(R)-quinuclidin-3-yl carbonochloridate → (R)-methyl-3-(((4-fluorophenyl)((quinuclidin-3-yloxy)carbonyl)amino)-methyl)benzoate

HRID 1497975Notes

Reaction equation

HRID 1497975 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.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>[NH3:8].[CH3:16][O:15][C:13](=[O:14])[C:12]1[CH:17]=[CH:18][CH:19]=[C:10]([CH2:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:21]([O:22][C@@H:23]2[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]2)=[O:31])[CH:11]=1

Participants

6

Reactant 3

HCID 20812191(R)-quinuclidin-3-yl carbonochloridateHCID 86676896(3R)-1-azabicyclo[2.2.2]octan-3-yl carbonochloridate hydrochlorideHCID 86720703Methyl 3-(((4-fluorophenyl)amino)methyl)benzoate

Product 2

HCID 222AmmoniaYield 10%HCID 86720704(R)-methyl-3-(((4-fluorophenyl)((quinuclidin-3-yloxy)carbonyl)amino)-methyl)benzoateYield 197.4%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Conditions

Temperature
0 °C

Procedure

To a stirred solution of methyl 3-(((4-fluorophenyl)amino)methyl)benzoate (0.3 g, 1.157 mmol) in anhydrous pyridine (6 mL) at 0° C. under N2 was added (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 25 minutes, further (R)-quinuclidin-3-yl carbonochloridate (0.314 g, 1.39 mmol) was added, and the reaction was stirred at room temperature for 18 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 red oil. The crude material was purified by silica gel column chromatography eluting sequentially with ethyl acetate, 10% 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 (0.471 g, 98%).

Workup

  1. temperatureto warm to room temperature
  2. waitAfter 25 minutes
  3. stirringthe reaction was stirred at room temperature for 18 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 red oil
  11. customThe crude material was purified by silica gel column chromatography
  12. washeluting sequentially with ethyl acetate, 10% methanol in ethyl acetate, 5% 7N methanolic ammonia in ethyl acetate

Sources & evidence

ORD record
ord-e10aec02bb2447b898e683f7a82537a1
Source dataset
uspto-grants-2015_12
Patent number
US09199980B2

Reaction notes

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