Research on the application of 7-chloro-quinaldine adducts in 7-chloro-quinaldine separation process

Highlights

• Research on equilibrium of 7-chloro-quinaldine and its salts in pure solvents.

• Values of the experimental solubility were correlated with two thermodynamic models.

• Prepare 7-chloro-quinaldine adducts and characterize by XRD, TGA/DSC and IR.

Abstract

Equilibrium solubility of 7-chloro-quinaldine, 7-chloro-quinaldine L-tartrate or 7-chloro-quinaldine p-nitrophthalate in methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and acetone was measured by static gravimetric method at temperatures from 283.15 K to 323.15 K under p = 101.2 kPa. Within the studied temperature, the solubility of these three compounds in the solvents increased with a rise of temperature. The sequence of solubility of 7-chloro-quinaldine in these solvents (high to low) is acetone > isopropanol > isobutanol > methanol > ethanol > n-propanol > n-butanol. The solubility of 7-chloro-quinaldine tartrate in studied solvents obeys the following order: acetone > isopropanol > isobutanol > ethanol > n-propanol > n-butanol > methanol. While 7-chloro-quinaldine p-nitrophthalate + solvents, it ranked as: isobutanol > n-butanol > isopropanol > acetone > n-propanol > ethanol > methanol. The modified Apelblat equation was used to correlate the solubility values in neat solvents. The maximum values of root-mean-square deviation (RMSD) and relative average deviation (RAD) were 0.83 × 10⁻⁴ and 0.93%, respectively. Compared with the results of modified Apelblat equation, the calculated solubility provided good results with the experimental data. The experimental solubility values would be very helpful for application of 7-chloro-quinaldine, 7-chloro-quinaldine L-tartrate or 7-chloro-quinaldine p-nitrophthalate in industry.

Introduction

7-Chloro-quinaldine (CAS No. 4965-33-7, Fig. 1) serves as an intermediate product for the production of pharmaceuticals [1]. For example, 7-chloroquinaldine is a starting material to prepare 2-substituted quinoline dioic acids, which are leukotriene-receptor antagonists MK-0679 and useful as anti-asthma drugs motelukast sodium [2], [3], [4], [5], [6]. As a result, it has attracted a great deal of attention from synthetic chemists and different methods for the preparation of 7-chloro-quinaldine have been extensively investigated at home and abroad [1], [3], [4], [5], [6], [7], [8], [9]. The traditional preparation method of 7-chloro-quinaldine is using 3-chloroaniline and croton aldehyde as raw material via Skraup-Doebner-Von Miller reaction, the cyclization leads to an isomer mixtures of predominantly 5- and 7-chloro-quinaldine [1], [3], [4]. It faces the low yields and purification problems [7], [10]. Surprisingly it was found that with the aid of L-tartaric acid or p-nitrophthalic acid a good separation of the 7-chloro-quinaldine from the reaction mixture, particularly from the 5-cholro-isomer and from by-products and residues contained in the crude product from the synthesis reaction, can be obtained. It is possible with tartaric acid or p-nitrophthalic acid to separate 75 to 90% of the 7-chloro-quinaldine contained in the isomer mixture [1]. Up to now, the 5- and 7- isomers separation needs a large number of flammable tetrahydrofuran, even vacuum distillation is used. The harsh process conditions and higher requirements for equipment result in higher costs. So it’s not suiTable for industrialization [4], [5], [6], [11], [12]. Therefore, separation and purification of 5- and 7- isomers is still an urgent problem. In order to obtained higher purity 7-chloro-quinaldine, the purification and separation of 7-chloro-quinaldine is the last process in the whole synthesis of 7-chloro-quinaldine. Thus, knowing the liquid-solid equilibrium of 7-chloro-quinaldine and its adducts are of great significance for separation process, and for the yield improvement.

In this research, the solubility of 7-chloro-quinaldine, 7-chloro-quinaldine L-tartrate or 7-chloro-quinaldine p-nitrophthalate in seven pure organic solvents including methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and acetone were measured by a static method in the temperature range from 283.15 K to 323.15 K under P = 0.1 MPa [13]. The solubility data were correlated by the modified Apelblat equation. This model can correlate the experimental values very well, and can help to understand the relationship between the solubility and temperature as well as solvent. All the results can help to optimize the application of 7-chloro-quinaldine in industry.