Isopilocarpic acid

Fig. 7.13. HO -Catalyzed ring opening of pilocarpine (7.76) and isopilocarpine (7.77) to pilocarpic acid and isopilocarpic acid, respectively, and proton-catalyzed lactonization of the two acids to the respective lactone. Note that pilocarpine and isopilocarpine interconvert by a base-catalyzed reaction of epimerization (Reaction a).

The reverse reaction of lactonization of pilocarpic acid is proton-catalyzed and, hence, favored at low pH. Thus, the pilocarpine/pilocarpic acid ratio was 1.0, 1.6, 2.7, 4.0, 5.1, and 6.7 at pH values of 6.0, 5.6, 5.2, 4.8, 4.4, and 4.0, respectively [161]. Interestingly, the lactonization of isopilocarpic acid is ca. 17-fold faster than the lactonization of pilocarpic acid, since the second-order rate constants of proton-catalyzed lactonization at 25° were 0.96 and 0.055 M-1 min-1 for isopilocarpine and pilocarpine, respectively [162], A lack of planarity in the lactone ring of pilocarpine, and a more lac-tone-like planarity in isopilocarpine, appear to account for this difference in reactivity between the two epimers. 

HPLC Water Cyano Spherisorb, 25°C Aq. 0.1% TEA (pH 2.5) 220 nm Resolved from pilocarpine, pilocarpic acid, and isopilocarpic acid... 

Column Lichrosorb RP18 10 um (300x4 mm ID), mobile phase 6% potassium dihydrogen phosphate in water - methanol (97 3)(pH 2.5), flow rate 1.5 ml/min, detection with differential re-fractometer. Peaks 1, pilocarpine 2, isopilocarpine 3, pilocarpic acid 4, isopilocarpic acid. 

Scheme 67. Cyclization of pilocarpic acid and isopilocarpic acid to pilocarpine and isopilccarpine, respectively.

Degradation of pilocarpine in the neutral pH region appears to conform to this model (Fig. 1 3).254 Technically, however, isopilocarpine can also degrade to isopilocarpic acid therefore, a more complete scheme for the degradation of polocarpine is... 

Hydrochloride ( + HiO) Isopilocarpic acid 136 White prisms (acetone) 64... 

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