Pilocarpine-isopilocarpine isomerization

It was found long ago that pilocarpine (7) isomerizes to isopilocarpine (8) under a wide variety of conditions. In 1880 it already was observed that pilocarpine undergoes a change when heated alone or with hydrochloric acid (37). Other investigators noted a change when the alkaloid was heated with aqueous sodium hydroxide. This isomerization is discussed in Section III,D,3. 

In order to avoid the undesirable isomerization to isopilocarpine (Section III,D,3) and, probably, to avoid enzymatic degradation, the Jaborandi leaves are processed as rapidly as possible. Acidification converts the alkaloids to their water-soluble salts, which allows defatting of the leaves with, for example, petroleum ether. Alkalinization and extraction with a suitable lipid-extracting solvent or solvent mixture gives the crude alkaloid mixture. (+)-Pilocarpine (mp 34°C) crystallizes only with difficulty it can be obtained readily as the nitrate salt (mp 178°C) in the absence of isopilocarpine. The separation of isopilocarpine nitrate from pilocarpine nitrate by crystallization is often difficult because mixtures may give products of constant melting points the same holds for the hydrochlorides. 

The phenomenon of isomerization of pilocarpine to isopilocarpine was already discussed in 1880. The change takes place under a wide variety of conditions, which were reviewed earlier (7). Dopke and d Heureuse (54) in 1968 proved that the isomerization (inter alia an undesirable side reaction occurring during the isolation of pilocarpine from plant material) is not caused by an opening of the lactone ring, but proceeds via epimerization at... 

Scheme 1. Pilocarpine (7)-isopilocarpine (8) isomerization according to Dopke and d Heureuse (54).

The reverse change can also be achieved to a small extent when isopilocarpine is heated with alcoholic potash for 3 hours, a little pilocarpine can be isolated from the product (35). The nature of the isomerism of the two bases will be discussed in a later section. 

Elegant work by W. Langenbeck (168) provided clear evidence that the two alkaloids are stereoisomers. First, he showed that the quaternary salts formed by methylating the two alkaloids are not identical, whereas the structures XVI and XVII would, like 1 4- and 1 5-dimethylimidazole (44), give identical metho salts. He then subjected each alkaloid to ozonolysis isopilocarpine yielded the methylamide XXVI of the known homoisopilopic acid, but pilocarpine gave rise to the methylamide of the hitherto unknown homopilopic acid, in 97 % yield. Thus the isomerism shown by the two alkaloids persists when the imidazole ring is destroyed under mild conditions, and it must therefore be due to a stereochemical difference in the lactonic portion of the molecule. Furthermore, the isolation of methylamides from both alkaloids confirms the 1 5 orientation of substituents in the imidazole nucleus. 

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