Cesium carbonate → (1S,2R,4S)-N-(isoquinolin-3-yl)-4'H-4-azaspiro[bicyclo[2.2.2]octane-2,5'-oxazol]-2'-amine

HRID 1875923노트

반응식

HRID 1875923 반응식
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[N:24]=[CH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:21]=S.C(N=C=NC(C)C)(C)C>CN(C)C=O>[CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[C:23]([NH:20][C:21]2[O:13][C@:5]3([CH2:4][N:3]=2)[CH:10]2[CH2:9][CH2:8][N:7]([CH2:12][CH2:11]2)[CH2:6]3)[N:24]=1

참가 물질

6

반응물 4

HCID 10796Cesium carbonateHCID 12734DiisopropylcarbodiimideHCID 574765653-IsothiocyanatoisoquinolineHCID 66724709(S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride

생성물 1

HCID 44247585(1S,2R,4S)-N-(isoquinolin-3-yl)-4'H-4-azaspiro[bicyclo[2.2.2]octane-2,5'-oxazol]-2'-amine수율 58.2%

시약·촉매·용매 1

HCID 6228Dimethylformamide용매

실험 절차

To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.2 g, 0.873 mmol) in N,N-dimethylformamide (20 mL) was added Cs2CO3 (0.711 g, 2.182 mmol) and 3-isothiocyanatoisoquinoline (0.163 g, 0.873 mmol). The suspension was stirred at room temperature for 30 minutes. N,N′-Diisopropylcarbodiimide (0.408 mL, 2.62 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 (5-25% [9:1 methanol:ammonium hydroxide]-ethyl acetate) to afford (R)—N-(isoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.16 g, 0.508 mmol, 58% yield) as an off-white solid. M.P. 196-200° C. 1H NMR (400 MHz, MeOD) δ ppm 9.00 (1H, s), 7.92 (1H, d), 7.71 (1H, d), 7.59 (1H, t), 7.20-7.45 (2H, m), 3.96 (1H, d), 3.65 (1H, d), 3.22 (1H, d), 3.08 (1H, d), 2.66-3.00 (4H, m), 2.05-2.23 (2H, m), 1.50-1.86 (3H, m). R.T.=1.37; [M+H]+=309.31.

후처리

  1. stirringthe mixture was stirred at room temperature for 18 hours
  2. concentrationThe mixture was concentrated
  3. custompurified by silica gel chromatography (5-25% [9:1 methanol:ammonium hydroxide]-ethyl acetate)

출처 및 근거

ORD 기록
ord-ad420286641741a9a47ce06b86a16455
출처 데이터셋
uspto-grants-2012_11
특허 번호
US08309577B2

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