Hützler Wilhelm Maximilian, Egert Ernst, Bolte Michael
Institut für Organische Chemie und Chemische Biologie, Goethe-Universität Frankfurt, Max-von-Laue-Strasse 7, 60438 Frankfurt am Main, Germany.
Institut für Anorganische und Analytische Chemie, Goethe-Universität Frankfurt, Max-von-Laue-Strasse 7, 60438 Frankfurt am Main, Germany.
Acta Crystallogr C Struct Chem. 2016 Aug 1;72(Pt 8):634-46. doi: 10.1107/S2053229616011281. Epub 2016 Jul 20.
The understanding of intermolecular interactions is a key objective of crystal engineering in order to exploit the derived knowledge for the rational design of new molecular solids with tailored physical and chemical properties. The tools and theories of crystal engineering are indispensable for the rational design of (pharmaceutical) cocrystals. The results of cocrystallization experiments of the antithyroid drug 6-propyl-2-thiouracil (PTU) with 2,4-diaminopyrimidine (DAPY), and of 6-methoxymethyl-2-thiouracil (MOMTU) with DAPY and 2,4,6-triaminopyrimidine (TAPY), respectively, are reported. PTU and MOMTU show a high structural similarity and differ only in the replacement of a methylene group (-CH2-) with an O atom in the side chain, thus introducing an additional hydrogen-bond acceptor in MOMTU. Both molecules contain an ADA hydrogen-bonding site (A = acceptor and D = donor), while the coformers DAPY and TAPY both show complementary DAD sites and therefore should be capable of forming a mixed ADA/DAD synthon with each other, i.e. N-H...O, N-H...N and N-H...S hydrogen bonds. The experiments yielded one solvated cocrystal salt of PTU with DAPY, four different solvates of MOMTU, one ionic cocrystal of MOMTU with DAPY and one cocrystal salt of MOMTU with TAPY, namely 2,4-diaminopyrimidinium 6-propyl-2-thiouracilate-2,4-diaminopyrimidine-N,N-dimethylacetamide-water (1/1/1/1) (the systematic name for 6-propyl-2-thiouracilate is 6-oxo-4-propyl-2-sulfanylidene-1,2,3,6-tetrahydropyrimidin-1-ide), C4H7N4(+)·C7H9N2OS(-)·C4H6N4·C4H9NO·H2O, (I), 6-methoxymethyl-2-thiouracil-N,N-dimethylformamide (1/1), C6H8N2O2S·C3H7NO, (II), 6-methoxymethyl-2-thiouracil-N,N-dimethylacetamide (1/1), C6H8N2O2S·C4H9NO, (III), 6-methoxymethyl-2-thiouracil-dimethyl sulfoxide (1/1), C6H8N2O2S·C2H6OS, (IV), 6-methoxymethyl-2-thiouracil-1-methylpyrrolidin-2-one (1/1), C6H8N2O2S·C5H9NO, (V), 2,4-diaminopyrimidinium 6-methoxymethyl-2-thiouracilate (the systematic name for 6-methoxymethyl-2-thiouracilate is 4-methoxymethyl-6-oxo-2-sulfanylidene-1,2,3,6-tetrahydropyrimidin-1-ide), C4H7N4(+)·C6H7N2O2S(-), (VI), and 2,4,6-triaminopyrimidinium 6-methoxymethyl-2-thiouracilate-6-methoxymethyl-2-thiouracil (1/1), C4H8N5(+)·C6H7N2O2S(-)·C6H8N2O2S, (VII). Whereas in (I) only an AA/DD hydrogen-bonding interaction was formed, the structures of (VI) and (VII) both display the desired ADA/DAD synthon. Conformational studies on the side chains of PTU and MOMTU also revealed a significant deviation for cocrystals (VI) and (VII), leading to the desired enhancement of the hydrogen-bond pattern within the crystal.
理解分子间相互作用是晶体工程的一个关键目标，以便利用所获得的知识来合理设计具有定制物理和化学性质的新型分子固体。晶体工程的工具和理论对于（药物）共晶体的合理设计是不可或缺的。本文分别报道了抗甲状腺药物6-丙基-2-硫脲嘧啶（PTU）与2,4-二氨基嘧啶（DAPY），以及6-甲氧基甲基-2-硫脲嘧啶（MOMTU）与DAPY和2,4,6-三氨基嘧啶（TAPY）的共结晶实验结果。PTU和MOMTU具有高度的结构相似性，仅侧链中的一个亚甲基（-CH2-）被一个O原子取代，从而在MOMTU中引入了一个额外的氢键受体。两个分子都含有一个ADA氢键位点（A = 受体，D = 供体），而共形成物DAPY和TAPY都显示出互补的DAD位点，因此应该能够相互形成混合的ADA/DAD合成子，即N-H...O、N-H...N和N-H...S氢键。实验得到了一种PTU与DAPY的溶剂化共晶盐、四种不同的MOMTU溶剂化物、一种MOMTU与DAPY的离子共晶体以及一种MOMTU与TAPY的共晶盐，分别为2,4-二氨基嘧啶鎓6-丙基-2-硫脲嘧啶-2,4-二氨基嘧啶-N,N-二甲基乙酰胺-水（(1/1/1/1)（6-丙基-2-硫脲嘧啶盐的系统名称是6-氧代-4-丙基-2-硫亚基-1,2,3,6-四氢嘧啶-1-鎓），C4H7N4(+)·C7H9N2OS(-)·C4H6N4·C4H9NO·H2O，(I)）、6-甲氧基甲基-2-硫脲嘧啶-N,N-二甲基甲酰胺（(1/1)，C6H8N2O2S·C3H7NO，(II)）、6-甲氧基甲基-2-硫脲嘧啶-N,N-二甲基乙酰胺（(1/1)，C6H8N2O2S·C4H9NO，(III)）、6-甲氧基甲基-2-硫脲嘧啶-二甲基亚砜（(1/1)，C6H8N2O2S·C2H6OS，(IV)）、6-甲氧基甲基-2-硫脲嘧啶-1-甲基吡咯烷-2-酮（(1/1)，C6H8N2O2S·C5H9NO，(V)）、2,4-二氨基嘧啶鎓6-甲氧基甲基-2-硫脲嘧啶盐（6-甲氧基甲基-2-硫脲嘧啶盐的系统名称是4-甲氧基甲基-6-氧代-2-硫亚基-1,2,3,6-四氢嘧啶-1-鎓），C4H7N4(+)·C6H7N2O2S(-)，(VI)）以及2,4,6-三氨基嘧啶鎓6-甲氧基甲基-2-硫脲嘧啶-6-甲氧基甲基-2-硫脲嘧啶（(1/1)，C4H8N5(+)·C6H7N2O2S(-)·C6H8N2O2S，(VII)）。在(I)中仅形成了AA/DD氢键相互作用，而(VI)和(VII)的结构都显示出了所需的ADA/DAD合成子。对PTU和MOMTU侧链的构象研究还揭示了共晶体(VI)和(VII)存在显著偏差，从而导致晶体中氢键模式得到了所需的增强。
