Sodium hydride → Solifenacin

HRID 1056487Notes

Reaction equation

HRID 1056487 reaction equation
[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([OH:9])[CH2:2]2.[H-].[Na+].[C:12]1([C@H:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20][N:19]2[C:28](OCCC)=[O:29])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH:15]1[CH:16]=[CH:17][C:12]([C@@H:18]2[N:19]([C:28]([O:9][C@@H:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[O:29])[CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]2=3)=[CH:13][CH:14]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 914043-Quinuclidinol, (-)-HCID 131736431propyl (1s)-1-phenyl-3,4-dihydro-2(1H)-isoquinoline-carboxylate

Product 1

HCID 154059Solifenacin

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Conditions

Temperature
80 °C

Procedure

(R)-quinuclidin-3-ol (0.66 g, 5.2 mmol) and sodium hydride (0.21 g, 0.52 mmol, 60%) are dissolved in anhydrous toluene and stirred for 1 hour at 80° C. A solution of propyl (1s)-1-phenyl-3,4-dihydro-2(1H)-isoquinoline-carboxylate (1.4 g, 4.75 mmol) in toluene (10 ml) is added and refluxed for 18 hours. Isopropyl alcohol is removed from the solution by azeotropic distillation during which toluene is necessarily added. The reaction is cooled to ambient temperature when propyl carboxylate is consumed completely according to TLC analysis. The toluene is washed with water and aq. HCl (1N)(10 ml), the organic phase is separated. Saturated sodium bicarbonate (20 ml) is added to the aqueous phase, then extracted with ethyl acetate (20 ml). The combined organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated to afford yellow oil as crude Solifenacin base, 1.1 g, 63.9% with the following characteristics: HPLC: 95.8%; Chiral Purity: 99%; MS (ESI): m/z 363.2 (M+H+); 1-H-NMR (400 M, CDCl3): δ 7.32-7.17 (m, 9H), 6.55-6.17 (m, 1H), 4.20-2.90 (m, 1H), 3.36-2.86 (br, 10H), 2.18-1.47 (m, 5H).

Workup

  1. temperaturerefluxed for 18 hours
  2. customIsopropyl alcohol is removed from the solution by azeotropic distillation during which toluene
  3. additionis necessarily added
  4. temperatureThe reaction is cooled to ambient temperature when propyl carboxylate
  5. customis consumed completely
  6. washThe toluene is washed with water and aq. HCl (1N)(10 ml)
  7. customthe organic phase is separated
  8. additionSaturated sodium bicarbonate (20 ml) is added to the aqueous phase
  9. extractionextracted with ethyl acetate (20 ml)
  10. dry with materialThe combined organic phase is dried over anhydrous sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-7714429a84d9455cb6181f2f7f29aaa2
Source dataset
uspto-grants-2016_07
Patent number
US09399624B2

Reaction notes

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