Sodium Carbonate → Physostigmine

HRID 1440496Notes

Reaction equation

HRID 1440496 reaction equation
[CH3:1][C@:2]12[C:9]3[CH:10]=[C:11]([O:14][C:15]([NH:17][CH3:18])=[O:16])[CH:12]=[CH:13][C:8]=3[N:7]([CH3:19])[C@H:6]1[N:5]([CH3:20])[CH2:4][CH2:3]2.C1C=CC(O)=C(C(O)=O)C=1.C([O-])([O-])=O.[Na+].[Na+]>ClCCl.O>[CH3:1][C@:2]12[C:9]3[CH:10]=[C:11]([O:14][C:15]([NH:17][CH3:18])=[O:16])[CH:12]=[CH:13][C:8]=3[N:7]([CH3:19])[C@H:6]1[N:5]([CH3:20])[CH2:4][CH2:3]2

Participants

5

Reactant 2

HCID 10340Sodium CarbonateHCID 657348(-)-Physostigmine salicylate

Product 1

HCID 5983PhysostigmineYield 100.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

To a heterogeneous mixture of physostigmine salicylate (450 g) in dichloromethane (1.35L) and water (1.35L) was added Na2CO3 (150 g) over 0.5-1.0 hour while maintaining 18°-20° C. During the addition the pH of the aqueous phase increases from 5.5 to 9.5. After stirring at 18°-20° C. for 0.5 hour the aqueous phase was separated and extracted with dichloromethane (2×112 mL). The combined dichloromethane phase was treated again with water (500 mL) and Na2CO3 (23 g) at 18°-20° C. and stiffed for 0.5 hour. The aqueous phase was separated, extracted with dichloromethane (2×112 mL) and the combined dichloromethane phases were washed with water (450 mL), dried over K2CO3 (20 g) and concentrated under reduce pressure below 30° C. to give 302 g of crystalline physostigmine free base (100.8% of theory, 99.0% HPLC purity).

Workup

  1. temperaturewhile maintaining 18°-20° C
  2. additionDuring the addition the pH of the aqueous phase
  3. temperatureincreases from 5.5 to 9.5
  4. customwas separated
  5. extractionextracted with dichloromethane (2×112 mL)
  6. additionThe combined dichloromethane phase was treated again with water (500 mL) and Na2CO3 (23 g) at 18°-20° C.
  7. waitstiffed for 0.5 hour
  8. customThe aqueous phase was separated
  9. extractionextracted with dichloromethane (2×112 mL)
  10. washthe combined dichloromethane phases were washed with water (450 mL)
  11. dry with materialdried over K2CO3 (20 g)
  12. concentrationconcentrated
  13. custompressure below 30° C.

Sources & evidence

ORD record
ord-ca543a15df40455a9a36932f289305de
Source dataset
uspto-grants-1996_03
Patent number
US05498726

Reaction notes

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