Careful Navigation of the Crystallographic Landscape of MK-8970: A聽Racemic Acetal Carbonate Prodrug of Raltegravir
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- 作者：Nancy Tsou ; C. Scott Shultz ; Teresa Andreani ; Richard G. Ball ; Andrew Brunskill ; Jaume Balsells ; Ryan D. Cohen ; Jimmy DaSilva ; Jing Li ; Robert A. Reamer ; Manuel de Lera Ruiz ; Narayan Variankaval ; Richard J. Varsolona ; Nobuyoshi Yasuda ; Gregory York
- 刊名：Organic Process Research & Development
- 出版年：2015
- 出版时间：December 18, 2015
- 年：2015
- 卷：19
- 期：12
- 页码：1882-1890
- 全文大小：487K
- ISSN：1520-586X
文摘
MK-8970 is an acetal carbonate prodrug of raltegravir (Isentress). This work presents the Merck team鈥檚 investigations into the polymorphism of MK-8970, the thermodynamic relationship between the discovered crystalline forms, and implementation of that knowledge toward solving key processing challenges. MK-8970 was found to exist in two enantiotropic polymorphs, with a crossover temperature of approximately 117 掳C, as determined from solubility data. Form 2 of MK-8970, the stable form at ambient temperature, was confirmed to be a true racemic crystal form and not a conglomerate on the basis of single-crystal X-ray structure data. In preparation for scale-up of MK-8970, form control was established by mapping out solubility curves for the relevant crystalline forms in ethyl acetate as a function of temperature. Lastly an investigation of the relative solubilities of MK-8970 and a troublesome imidate impurity identified improved solvent systems for maximizing rejection of this impurity while avoiding significant yield losses.