The carbostyril compound of the invention, which means a carbostyril compound (chemical name: 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic acid) of the following formula (1), is a medicament that has a potent effect on the treatment of gastric ulcer, acute gastritis, or gastric mucosa lesion affected in acute exacerbation of chronic gastritis.

As an example of the process for preparing the carbostyril compounds (1) of the invention, a process shown in the following Scheme 1 is known (JP-A-60-19767). The process is illustrated as follows:
That is,
the compound (2) is reacted with the compound (3) in the presence of a base such as sodium ethoxide to give the compound (4);
the compound (4) is hydrolyzed and decarboxylated in the presence of a mineral acid such as hydrochloric acid to prepare the compound (5); and then
the compound (5) is acylated with 4-chlorobenzoyl-chloride (6) to prepare the desired compound of the formula (1).

In the process for preparing the compound (5) from the compound (4) which is shown in the above scheme, the compound (4) needs to be heated under reflux, for example, in 20% hydrochloric acid. In this reaction process, however, ethanol, carbon dioxide, acetic acid and ethyl acetate are by-produced as the reaction proceeds. Accordingly, the surface of the reaction mixture is intensely bubbled by the generated carbon dioxide and additionally the bubbles do not disappear shortly. Especially when the amount of hydrochloric acid for the compound (4) is small, the surface of the reaction mixture is intensely developed by such bubbles, and hence it often becomes difficult to continue refluxing. In addition, such intense development of the surface is accompanied with a dangerous bumping, and hence the safety for the development is a big problem when the desired carbostyril compound (1) is produced in bulk. In order to prevent such bubbles, it is necessary to keep the reaction heated gently, therefore, a sufficient heating could not be given to promote the reaction. Furthermore, ethanol, ethyl acetate, etc. which are by-produced in the above-mentioned reaction process make the reflux temperature lowered and thereby there arises a problem inducing the delay of the reaction rate. Therefore, it is an important factor on the industrial preparation of the carbostyril compound (1) of the invention how the process from the compound (4) to compound (5) is carried out safely and efficiently.
USPTO Backgrounds
USPTO Backgrounds