(R)-quinuclidin-3-yl carbonochloridate → (R)-methyl 3-(((2-fluorophenyl)((quinuclidin-3-yloxy)carbonyl)amino)-methyl)benzoate

HRID 1754316Notes

Reaction equation

HRID 1754316 reaction equation
[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]

Participants

7

Reactant 3

HCID 20812191(R)-quinuclidin-3-yl carbonochloridateHCID 86676896(3R)-1-azabicyclo[2.2.2]octan-3-yl carbonochloridate hydrochlorideHCID 86720274Methyl 3-[(2-fluoroanilino)methyl]benzoate

Product 2

HCID 222AmmoniaYield 10%HCID 86720275(R)-methyl 3-(((2-fluorophenyl)((quinuclidin-3-yloxy)carbonyl)amino)-methyl)benzoateYield 146.3%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 1049PyridineSolvent

Conditions

Temperature
0 °C

Procedure

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%).

Workup

  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

Sources & evidence

ORD record
ord-b40a37184eca4ad38cd29f8c2716dbc2
Source dataset
uspto-grants-2015_10
Patent number
US09169245B2

Reaction notes

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