Tropacocaine from Pseudo-tropine Benzoic Anhydride

Tropacocaine from Pseudo-tropine and Benzoic Anhydride 

Approximately one mole of pseudotropine is heated with appox. one mol. of water and then refluxed with a slight excess of benzoic anhydride. The mixture is gently refluxed for approx 4 hours. The product is mixed with ether and hydrochloric acid. The aqueous layer is separated and diluted with more water. The aqueous mixture is extracted with half its volume with ether or appropriated solvent. The majority of unchanged pseudo-tropine remains in the aqueous layer. The ether solution is cooled, and the tropacocaine salt precipitated by the addition of an acid. Evaporation of ether will produce more tropacocaine. Refs. Blount 1933 

Tropine and pseudo-tropine both possess the same structural formula, for, on oxidation, they each 3deld tropinone, whilst the latter, when reduced, gives a mixture of the two hydroxy-bases (Willstatter and Iglauer, Ben, 1900, 33,1170). Willstatter concluded, therefore, that a cis-/rans-isomerism, dependent on the relative positions in space of the hydroxyl and methyl groups, existed between tropine and pseudo-tropine. Objection to this explanation might be made on the ground that no quite parallel case of isomerism seems to have been observed, and it therefore appeared to the present authors that it should not be accepted unreservedly so long as another explanation is possible. 

The tropine molecule contains two similar asymmetric carbon atoms, and the base should therefore be capable of existing in a racemic and an internally compensated form. The possibility of these two optically inactive modifications being represented by tropine and pseudo-tropine had been considered by Willstatter, but he rejected this explanation, as both bases, on oxidation, yielded the same ketone. It seemed to the present authors, however, that the possibility of the difference 

In view of the above considerations, therefore, it would appear that the formation of pseudo-tropine by the action of sodium amyloxide on tropine might be a process of racemisation, and this seemed to be in harmony with the experimental facts, since the change in question is never complete. Thus, in our experiments on the preparation of pseudo-tropine, about 35 per cent, of the basic product resulting from the treatment with sodium amyloxide was found to consist of an uncrystallisable mixture of tropine and pseudo-tropine, and Willstatter mentions that the yield of pure pseudo-base obtained by him did not exceed 50 to 55 per cent, of that theoretically possible. It appeared, therefore, that, the action of sodium amyloxide on tropine resulted in the formation of an equilibrium mixture of this base and pseudo-tropine, just as the action of alkali on pilocarpine or isopilocarpine results in the production of an equilibrium mixture of these two stereoisomeric bases (Jowett, Trans., 1905, 87, 794). This, however, is not the case, since the change is irreversible, no tropine being formed by the action of sodium amyloxide on pseudo-tropine. 

---