Synthesis, Crystal Structure and Solid State Transformation of 1,2-Bis[(1-methyl-1H-imidazole-2-yl)thio]ethane

Leo Štefan,Miljenko Dumić,Dubravka Matković-Čalogović,Darko Filić

doi:10.3390/cryst10080667

Leo Štefan, Miljenko Dumić + Show 2 more

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https://doi.org/10.3390/cryst10080667

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Abstract

The spontaneous S-alkylation of the thyreostatic drug methimazole (1-methyl-1,3-dihydro-1H-imidazole-2-thione, 1) with 1,2-dichloroethane at room temperature, in dark or light conditions, led to the formation of its related substance 1,2-bis[(1-methyl-1H-imidazole-2-yl)thio]ethane, C10H14N4S2 (2a), primarily isolated in the form of dihydrochloride tetrahydrate [C10H16N4S2]Cl2·4(H2O) (2b), which crystallized in the monoclinic P21/c space group. Neutralization of 2b, followed by crystallization from the acetone/water mixture, produced dihydrate C10H14N4S2·2(H2O) (2c), which crystallized in the trigonal R-3 space group. Six water molecules in 2c are H-bonded mutually and to the nitrogen atoms of six molecules of 2a. DSC and TGA showed that 2c melts at 65 °C and loses water up to 120 °C. By cooling to room temperature, anhydrous 2a was obtained. Single crystals of 2a that are suitable for X-ray structure analysis were obtained by neutralization of 2b, followed by crystallization from dry dichloromethane. Anhydrous 2a crystallizes in the monoclinic P21/c space group. The dehydration of 2c led to the formation of the anhydrous product 2a, which is identical to the one obtained by crystallization, as was found by complementary solid-state techniques. No intermediate monohydrate or hemihydrate phases were detected. Powder diffraction showed the same pattern of 2c via both preparation procedures. The structures of all the forms were elucidated by spectroscopy, microscopy and thermal methods and confirmed by single crystal X-ray analysis.

Highlights

Methimazole (1-methyl-1,3-dihydro-1H-imidazole-2-thione, 1), a well-known commercially available thyreostatic drug [1], has an ambidentate heterocyclic anion of the type [N-C-S] and was used as the terminal group in the synthesis of noncyclic crown ethers as scorpionate ligands in diverse aspects of the coordination chemistry [2,3].Among the bridged bis(methimazole) compounds, 1,2-bis[(1-methyl-1H-imidazole-2-yl)thio]methane (A) and an analogous ethane derivative 1,2-bis[(1-methyl-1H-imidazole-2-yl)thio]ethane (2a) were synthesized from 1 and dichloromethane or 1,2-dibromoethane
Anhydrous 2a crystallizes in the monoclinic P21 /c space group
In the context of the pharmaceutical purity profile, these compounds are considered as potential methimazole related substances [6], especially if common solvents, e.g., dichloromethane (DCM) and 1,2-dichloroethane (DCE), are used in the synthetic transformations, isolation, purification and methimazole analytics

Summary

Introduction

Methimazole (1-methyl-1,3-dihydro-1H-imidazole-2-thione, 1), a well-known commercially available thyreostatic drug [1], has an ambidentate heterocyclic anion of the type [N-C-S] and was used as the terminal group in the synthesis of noncyclic crown ethers as scorpionate ligands in diverse aspects of the coordination chemistry [2,3].Among the bridged bis(methimazole) compounds, 1,2-bis[(1-methyl-1H-imidazole-2-yl)thio]methane (A) and an analogous ethane derivative 1,2-bis[(1-methyl-1H-imidazole-2-yl)thio]ethane (2a) were synthesized from 1 and dichloromethane or 1,2-dibromoethane. In the context of the pharmaceutical purity profile, these compounds are considered as potential methimazole related substances [6], especially if common solvents, e.g., dichloromethane (DCM) and 1,2-dichloroethane (DCE), are used in the synthetic transformations, isolation, purification and methimazole analytics. Crystals 2020, 10, x FOR PEER REVIEW dichloromethane (DCM) and 1,2-dichloroethane (DCE), are used in the synthetic transformations, it was important to understand their behaviour from a chemical, structural and isolation, purification and methimazole analytics. To evaluate these factors, we carried out stabilityand study of 1 in was important to understand their behaviour froma apreliminary chemical, structural solidDCMstate andpoint

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