Cesium carbonate → (R)-N-(7-bromoisoquinolin-3-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amine

HRID 250138Notes

Reaction equation

HRID 250138 reaction equation
Cl.Cl.[NH2:3][CH2:4][C@@:5]1([OH:13])[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[C:26]([N:31]=[C:32]=S)[N:27]=[CH:28]2)=[CH:23][CH:22]=1.C(N=C=NC(C)C)(C)C>CN(C)C=O>[Br:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[C:26]([NH:31][C:32]3[O:13][C@:5]4([CH2:4][N:3]=3)[CH:10]3[CH2:9][CH2:8][N:7]([CH2:12][CH2:11]3)[CH2:6]4)[N:27]=[CH:28]2)=[CH:23][CH:22]=1

Participants

6

Reactant 4

HCID 10796Cesium carbonateHCID 12734DiisopropylcarbodiimideHCID 574766077-Bromo-3-isothiocyanatoisoquinolineHCID 66724709(S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride

Product 1

HCID 58087984(R)-N-(7-bromoisoquinolin-3-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amineYield 17.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.207 g, 0.905 mmol) in N,N-dimethylformamide (20 mL) was added Cs2CO3 (0.737 g, 2.263 mmol) and 7-bromo-3-isothiocyanatoisoquinoline (0.24 g, 0.905 mmol). The suspension was stirred at room temperature for 30 minutes. N,N′-Diisopropylcarbodiimide (0.423 mL, 2.72 mmol) was then added and the mixture was stirred at room temperature for 18 hours. The mixture was concentrated and purified by silica gel chromatography using 5-15% [9:1 methanol:ammonium hydroxide] in ethyl acetate. The desired fractions were concentrated and further purified using 5-15% [9.5:0.5 methanol:ammonium hydroxide] in ethyl acetate to afford ((R)—N-(7-bromoisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.061 g, 0.156 mmol, 17% yield) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 8.96 (1H, s), 8.12 (1H, s), 7.66 (2H, s), 7.32 (1H, s), 4.01 (1H, d), 3.73 (1H, d), 3.35-3.42 (1H, m), 3.22-3.29 (1H, m), 2.84-3.17 (4H, m), 2.13-2.35 (2H, m), 1.62-1.96 (3H, m). LCMS:R.T.=1.76; [M+]+=387.21.

Workup

  1. stirringthe mixture was stirred at room temperature for 18 hours
  2. concentrationThe mixture was concentrated
  3. custompurified by silica gel chromatography
  4. concentrationThe desired fractions were concentrated
  5. customfurther purified

Sources & evidence

ORD record
ord-cde9585b2cd74820928ed350688b7198
Source dataset
uspto-grants-2011_01
Patent number
US07863291B2

Reaction notes

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