Aniline → ethyl 2-[3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]phenyl]acetate

HRID 1497989Notes

Reaction equation

HRID 1497989 reaction equation
Br[CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[C:29](Cl)(=[O:39])[O:30][C@@H:31]1[CH:36]2[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]2)[CH2:32]1>>[N:33]12[CH2:38][CH2:37][CH:36]([CH2:35][CH2:34]1)[C@@H:31]([O:30][C:29]([N:15]([CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:39])[CH2:32]2

Participants

5

Reactant 4

HCID 6115AnilineHCID 11430Potassium CarbonateHCID 10563066Ethyl 2-(3-(bromomethyl)phenyl)acetateHCID 86676896(3R)-1-azabicyclo[2.2.2]octan-3-yl carbonochloridate hydrochloride

Product 1

HCID 86720711ethyl 2-[3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]phenyl]acetateYield 35.4%

Conditions

Temperature
90 °C

Procedure

A mixture of ethyl 2-[3-(bromomethyl)phenyl]acetate (600 mg, 2.33 mmol), aniline (202 mg, 2.21 mmol) and potassium carbonate (420 mg, 3.04 mmol) in 1V, N-dimethylformamide (15 mL) was heated to 90° C. for 18 hours. After cooling to room temperature, the reaction was filtered and the solvent was removed in vacuo. The residue was taken up in ethyl acetate and washed with brine (3×20 mL). The organic phase was passed through a hydrophobic fit and the solvent was removed in vacuo. The crude material was dissolved in acetonitrile (5 mL), and (R)-quinuclidin-3-yl carbonochloridate hydrochloride (530 mg, 2.35 mmol) was added. The resulting mixture was heated to 100° C. for 30 minutes under microwave irradiation. The solvent was removed in vacuo, then the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, passed through a hydrophobic fit and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluting sequentially with ethyl acetate, 10% methanol in ethyl acetate and 10% 7N methanolic ammonia in ethyl acetate to afford the title compound as a yellow solid (331 mg, 35%).

Workup

  1. temperatureAfter cooling to room temperature
  2. filtrationthe reaction was filtered
  3. customthe solvent was removed in vacuo
  4. washwashed with brine (3×20 mL)
  5. customthe solvent was removed in vacuo
  6. dissolutionThe crude material was dissolved in acetonitrile (5 mL)
  7. temperatureThe resulting mixture was heated to 100° C. for 30 minutes under microwave irradiation
  8. customThe solvent was removed in vacuo
  9. customthe residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution
  10. washThe organic layer was washed with brine
  11. customthe solvent was removed in vacuo
  12. customThe residue was purified by silica gel column chromatography
  13. washeluting sequentially with ethyl acetate, 10% methanol in ethyl acetate and 10% 7N methanolic ammonia in ethyl acetate

Sources & evidence

ORD record
ord-381900e37c6248fa9f968acd878e59b5
Source dataset
uspto-grants-2015_12
Patent number
US09199980B2

Reaction notes

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