Acetic Acid → Physostigmine

HRID 1440495Notes

Reaction equation

HRID 1440495 reaction equation
CC(O)=O.C1C2C(=CC=CC=2)CCN1.[CH2:15]1C2C(=CC=CC=2)CC[N:16]1[C:25]([O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH3:37])[C@H:32]1[N:38]([CH3:41])[CH2:39][CH2:40][C@@:31]21[CH3:42])=[O:26].C[C@]12C3C=C(O)C=CC=3N(C)[C@H]1N(C)CC2.[OH-].[Na+]>C1COCC1.C1(C)C=CC=CC=1.O>[CH3:42][C@:31]12[C:30]3[CH:29]=[C:28]([O:27][C:25]([NH:16][CH3:15])=[O:26])[CH:36]=[CH:35][C:34]=3[N:33]([CH3:37])[C@H:32]1[N:38]([CH3:41])[CH2:39][CH2:40]2

Participants

9

Reactant 5

HCID 176Acetic AcidHCID 70461,2,3,4-TetrahydroisoquinolineHCID 14798Sodium HydroxideHCID 119198EserolineHCID 132228Quilostigmine

Product 1

HCID 5983PhysostigmineYield 89%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
20 °C

Procedure

To a solution of physostigmine (290 g) in dry THF (2.3 L) at 15° C. under a nitrogen atmosphere was treated with KOtBu (126.4 g), added over 0.05 hour. The mixture was kept at 15° C. for 0.5 hour, then treated with glacial HOAc (64.1 mL, 1 equiv., pH=10) to give a mixture containing physostigmine (II) and eseroline (III) in a 1/99 HPLC ratio. Addition of 1,1'-carbonyldiimidazole (195.8 g, 1.15 equiv) in 10 (0.1 equiv.) and 3 (0.05 equiv.) portions at -30° C. over 2 hours gave the following HPLC ratios of imidazolecarbonyl intermediate (V) and eseroline after 1.0, 1.1 and 1.15 equiv.: 92/8, 98/2 and 99/1. Addition of glacial HOAc (482 mL, 8 equiv., pH-5) followed by 1,2,3,4-tetrahydroisoquinoline (175 g, 1.25 equiv., added over 1.5 hours at - 10° C.) and warming to 20° C. for 15 hours gave a mixture containing (3aS-cis)- 1,2,3,3a,8,8a-hexahydro- 1,3a,8-trimethylpyrrolo-[2,3-b]indol-5-yl 3,4-dihydro-2(1H)-isoquinolinecarboxylate and eseroline in a 99/1 HPLC ratio. Addition of water (500 mL), cooling to -10° C., partial neutralization to pH=8 with 50% NaOH (471 g, 0.7 equiv based in HOAc), concentration of the THF under 30° C., toluene extraction (1×1L and 2×0.5L) of the residue, washing with water (500 mL), 5% NaCl (500 mL) and concentration under reduced pressure at 50° C. gave 370 g of crude product. This material was further purified by silica gel chromatography using ethyl acetate/methanol to give 346 g of 99% pure product in 89% yield from physostigmine. Recrystallization from methanol/water gave 321 g of crystalline product in 99% PHLC purity and 84 % yield.

Workup

  1. customgave a mixture
  2. temperaturecooling to -10° C.
  3. washwashing with water (500 mL), 5% NaCl (500 mL) and concentration under reduced pressure at 50° C.
  4. customgave 370 g of crude product
  5. customThis material was further purified by silica gel chromatography

Sources & evidence

ORD record
ord-7b7afcd69779487c81cc8c4449671e57
Source dataset
uspto-grants-1996_03
Patent number
US05498726

Reaction notes

Loading…