Solubility determination and thermodynamic modelling of 2,4-dihydro-5-methyl-2-(4-methylphenyl)-3H-pyrazol-3-one in twelve organic solvents from T = (278.15 to 313.15) K and mixing properties of solutions
Graphical abstract
Introduction
2,4-Dihydro-5-methyl-2-(4-methylphenyl)-3H-pyrazol-3-one (CAS Reg. No. 86-92-0; also named 1-(p-tolyl)-3-methyl-5-pyrazolone (abbreviated as PTMP); structure shown in Fig. 1) is an important intermediate of pharmaceutical. As a type of brain-protecting agent, it can inhibit oxidative damage to brain cells and nerve cells [1]. It also offers immense therapeutic value due to their broad biological spectrum which includes antimicrobial, antibacterial, anti-inflammatory, antitumor, antidepressant and neuro-protective activity [2], [3], [4], [5]. What’s more, it can be used as a raw material to produce dyestuff [6]. Some methods have been put forward to synthesize the PTMP [1], [2], [7], [8], [9], [10], [11], [12]. At present, the main preparation method of PTMP is using phenylhydrazine hydrochloride and ethyl acetoacetate as raw material. During the reaction process, some unknown by-products are also produced [7], [8], [9], [10], [11], [12]. With the development of pharmaceutical industry, the requirements for product purity are becoming greater. The crude PTMP restricts its further applications in many aspects.
As is known, solvent crystallization is an effective method in solid purification. The solubility of solid in different solvents is an important physicochemical property which plays an important role for understanding the (solid + liquid) equilibrium (SLE) or phase equilibrium in the development of a crystallization process. More particularly, the knowledge of accurate solubility is needed for the design of crystallization process. In previous publications, the purification of PTMP is recommended via a twofold recrystallization from ethyl acetate [1], or recrystallization from ethanol [7]. The solubility data are necessary in designing the crystallization process and conducting further thermodynamic research. These data are very important in the purification process of PTMP via the solvent crystallization method. Nevertheless, to the best of the authors’ present knowledge, no solubility data of PTMP are reported in the previous works. In order to acquire high purity PTMP, the knowledge of PTMP solubility in different solvents at various temperatures and the thermodynamic properties of solution is a necessary procedure.
In general, the purification process of PTMP is performed in organic solvents at below 320 K. In order to find a suitable solvent to purify PTMP, the purposes of the work are to (1) determine the solubility of PTMP in methanol, ethanol, n-propanol, isopropanol, ethylbenzene, toluene, n-butanol, acetonitrile, ethyl acetate, 1,4-dioxane, cyclohexane and isopentanol at temperatures ranging from (278.15 to 313.15) K by using the isothermal saturation method; (2) correlate the solubility data with different thermodynamic models; and (3) calculate the mixing properties for the solution process of PTMP in different solvents.
Section snippets
Solid-liquid phase equilibrium models
In order to find an appropriate model to describe the solubility behaviour of PTMP in the studied solvents, in this work, four models are employed to correlate the solubility data, which correspond to the modified Apelblat equation [13], [14], λh equation [15], Wilson model [16] and NRTL model [17].
Materials and apparatus
PTMP having a mass fraction of 0.985 was provided by Beijing HWRK Chemical Co., Ltd. It was crystallized three times in ethyl acetate. The purified sample had a mass fraction purity of 0.997, which was determined by high-performance liquid phase chromatograph (HPLC, Agilent-1260). The solvents, including methanol, ethanol, n-propanol, isopropanol, ethylbenzene, toluene, n-butanol, acetonitrile, ethyl acetate, 1,4-dioxane, cyclohexane and isopentanol were of analytical grade and all provided by
Melting properties of PTMP
The DSC scan of PTMP is shown in Fig. 3. From the DSC scan results, the melting temperature Tm and melting enthalpy ΔfusH of PTMP are 406.65 K and 26.52 kJ·mol−1, respectively. The melting temperature Tm determined in this work is lower than the values determined by Hiroyoshi [7] and Baraeva [8], and higher than that determined by Yu [9], but in the range presented in Ref. [21]. This case may be due to the difference in equipment, purity of samples and/or measured conditions.
According to the
Conclusions
In this work, the equilibrium solubility was acquired experimentally for PTMP in twelve pure organic solvents within the temperature range from (278.15 to 313.15) K under 101.3 kPa. The solubility of PTMP in the selected pure solvents increased with increase in temperature. At a certain temperature, the mole fraction solubility ranked as isopentanol > 1,4-dioxane > n-butanol > n-propanol > ethyl acetate > methanol > ethanol > isopropanol > ethylbenzene > toluene > acetonitrile > cyclohexane. The experimental
Acknowledgment
This work is financial supported by the Natural Science Foundation of the Anhui Province (Project numbers: 1408085MB40 and KJ2016A888). The authors would also like to express their gratitude for the National Natural Science Foundation of China (Project number: 21406192) and the Priority Academic Program Development of Jiangsu Higher Education Institutions.
References (28)
- et al.
Diversification of edaravone via palladium-catalyzed hydrazine cross-coupling: Applications against protein misfolding and oligomerization of beta-amyloid
Bioorg. Med. Chem. Lett.
(2016) - et al.
Synthesis, biological evaluation and SAR study of novel pyrazole analogues as inhibitors of Mycobacterium tuberculosis
Bioorg. Med. Chem.
(2008) - et al.
Novel hybrids of 3-n-butylphthalide and edaravone: design, synthesis and evaluations as potential anti-ischemic stroke agents
Bioorg. Med. Chem. Lett.
(2015) - et al.
Solubilities of o-acetylsalicylic, 4-aminosalicylic, 3,5-dinitrosalicylic, and p-toluic acid, and magnesium-dl-aspartate in water from T = (278 to 348) K
J. Chem. Thermodyn.
(1999) - et al.
Solubility determination and thermodynamic models for dehydroepiandrosterone acetate in mixed solvents of (ethyl acetate + methanol), (ethyl acetate + ethanol) and (ethyl acetate + isopropanol)
J. Chem. Thermodyn.
(2016) - et al.
Solubility of 3-chloro-N-phenylphthalimide in ten organic solvents from T = (288.15 to 323.15) K: determination and modeling
J. Chem. Thermodyn.
(2016) - et al.
Determination and prediction of solid-liquid phase equilibrium for quaternary system of terephthalic acid + isophthalic acid + phthalic acid + N-methyl-2-pyrrolidone at 303.15 K and 313.15 K
Fluid Phase Equilibr.
(2015) - et al.
Solubility measurement and modelling of 1,8-dinitronaphthalene in nine organic solvents from T = (273.15 to 308.15) K and mixing properties of solutions
J. Chem. Thermodyn.
(2015) - B. Liu, Y. Zhou, Y. Liang, C.Q. Miao, Synthesis method of pyrazolone, CN Patent 103,396,365, Nov. 20,...
- et al.
Synthesis of novel heterocyclic 4-thiazolidinone derivatives and their antibacterial activity
J. Chem.
(2004)