Water → (R)-N5,N5-dimethyl-N2-(4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octane]-2-yl)thiazolo[5,4-d]pyrimidine-2,5-diamine

HRID 1875973

Reaction equation

HRID 1875973 reaction equation
[CH3:1][N:2]([CH3:18])[C:3]1[N:4]=[CH:5][C:6]2[N:11]=[C:10]([N:12]=[C:13](SC)SC)[S:9][C:7]=2[N:8]=1.Cl.Cl.[NH2:21][CH2:22][C@@:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][N:2]([CH3:18])[C:3]1[N:4]=[CH:5][C:6]2[N:11]=[C:10]([NH:12][C:13]3[O:31][C@:23]4([CH2:22][N:21]=3)[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]4)[S:9][C:7]=2[N:8]=1

Participants

6

Reactant 4

HCID 962WaterHCID 10796Cesium carbonateHCID 58088064Dimethyl (5-(dimethylamino)thiazolo[5,4-d]pyrimidin-2-yl)carbonimidodithioateHCID 66724709(S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride

Product 1

HCID 58088194(R)-N5,N5-dimethyl-N2-(4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octane]-2-yl)thiazolo[5,4-d]pyrimidine-2,5-diamineYield 74.9%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of dimethyl 5-(dimethylamino)thiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate (90 mg, 0.301 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (83 mg, 0.361 mmol) and cesium carbonate (196 mg, 0.60 mmol) in DMF (1.0 mL) was heated to 100° C. for 1.5 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, concentrated in vacuo, and the crude residue was purified by silica gel chromatography (2-40% 9:1 methanol: ammonium hydroxide-chloroform) to afford (R)—N5,N5-dimethyl-N2-(4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-yl)thiazolo[5,4-d]pyrimidine-2,5-diamine (81 mg, 71% yield) as a tan solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.07 (br. s., 1H) 8.50 (s, 1H) 4.01 (d, J=9.54 Hz, 1H) 3.67 (d, J=9.54 Hz, 1H) 3.39 (dd, J=14.93, 1.63 Hz, 1H) 3.23 (s, 6H) 2.71-3.10 (m, 5H) 2.10-2.24 (m, 2H) 1.68-1.84 (m, 1H) 1.46-1.68 (m, 2H). MS (LC/MS) R.T.=0.87; [M+H]+=360.23.

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 crude residue was purified by silica gel chromatography (2-40% 9:1 methanol: ammonium hydroxide-chloroform)

Sources & evidence

ORD record
ord-40768f68a6f24acc8ab6827b3d6dfca7
Source dataset
uspto-grants-2012_11
Patent number
US08309577B2

Linked notes

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