Acetic Acid → Quilostigmine

HRID 1440494Notes

Reaction equation

HRID 1440494 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.CC([O-])(C)C.[K+].CC(O)=O.[CH3:31][C@:32]12[C:39]3[CH:40]=[C:41](O)[CH:42]=[CH:43][C:38]=3N(C)[C@H]1N(C)CC2.C(N1C=CN=C1)(N1C=CN=C1)=O.C1C2C(=CC=CC=2)CCN1>C1COCC1>[CH2:18]1[C:40]2[C:39](=[CH:38][CH:43]=[CH:42][CH:41]=2)[CH2:32][CH2:31][N:17]1[C:15]([O:14][C:11]1[CH:10]=[C:9]2[C:8](=[CH:13][CH:12]=1)[N:7]([CH3:19])[C@H:6]1[N:5]([CH3:20])[CH2:4][CH2:3][C@@:2]21[CH3:1])=[O:16]

Participants

8

Reactant 6

HCID 176Acetic Acid2×HCID 5983Physostigmine2×HCID 70461,2,3,4-TetrahydroisoquinolineHCID 682631,1'-CarbonyldiimidazoleHCID 119198Eseroline3×HCID 23665647Potassium tert-butoxide

Product 1

HCID 132228Quilostigmine

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of physostigmine (2.75 g) in dry THF (28 mL) at 25° C. under a nitrogen atmosphere was treated with KOtBu (1.28 g), added over 0.25 hour, aged 0.5 hour at 25° C., then treated with glacial HOAc (0.6 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 (1.7 g, 1.05 equiv) added in 1.0 and 0.05 equiv. portions at 1.25 hour intervals at -20° C. gave after 1.0 hour following each addition the following HPLC ratio of imidazolecarbonyl intermediate (V) and eseroline: 97/3 and 99/1. Addition of glacial HOAc (3.4 mL, 6 equiv., pH=5) followed by 1,2,3,4-tetrahydroisoquinoline (1.5 g, 1.1 equiv., added over 0.5 hour at 15° C.) gave after 4 hours at 25° C. a mixture containing (3aS-cis)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-yl 3,4-dihyclro-2(1H)-isoquinolinecarboxylate and eseroline in a 98/2 HPLC ratio.

Workup

  1. additionadded over 0.25 hour, aged 0.5 hour at 25° C.
  2. customto give a mixture
  3. additionadded in 1.0 and 0.05 equiv. portions at 1.25 hour intervals at -20° C.
  4. customgave after 1.0 hour
  5. customgave after 4 hours at 25° C. a mixture

Sources & evidence

ORD record
ord-12c3468d03aa422abcf25d26e5eddb6a
Source dataset
uspto-grants-1996_03
Patent number
US05498726

Reaction notes

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