation

HRID 1875964 reaction equation
[Br:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([N:11]=[C:12](SC)SC)=[N:10][C:5]2=[N:4][CH:3]=1.Cl.Cl.[NH2:19][CH2:20][C@@:21]1([OH:29])[CH:26]2[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]2)[CH2:22]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[Br:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12]3[O:29][C@:21]4([CH2:20][N:19]=3)[CH:26]3[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]3)[CH2:22]4)=[N:10][C:5]2=[N:4][CH:3]=1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 58088150Dimethyl (6-bromothiazolo[4,5-b]pyrazin-2-yl)carbonimidodithioateHCID 66724709(S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride

Product 1

HCID 58088190(R)-N-(6-bromothiazolo[5,4-b]pyrazin-2-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amineYield 57%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of dimethyl 6-bromothiazolo[5,4-b]pyrazin-2-ylcarbonimidodithioate (300 mg, 0.895 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (210 mg, 0.895 mmol) and cesium carbonate (600 mg, 1.79 mmol) in acetonitrile (25 mL) was heated on a 100° C. oil bath for 2 hours in an open flask, with nitrogen bubbling through the solution the entire time to help in the removal of methanethiol. After 2 hours, TLC showed the reaction to be complete, so the mixture was cooled to ambient temperature, diluted with water and concentrated in vacuo. The mixture was extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo, and the crude residue 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-(6-bromothiazolo[5,4-b]pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (200 mg, 57% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.39 (br. s., 1H) 8.48 (s, 1H) 4.05 (d, J=9.79 Hz, 1H) 3.72 (d, J=9.79 Hz, 1H) 3.42 (dd, J=15.06, 1.76 Hz, 1H) 2.73-3.08 (m, 5H) 2.10-2.22 (m, 2H) 1.73-1.84 (m, J=14.09, 9.94, 4.17, 4.17 Hz, 1H) 1.52-1.65 (m, 2H). MS (LC/MS) R.T.=1.29; [M+H]+=394.99.

Workup

  1. customwith nitrogen bubbling through the solution the entire time to help in the removal of methanethiol
  2. customthe reaction
  3. temperaturewas cooled to ambient temperature
  4. concentrationconcentrated in vacuo
  5. extractionThe mixture was extracted with chloroform (4×)
  6. washThe combined organics were washed with brine
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customthe crude residue was purified by silica gel chromatography (2-40% 9:1 methanol:ammonium hydroxide-chloroform)
  11. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-4fa349b6d87149b89cb6a6565cd88030
Source dataset
uspto-grants-2012_11
Patent number
US08309577B2

Reaction notes

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