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

HRID 1875962Notes

Reaction equation

HRID 1875962 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:14]([O-:17])([O-])=[O:15].[Cs+].[Cs+].[Cl:20][C:21]1[CH:22]=[C:23]([C:27]2[CH:32]=[C:31]([N:33]=[C:34]=S)[N:30]=[CH:29][N:28]=2)[CH:24]=[CH:25][CH:26]=1.C(N=C=NC(C)C)(C)C>CN(C)C=O.CO>[OH-:13].[NH4+:3].[C:14]([O:17][CH2:4][CH3:5])(=[O:15])[CH3:21].[Cl:20][C:21]1[CH:22]=[C:23]([C:27]2[N:28]=[CH:29][N:30]=[C:31]([NH:33][C:34]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)[CH:32]=2)[CH:24]=[CH:25][CH:26]=1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 12734DiisopropylcarbodiimideHCID 574765894-(3-Chlorophenyl)-6-isothiocyanatopyrimidineHCID 66724709(S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride

Product 2

HCID 21904419Ammonium hydroxide ethyl acetateHCID 58087986(R)-N-(6-(3-chlorophenyl)pyrimidin-4-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amineYield 91.3%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6228DimethylformamideSolvent

Procedure

To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.111 g, 0.484 mmol) in N,N-dimethylformamide (15 mL) was added Cs2CO3 (0.395 g, 1.211 mmol) and 4-(3-chlorophenyl)-6-isothiocyanatopyrimidine (0.12 g, 0.484 mmol). The suspension was stirred at room temperature for 30 minutes. N,N′-diisopropylcarbodiimide (0.226 mL, 1.453 mmol) was then added and the mixture was continued to stir at room temperature for 18 hours. The mixture was concentrated and purified by silica gel chromatography (5-25%, then, 2-10% 9:1 methanol:ammonium hydroxide-ethyl acetate) to afford (R)—N-(6-(3-chlorophenyl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.086 g, 0.221 mmol, 46% yield) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 8.82 (1H, d), 8.05 (1H, d), 7.93 (1H, ddd), 7.43-7.52 (2H, m), 7.35 (1H, br. s.), 4.13 (1H, d), 3.93 (1H, d), 3.63-3.81 (2H, m), 3.42-3.53 (1H, m), 3.30-3.40 (3H, m), 2.46 (1H, d), 2.26-2.40 (1H, m), 1.88-2.16 (3H, m). LCMS R.T.=1.90; [M]+=370.28.

Workup

  1. stirringto stir at room temperature for 18 hours
  2. concentrationThe mixture was concentrated
  3. custompurified by silica gel chromatography (5-25%

Sources & evidence

ORD record
ord-fb29784b40bf44e4a5fcaaa334a62c73
Source dataset
uspto-grants-2012_11
Patent number
US08309577B2

Reaction notes

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