Solubility Measurement and Thermodynamic Modeling of N-(4-Methylphenyl-Z-3-chloro-2-(phenylthio)propenamide in 12 Pure Solvents at Temperatures Ranging from 278.15 to 318.15 K

Abstract

α-Thio-β-chloroacrylamides are of considerable synthetic utility due to their versatile reactivity profile enabling a diverse range of useful transformations. Availability of accurate and extensive solubility data and models is a prerequisite for advanced process optimization of such valuable pure synthetic intermediate compounds, in particular facilitating their isolation with a high degree of efficiency and control. As an illustrative example the solubility of one such derivative, N-(4methylphenyl-Z-3-chloro-2-(phenylthio)propenamide (Z-1), is described in the present work. Solubility data is reported in 12 pure solvents specifically selected for their potential utility in synthesis and isolation at scale. Solubility data are determined using the gravimetric method across a range of temperatures T= (278.15 to 318.15) K under pressure of 0.1 MPa. On a molar basis, the solubility of Z-1 at temperature T = 298.15 K was observed to follow the order: tetrahydrofuran > 1,2-dichloroethane > 2-methyltetrahydrofuran > butanone > acetone > ethyl acetate > methyl acetate > toluene > tert-butyl methyl ether > acetonitrile > 2-propanol > 2-methyl-2-butanol. The experimental solubility data were correlated by the modified Apelblat, Margules, Van-Laar, Wilson, and nonrandom two-liquid (NRTL) models. The NRTL model was found to result in the lowest error for 8 of the 12 solvents tested. In the case of acetonitrile, the Wilson model had a slightly lower mean square error of 3.52 × 10 −4 while for methyl acetate and 1,2-dichloroethane the Van-Laar model had the smallest mean square error of 1.47 × 10 −3 and 3.54 × 10 −4 , respectively. The provision of solubility data and models for such a prized and versatile compound will assist with further development of continuous isolation strategies.

Experiment and Computation of Solubility and Dissolution Properties for Enalapril Maleate and Its Intermediate in Pure Solvents

“…It indicates that the solubility is affected not only by solvent properties but also by different types of interactions in the system such as polarity, the role of hydrogen bonds, van der Waals forces, etc. Analysis of several properties including Hildebrand solubility parameters, dielectric constants, and dipole moments of the solvents reveals that the factors determining the solubility are complex and multifactorial. ,− …”

Solubility and Solution Thermodynamics of Tylosin in Pure Solvents and Mixed Solvents at Various Temperatures

“…Another about activity coefficient equal is expressed as NRTL model, where three parameters exist in binary interaction, NRTL model can be 16,17,18 organized and simplified into the following equations. and B are presented in Table 7.…”

Scale-up and Optimization of a Continuous Flow Synthesis of an α-Thio-β-chloroacrylamide

“…Recent work has assessed the challenges associated with scaling-up this three-step process, successfully enabling samples of up to 25 g of the α-thioamide 2 to be prepared (Scheme ). , However, scale-up of the final cascade step has posed more serious practical considerations with regard to achieving the hot plunge effect in batch. Heat transfer through larger volumes results in a delay reaching the desired temperature in the bulk of the reaction medium.…”

“…This approach enabled the production of more material than would be possible in batch, through scaling-out the process and therefore removing the any potential problems associated with heat and mass transfer in scale-up. Significant difficulties still remained in achieving a complete process operable on the desired scale, including management of the various impurities generated in the cascade process, removal of the poorly soluble succinimide byproduct, and isolation of batches of solid Z -3 in acceptable yield and purity. , …”

“…Significant difficulties still remained in achieving a complete process operable on the desired scale, including management of the various impurities generated in the cascade process, removal of the poorly soluble succinimide byproduct, and isolation of batches of solid Z-3 in acceptable yield and purity. 10,11 In the batch process, toluene was used as the reaction solvent for the final step (Scheme 1). The succinimide byproduct is only soluble in toluene at higher temperatures, allowing it to be effectively removed by precipitation and filtration on cooling the reaction mixture.…”