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

HRID 250122Notes

Reaction equation

HRID 250122 reaction equation
[Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([N:13]=[C:14]=S)[N:6]=[CH:7]2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl.[NH2:24][CH2:25][C@@:26]1([OH:34])[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1.C(N=C=NC(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([NH:13][C:14]1[O:34][C@:26]3([CH2:25][N:24]=1)[CH:31]1[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]1)[CH2:27]3)[N:6]=[CH:7]2

Participants

6

Reactant 4

HCID 10796Cesium carbonateHCID 12734DiisopropylcarbodiimideHCID 574766045,6-Dichloro-3-isothiocyanatoisoquinolineHCID 66724709(S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride

Product 1

HCID 58087979(R)-N-(5,6-dichloroisoquinolin-3-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amineYield 50.6%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
70 °C

Procedure

To 5,6-dichloro-3-isothiocyanatoisoquinoline (0.11 g, 0.431 mmol) in DMF (10 mL) was added cesium carbonate (0.351 g, 1.078 mmol) and (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.100 g, 0.435 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude urea was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH). The product was then treated with DMF (10 mL) and N,N′-diisopropylcarbodiimide (0.202 mL, 1.293 mmol). The reaction was heated to 90° C. for 18 hours. The reaction was cooled to room temperature and concentrated to yield the crude product. The crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH) to yield (R)—N-(5,6-dichloroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.084 g, 0.218 mmol, 50.6% yield) as a yellow powder. 1H NMR (500 MHz, CDCl3) δ ppm 9.09 (s, 1 H), 8.93 (s, 1 H), 7.63-7.82 (m, 2 H), 7.40 (d, J=8.55 Hz, 1 H), 3.99 (d, J=9.16 Hz, 1 H), 3.78 (d, J=8.85 Hz, 1 H), 3.51 (d, J=14.65 Hz, 1 H), 3.30 (d, J=14.65 Hz, 1 H), 2.90-3.23 (m, 4 H), 2.33-2.48 (m, 1 H), 2.29 (s, 1 H), 1.83-1.94 (m, 1 H), 1.62-1.83 (m, J=42.12 Hz, 2 H). MS (LC/MS) R.T.=1.57; [M+H]+=377.1.

Workup

  1. temperatureThe reaction was cooled to room temperature
  2. concentrationconcentrated in vacuo
  3. customThe crude urea was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH)
  4. temperatureThe reaction was heated to 90° C. for 18 hours
  5. temperatureThe reaction was cooled to room temperature
  6. concentrationconcentrated
  7. customto yield the crude product
  8. customThe crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH)

Sources & evidence

ORD record
ord-2183828d3053407d9d847264b2965a7e
Source dataset
uspto-grants-2011_01
Patent number
US07863291B2

Reaction notes

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