Cesium carbonate → (R)-N-(6,8-dichloroisoquinolin-3-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amine

HRID 250117ノート

反応式

HRID 250117 の反応式
[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH:8]=[N:7][C:6]([N:13]=[C:14]=S)=[CH:5]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[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH:8]=[N:7][C:6]([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)=[CH:5]2

参加物

6

反応物 4

HCID 10796Cesium carbonateHCID 12734DiisopropylcarbodiimideHCID 574765996,8-Dichloro-3-isothiocyanatoisoquinolineHCID 66724709(S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride

生成物 1

HCID 58088169(R)-N-(6,8-dichloroisoquinolin-3-yl)-4H-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octan]-2-amine収率 36.6%

試薬・触媒・溶媒 1

HCID 6228Dimethylformamide溶媒

反応条件

温度
70 °C

実験手順

To 6,8-dichloro-3-isothiocyanatoisoquinoline (0.17 g, 0.67 mmol) in DMF (10 mL) was added cesium carbonate (0.543 g, 1.67 mmol) and (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.15 g, 0.67 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 product was treated with N,N′-diisopropylcarbodiimide (0.31 mL, 2.0 mmol). The reaction was heated to 90° C. for 4 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). The product was taken up in a small amount of ethyl acetate, which resulted in the formation of a precipate. It was filtered off, washed with a small amount of ethyl acetate, and dried in a vacuum oven to yield (R)—N-(6,8-dichloroisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.094 g, 0.24 mmol, 36.6% yield) as a white powder. 1H NMR (400 MHz, DMSO-D6) δ ppm 9.23 (s, 1H), 8.71-8.83 (m, 1H), 7.90-8.00 (m, 1H), 7.57-7.67 (m, 1H), 7.13-7.24 (m, 1H), 3.79-3.90 (m, 1H), 3.53-3.64 (m, 1H), 2.93-3.04 (m, 2H), 2.72-2.82 (m, 2H), 2.61-2.70 (m, 2H), 1.99 (s, 1H), 1.90 (s, 1H), 1.59 (d, J=4.78 Hz, 2H), 1.40-1.50 (m, 1H). MS (LC/MS) R.T.=1.68; [M+H]+=377.1.

後処理

  1. temperatureThe reaction was cooled to room temperature
  2. concentrationconcentrated in vacuo
  3. temperatureThe reaction was heated to 90° C. for 4 hours
  4. temperatureThe reaction was cooled to room temperature
  5. concentrationconcentrated
  6. customto yield the crude product
  7. customThe crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH)
  8. customresulted in the formation of a precipate
  9. filtrationIt was filtered off
  10. washwashed with a small amount of ethyl acetate
  11. customdried in a vacuum oven

出典と根拠

ORDレコード
ord-d3419dea14f944a0946e5a2b6a260aec
出典データセット
uspto-grants-2011_01
特許番号
US07863291B2

反応ノート

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