Triethylamine → (R)-N-(6-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-4H-1'-azaspiro-[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amine

HRID 1875887Notes

Reaction equation

HRID 1875887 reaction equation
[N:1]([C:4]1[N:14]=[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][N:6]2[N:5]=1)=[C:2]=S.[CH2:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])C.[CH:22]([N:25]=C=NC(C)C)(C)C.[C:31](=[O:34])(O)[O-].[Na+].[CH:36](Cl)(Cl)Cl>CN(C)C=O>[CH3:13][O:12][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([N:5]=[C:4]([NH:1][C:2]3[O:34][C@:31]4([CH2:22][N:25]=3)[CH:36]3[CH2:21][CH2:20][N:17]([CH2:18][CH2:19]3)[CH2:15]4)[N:14]=2)[CH:11]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 12734DiisopropylcarbodiimideHCID 574765522-Isothiocyanato-6-methoxy-[1,2,4]triazolo[1,5-a]pyridineHCID 86635290Sodium bicarbonate chloroform

Product 1

HCID 58088152(R)-N-(6-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-4H-1'-azaspiro-[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amineYield 42%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
70 °C

Procedure

To 2-isothiocyanato-6-methoxy-[1,2,4]triazolo[1,5-a]pyridine (160 mg, 0.78 mmol) in N,N-dimethylformamide (5 ml) was added (S)-3-(aminomethyl)quinuclidin-3-ol, 2HCl (178 mg, 0.78 mmol) and triethylamine (0.32 ml, 2.33 mmol). The reaction was stirred at 70° C. for 1 hour. N,N′-Diisopropylcarbodiimide (0.36 ml, 2.33 mmol) was then added to the reaction mixture. The mixture was heated at 70° C. for 4 hours, then cooled and poured into aqueous sodium bicarbonate/chloroform. The product was extracted (3×) with chloroform. The combined organics were washed with water (3×), dried over sodium sulfate, filtered, and concentrated in vacuo, then purified via flash chromatography (2-20% [10% ammonium hydroxide:methanol]/chloroform) to yield (R)—N-(6-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-4H-1′-azaspiro-[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (114.5 mg, 0.33 mmol, 42% yield) as a white powder. 1H NMR (500 MHz, CDCl3) δ ppm 8.51 (1H, br. s.), 8.08 (1H, d, J=2.44 Hz), 7.35 (1H, d, J=9.77 Hz), 7.18 (1H, dd, J=9.46, 2.44 Hz), 3.92 (1H, d, J=8.85 Hz), 3.84 (3H, s), 3.58 (1H, d, J=8.85 Hz), 3.36-3.41 (1H, m), 2.72-3.05 (4H, m), 2.18-2.26 (1H, m, J=13.26, 9.98, 3.66, 3.49, 3.49 Hz), 2.13 (1H, br. s.), 1.79 (1H, br. s.), 1.67-1.76 (1H, m, J=13.96, 9.84, 4.27, 4.27 Hz), 1.45-1.63 (2H, m). MS (LC/MS) R.T.=0.86; [M+H]+=329.2.

Workup

  1. temperatureThe mixture was heated at 70° C. for 4 hours
  2. temperaturecooled
  3. extractionThe product was extracted (3×) with chloroform
  4. washThe combined organics were washed with water (3×)
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. custompurified via flash chromatography (2-20% [10% ammonium hydroxide:methanol]/chloroform)

Sources & evidence

ORD record
ord-0ff947c6da2b47aa872d71e3ff9d0fc9
Source dataset
uspto-grants-2012_11
Patent number
US08309577B2

Reaction notes

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