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

HRID 1875944Notes

Reaction equation

HRID 1875944 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+].[N:20]([C:23]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[N:26]=[CH:25][N:24]=1)=[C:21]=S.C(N=C=NC(C)C)(C)C>CN(C)C=O>[N:32]1[CH:31]=[CH:30][C:29]([C:27]2[N:26]=[CH:25][N:24]=[C:23]([NH:20][C:21]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:28]=2)=[CH:34][CH:33]=1

Participants

6

Reactant 4

HCID 10796Cesium carbonateHCID 12734DiisopropylcarbodiimideHCID 574765774-Isothiocyanato-6-(pyridin-4-yl)pyrimidineHCID 66724709(S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride

Product 1

HCID 58087971(R)-N-(6-(pyridin-4-yl)pyrimidin-4-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amineYield 16%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.059 g, 0.257 mmol) in N,N-dimethylformamide (15 mL) was added Cs2CO3 (0.209 g, 0.642 mmol) and 4-isothiocyanato-6-(pyridin-4-yl)pyrimidine (0.055 g, 0.257 mmol). The suspension was stirred at room temperature for 30 minutes. N,N′-diisopropylcarbodiimide (0.12 mL, 0.77 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 (0-10% [9:1 methanol:ammonium hydroxide]-ethyl acetate) to afford (R)—N-(6-(pyridin-4-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.014 g, 0.04 mmol, 16% yield) as a yellow film. 1H NMR (400 MHz, MeOD) δ ppm 8.85 (1H, d), 8.67 (2H, dd), 8.04 (2H, dd), 7.34 (1H, br. s.), 4.06 (1H, d), 3.76 (1H, d), 3.23 (1H, d), 3.10 (1H, d), 2.70-2.99 (4H, m), 2.01-2.22 (2H, m), 1.53-1.86 (3H, m). LCMS R.T.=0.42; [M+H]+=337.14.

Workup

  1. stirringto stir at room temperature for 18 hours
  2. concentrationThe mixture was concentrated
  3. custompurified by silica gel chromatography (0-10% [9:1 methanol:ammonium hydroxide]-ethyl acetate)

Sources & evidence

ORD record
ord-d78cda31d73544499046ae9b6ef98cbd
Source dataset
uspto-grants-2012_11
Patent number
US08309577B2

Reaction notes

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