The synthesis and polymerization of a vinyl derivative of 6-methylthiopurine

Abstract

The present work pertains to the modification of 6-mercaptopurine, a drug used in cancer therapy. The drug is highly toxic and non-specific towards abnormal cells. It is also absorbed by the normal cell and interferes in the biosynthesis. To overcome these inherent draw backs, attempts were made to modify 6-mercaptopurine so that one or more of the following characteristics are achieved: a) reduced toxicity, b) greater specificity, c) slow release of the drug into the system being treated.

The therapeutic value of the drug is associated with the reactivity of the 6-thio group. The 9-position offers the best site for the modification, since substitution at any other position, in most cases, reduces the anti-tumor activity of the drug. The general aim is to introduce at position-9 a side chain with a vinyl group so that the polymerization could be attempted through the unsaturated group.

Previous workers have introduced acryloyl and allylcarbamate groups at the 9-position with a hope to polymerize the monomer and thus obtain the desired objectives. These studies were only partially successful. The first monomer could not be isolated in pure form and the second pure monomer failed to polymerize, probably because of its allylic nature. With the failure of these two attempts, the next logical approach was to try a viyl-carbamate group. The present work is an attempt in this direction.

6-Mercaptopurine was first converted to 6-methylthiopurine to ensure the modification at the 9-position. Next the 6-methylthiopurine was reacted with vinyl isocyanate in anhydrous benzene in the presence of triethylamine. Hydroquinone was incorporated in the reaction system to prevent homopolymerization of vinyl isocyanate and/or the resulting monomer.

The preparation of the compound posed no serious problem. The most difficult part was purification and it consumed the major portion of the thesis work. The initial attempts were to recrystallize from chloroform/hexane mixture as reported in the literature for related compounds. About a dozen mixtures of solvents and non-solvents were tried with no success. A sample obtained after thirteen successive recrystallizations gave elemental values close to the theoretical expectations. Relying on melting point as a criteria of purity turned out to be misleading as the compound decomposed just at the melting point. The IR-specturm showed a C=C bond and the three amide peaks at the probable regions. Further continuation of recrystallization did not improve the degree of purity, therefore, resorted to a chromatographic technique. Elution of the monomer from a silica gel column using chloroform was very successful and is the most effective way of purifying the monomer.

Homopolymerization was run in anhydrous benzene at 80°C using 2,2'-azobisbutyronitrile as a free radical initiator. The polymer was isolated by precipitating the monomer from a benzene/methanol mixture and recovering the polymer by evaporating this solvent mixture. The IR-spectrum of this crude form showed the expected characteristic features of the polymer. The vinyl double bonds of the monomer disappeared and the melting temperature range broadened.