(R)-氯甲酸异丙酯 1-氮杂双环[2,2,2]辛-3-基酯 → (R)-methyl 3-(((2-fluorophenyl)((quinuclidin-3-yloxy)carbonyl)amino)-methyl)benzoate

HRID 1754316笔记

反应方程式

HRID 1754316 反应方程式
[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[NH:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].Cl.[C:21](Cl)(=[O:31])[O:22][C@@H:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(Cl)(=O)O[C@@H]1C2CCN(CC2)C1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[NH3:4].[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[N:4]([CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])[C:21]([O:22][C@@H:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1)=[O:31]

参与物

7

反应物 3

HCID 20812191(R)-氯甲酸异丙酯 1-氮杂双环[2,2,2]辛-3-基酯HCID 86676896(3R)-1-azabicyclo[2.2.2]octan-3-yl carbonochloridate hydrochlorideHCID 86720274Methyl 3-[(2-fluoroanilino)methyl]benzoate

产物 2

HCID 222氨收率 10%HCID 86720275(R)-methyl 3-(((2-fluorophenyl)((quinuclidin-3-yloxy)carbonyl)amino)-methyl)benzoate收率 146.3%

试剂、催化剂与溶剂 2

HCID 142844-二甲氨基吡啶(DMAP)催化剂HCID 1049吡啶溶剂

反应条件

温度
0 °C

实验过程

To a stirred solution of methyl 3-[(2-fluoroanilino)methyl]benzoate (0.3 g, 1.157 mmol) in anhydrous pyridine (6 mL) at 0° C. under N2 (g) was added 4-(dimethylamino)pyridine (0.014 g, 0.116 mmol) followed by (R)-quinuclidin-3-yl carbonochloridate hydrochloride (0.314 g, 1.39 mmol) in one portion. After stirring at 0° C. for 1 hour, the reaction was allowed to warm to room temperature. After 2.5 hours, further (R)-quinuclidin-3-yl carbonochloridate (0.628 g, 2.777 mmol) was added, and the reaction was stirred at room temperature for 65 hours. The reaction was quenched by addition of 10% aqueous potassium carbonate solution and extracted with ethyl acetate (×3). The combined organic extracts were washed with brine and dried (sodium sulfate), filtered, and the solvent was removed in vacuo to afford a brown oil. The crude material was purified by silica gel column chromatography eluting sequentially with ethyl acetate, 5% methanol in ethyl acetate, 5% 7N methanolic ammonia in ethyl acetate and 10% 7N methanolic ammonia in ethyl acetate to afford the title compound as a yellow oil (0.349 g, 73%).

后处理

  1. temperatureto warm to room temperature
  2. waitAfter 2.5 hours
  3. stirringthe reaction was stirred at room temperature for 65 hours
  4. customThe reaction was quenched by addition of 10% aqueous potassium carbonate solution
  5. extractionextracted with ethyl acetate (×3)
  6. washThe combined organic extracts were washed with brine
  7. dry with materialdried (sodium sulfate)
  8. filtrationfiltered
  9. customthe solvent was removed in vacuo
  10. customto afford a brown oil
  11. customThe crude material was purified by silica gel column chromatography
  12. washeluting sequentially with ethyl acetate, 5% methanol in ethyl acetate, 5% 7N methanolic ammonia in ethyl acetate

来源与证据

ORD记录
ord-b40a37184eca4ad38cd29f8c2716dbc2
来源数据集
uspto-grants-2015_10
专利号
US09169245B2

反应笔记

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