KR0164455B1 - Process for the preparation of water-soluble derivatives of n-hydroxymethyl cephalexin - Google Patents

Abstract

The present invention relates to a method for preparing N-hydroxymethyl cephalexin represented by the following structural formula (I), and more particularly, to an organic compound selected from methanol and dimethylformamide for the cephalexin compound represented by the following general formula (II) Suspended in a solvent, reacted with a formalin solution, precipitated by addition of a non-solvent such as ether, and filtered to prepare an N-hydroxy methyl cephalexin water-soluble derivative represented by the following general formula (I). While maintaining oral administration to increase the absorption rate, it shows a suitable solubility as an injection, especially after dissolution pH is suitable for human administration has the effect of enabling intravenous injection.

Wherein X is a basic amino acid, such as alginic acid, lysine, which can form pharmacologically acceptable salts.

Description

Method for preparing N-hydroxymethyl cephalek soluble derivative

1 is an NMR chart of a compound prepared in Examples.

The present invention relates to a method for producing N-hydroxymethyl cephalexin represented by the following structural formula (I).

Wherein X is a basic amino acid, such as alginic acid, lysine, which can form pharmacologically acceptable salts.

Cephalexin is poorly soluble in water, so its absorption rate is poor and injection is impossible.

The present invention provides a water-soluble derivative that increases the absorption rate during oral administration while maintaining the broad antimicrobial activity of cephalexin, shows a suitable solubility as an injection, and in particular, the pH after dissolution is suitable for human administration to enable intravenous injection.

Compounds of the present invention are known compounds and are described, for example, in Blancer Patent Nos. 2,220,533. According to this method, cephalexin is prepared by suspending in water at 5-10 ° C., adding formalin, reacting with lysine solution, freezing at -70 ° C. and freeze-drying.

The present inventors suspended a cephalexin resinate or cephalexin alginate represented by the following general formula (II), which is a known substance, in water or methanol, and added a small amount of an alkaline substance such as potassium carbonate and reacted with an aqueous solution of formalin at room temperature. Next, a method was developed in which a non-solvent such as ether was added to drop the resulting derivatives to precipitate to easily prepare the target substance. The reaction scheme is as follows.

Wherein X is a basic amino acid such as alginic acid or lysine.

It is therefore an object of the present invention to provide an improved process for the water soluble derivative of N-hydroxymethylcephalexin represented by the above formula (I).

The process of the present invention allows the product to be separated simply by reacting with formalin at room temperature and then adding a non-solvent to filter the resulting precipitate, eliminating the need for lyophilization and preparing the compounds of the present invention in high purity and yield.

Next, the present invention will be described in more detail by way of examples.

EXAMPLE

Preparation of N-hydroxymethyl cephalexin Resinate:

49.359 kg of known cephalexin resinate is suspended in 150 liters of methanol, a small amount of aqueous potassium carbonate solution is added, and 8.57 liters of 35% formalin is slowly added to the mixture and stirred. After stirring for 10 minutes, 150 liters of ether were added and the resulting precipitate was filtered. (Yield: 49.75 kg).

Yield: 95%

The NMR chart is shown in FIG.

[Comparative Example (Notice Method)]

18 g of cephalexin monohydrate was suspended in 100 ml of distilled water at a temperature of 5 to 10 degrees. 3.8 mL of 40% formaldehyde solution was added dropwise under vigorous stirring while maintaining the temperature of the suspension within this temperature range. Meanwhile, pure nitrogen was continuously passed through the reaction mixture to generate bubbles. Under these conditions, the mixture is stirred for about 10 minutes, and then 14 g of 50% lysine salt solution is added slowly. The reaction mixture dissolved little by little, and the pH value of the resulting solution was 7.3. Cooling distilled water was added to this solution to make the volume 150 ml. It was then sterile filtered and frozen in a freezer at −70 ° C. and finally lyophilized to give a pale yellow powder.

As can be seen from the above examples and comparative examples, the method of the present invention is extremely simple in its manufacturing process, and thus the method of the present invention almost quantitatively obtains the target compound.

Claims (1)

The cephalexin compound represented by the following general formula (II) is suspended in an organic solvent selected from methanol and dimethylformamide, reacted with a formalin solution, precipitated by addition of a non-solvent such as ether, filtered and represented by the following general formula (I). A process for preparing an N-hydroxy methyl cephalexin water soluble derivative. Wherein X is a basic amino acid such as alginic acid or lysine.