Abstract：
Ruxolitinib {RUX; systematic name: (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, C17H18N6} is an orally bioavailable JAK1/2 inhibitor approved for treating intermediate- or high-risk myelofibrosis (MF) and high-risk polycythemia vera (PV). Recent patents claim that RUX can exist in many different forms, information for which is important for the clinical utilization of RUX, especially for the formulation and bioavailability of the drug. But there has been no detailed study on its forms so far. Herein crystals of RUX and its dihydrate (RUX-2H; C17H18N6·2H2O) and phosphate (RUX-P; systematic name: 4-{1-[(1R)-2-cyano-1-cyclopentylethyl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-3-ium dihydrogen phosphate, C17H19N6+·H2PO4-) were prepared successfully and their structures studied in detail for the first time. Our study shows that the three crystals of RUX differ in the orientation of the pyrimidine ring relative to the pyrazole ring of the RUX molecule, and in their hydrogen-bond interactions. The water molecules in RUX-2H and the dihydrogen phosphate anion in RUX-P enrich the hydrogen-bond networks in these forms. The expected proton transfer occurs in RUX phosphate and the protonated N atom is engaged in a charge-assisted hydrogen bond with the counter-anion. Hydrogen-bonding interactions dominate in the crystal packing of the three forms. The detailed conformations and packing of the three forms were compared through the calculation of both Hirshfeld surfaces and fingerprint plots.
摘要：
Ruxolitinib{RUX;系统名称:(3R)-3-环戊基-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]丙腈,C17H18N6}是一种口服生物可利用的JAK1/2抑制剂，被批准用于治疗中度或高风险骨髓纤维化（MF）和高风险真性红细胞增多症（PV）。最近的专利声称RUX可以以许多不同的形式存在，这些信息对于RUX的临床应用很重要，特别是药物的配方和生物利用度。但是到目前为止，还没有对其形式进行详细的研究。本文中RUX及其二水合物（RUX-2H;C17H18N6·2H2O）和磷酸盐（RUX-P；系统名称：4-{1-[（1R）-2-氰基-1-环戊基乙基]-1H-吡唑-4-基}-7H-吡咯并[2,3-d]嘧啶-3-磷酸二氢铵，成功制备了C17H19N6·H2PO4-），并首次对其结构进行了详细研究。我们的研究表明，RUX的三种晶体的嘧啶环相对于RUX分子的吡唑环的取向不同，以及它们的氢键相互作用。RUX-2H中的水分子和RUX-P中的磷酸二氢阴离子以这些形式富集了氢键网络。预期的质子转移发生在RUX磷酸盐中，质子化的N原子与抗衡阴离子参与电荷辅助的氢键。氢键相互作用在三种形式的晶体堆积中占主导地位。通过计算Hirshfeld表面和指纹图谱，比较了三种形式的详细构象和堆积。
