Controlled Synthesis of New 5-Fluorocytosine Cocrystals Based on the pKa Rule

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• 作者：Cec铆lia C. P. da Silva ; Rebeka de O. Pepino ; Cristiane C. de Melo ; Juan C. Tenorio ; Javier Ellena
• 刊名：Crystal Growth & Design
• 出版年：2014
• 出版时间：September 3, 2014
• 年：2014
• 卷：14
• 期：9
• 页码：4383-4393
• 全文大小：650K
• ISSN：1528-7505

文摘

5-Fluorocytosine (5-FC) was investigated for the controlled synthesis of cocrystals by applying the pK_a rule. Five cocrystals were designed and developed with adipic, succinic, terephtalic, benzoic, and malic acids, all exhibiting negative 螖pK_a values ranging from close to zero up to roughly 鈭?. The synthesized cocrystals were analyzed by single crystal X-ray diffraction, and the observed supramolecular synthons were compared to the reported structures containing 5-FC. In the first four cocrystals, the intermolecular interactions between adjacent 5-FC molecules form two different homodimers showing R_{class="stack">2}^{class="stack">2}(8) motifs and assembled via complementary N鈥揌路路路O and N鈥揌路路路N hydrogen bonds, respectively. However, in the cocrystal with malic acid (螖pK_a = 鈭?.1), an intermediate supramolecular synthon pattern between salts and cocrystals is observed. In this crystal packing, the homodimer of 5-FC molecules held by the N鈥揌路路路O interactions is preserved, but a new heterodimer is formed between 5-FC and the acid molecule, such as the ones observed for 5-FC salts. These differences were analyzed using UNI Force Field Calculations to establish the intermolecular potentials of the synthons. As an application, we synthesized a cocrystal of 5-FC with 5-fluorouracil. This can be considered the first step toward the application of 5-FC for the design of new tailor-made drugs.