Department of Chemistry, Zhejiang University, Hangzhou 310028, China.
College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China.
Int J Mol Sci. 2020 Dec 3;21(23):9213. doi: 10.3390/ijms21239213.
Tenofovir alafenamide (TAF) is a prodrug of tenofovir as a potent nucleotide reverse transcriptase inhibitor. It serves as the key component of Genvoya for the first-line treatment of human immunodeficiency virus infection (HIV) and is the active component of Vemlidy for the treatment of chronic hepatitis B. Vemlidy is also a monotherapeutic regimen formulated as TAF hemifumarate (; TAF:fumarate = 2:1). In this work, we report for the first time the single-crystal structure of TAF fumarate hemihydrate (, TAF:fumarate:HO = 2:2:1). Compound is initially documented as a salt in which one proton of the fumaric acid migrates to the amine group of the adenine moiety in TAF. It was recently proposed that ca. 20-30% proton is transferred to the N atom on the aromatic adenine backbone. We herein provide definitive single-crystal X-ray diffraction results to confirm that , though phase pure, is formed as a mixture of co-crystal (75%) and salt (25%). It features two pairs of TAF fumarates, wherein one of the four H atoms on the fumaric acid is transferred to the N atom of the adjacent adenine moiety while the other three carboxylates remain in their intrinsic acid form. Compound is a metastable phase during the preparation of and can be isolated by halting the reaction during the refluxing of TAF and fumaric acid in acetonitrile (MeCN). Our report complements the previous characterizations of TAF monofumarate, and its elusive structural patterns are finally deciphered.
替诺福韦艾拉酚胺（TAF）是替诺福韦的前药，作为一种有效的核苷酸逆转录酶抑制剂。它是用于人类免疫缺陷病毒感染（HIV）一线治疗的 GENVOYA 的关键成分，也是用于治疗慢性乙型肝炎的 VEMLIDY 的活性成分。VEMLIDY 也是一种单药治疗方案，其配方为 TAF 富马酸半酯（；TAF:富马酸 = 2:1）。在这项工作中，我们首次报道了 TAF 富马酸半水合物（，TAF:富马酸:HO = 2:2:1）的单晶结构。化合物最初被记录为一种盐，其中富马酸的一个质子迁移到 TAF 中腺嘌呤部分的氨基上。最近有人提出，大约 20-30%的质子转移到芳香腺嘌呤主链上的 N 原子上。我们在此提供明确的单晶 X 射线衍射结果，以确认，尽管是纯相的，但它是由共晶（75%）和盐（25%）的混合物形成的。它具有两对 TAF 富马酸盐，其中富马酸的四个 H 原子中的一个转移到相邻腺嘌呤部分的 N 原子上，而其余三个羧酸盐保持其固有酸形式。化合物在 TAF 和富马酸在乙腈（MeCN）中的回流过程中制备时是一种亚稳相，可以通过在回流过程中停止反应来分离。我们的报告补充了 TAF 单富马酸盐的先前特征，其难以捉摸的结构模式终于被破解。
