JPS6221351B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel crystalline adduct of cefatridine and 2-methoxyethanol and a method for producing the same. Cefatridine is a formula A cephalosporin antibiotic represented by Addendum 31, public notice of August 27, 1978). In addition to the above-mentioned propylene glycol adduct, methanol adducts and sesquihydrates are conventionally known as crystalline solvent adducts of cefatridine (Japanese Patent Application Laid-Open Nos. 49-94696, 1973-
No. 105813, Japanese Patent Publication No. 51-1627). Cefatridine is difficult to crystallize as a zwitterionic compound without the addition of a solvent by conventional methods such as precipitation from a solution at its isoelectric point. Therefore, the above solvent adduct is used for crystallization and purification of cefatridine. In particular, when cefatridine is crystallized and isolated from a reaction mixture containing impurities, it is common to go through its methanol adduct, while propylene glycol adducts and sesquihydrates are usually isolated through the methanol adduct. Manufactured by In addition, the ethanol adduct of cefatridine has much lower crystallinity than the methanol adduct, is unstable, and is not suitable for purification purposes (Japanese Patent Application Laid-Open No. 1627-1983). However, even for the methanol adduct of cefatridine, which is highly crystalline, in order to recover the crystalline adduct with good yield from an aqueous solution of cefatridine, it is necessary to add a large amount of methanol to raise the methanol concentration of the solution to approximately 50% or more. There is. This relationship is the same for propylene glycol adducts, and the propylene glycol concentration of the solution is approximately 50%.
% or more, the adduct cannot be recovered in good yield (see Comparative Example). Therefore, to crystallize and isolate these adducts from dilute solutions of cefatridine, very equal amounts of methanol or propylene glycol must be added. As a result of studying various crystalline solvent adducts of cefatridine, the inventor discovered that the 2-methoxyethanol adduct has extremely high crystallinity and is suitable for the purpose of crystallization purification of cefatridine or recovery from a dilute aqueous solution. We have arrived at the present invention. Surprisingly, instead of 2-methoxyethanol, similar 2-substituted ethanols such as 2-ethoxyethanol, 2-butoxyethanol, 2-chloroethanol, 2-bromoethanol, 2-cyanoethanol, or 1,2- It has been found that even when dimethoxyethane or the like is used, the crystallinity of the adduct is much inferior to that of the 2-methoxyethanol adduct. The findings obtained by the inventors are as follows: (1) A novel crystalline adduct can be obtained by reacting cephatridine with 2-methoxyethanol. (2) The adduct is stable and has good purification efficiency, making it extremely easy to obtain crystals of high purity. (3) The adduct is poorly soluble, and it is sufficient to add 3 to 10 moles of 2-methoxyethanol when recovering cefatridine from a dilute solution. (4) The adduct can be easily converted into other solvent adducts, such as propylene glycol adducts, and is extremely suitable as an intermediate in the production of cefatridine. The compound of the present invention can be obtained by adding 2-methoxyethanol to a solution containing cefatridine and collecting the adduct of the two as a solid. The solution containing cefatridine includes, for example, an aqueous solution of cefatridine at a concentration of 0.01 to 10%, and this solution may contain an organic solvent such as methanol, ethanol, propylene glycol, acetone, acetonitrile, or the like. If the liquid properties of the solution are close to the isoelectric point of cefatridine (PH3-5) and the concentration of cefatridine is too dilute, adding 2-methoxyethanol to the solution will immediately precipitate the adduct of both as crystals. do. The water solubility of cefatridine increases on the acidic side, but in order to recover the adduct in good yield from such acidic aqueous solutions, cefatridine must be isolated using an appropriate base after adding 2-methoxyethanol. It is desirable to adjust the pH to near the electrical point. In such cases, both adducts can be recovered as solids by adjusting the pH. 2-Methoxyethanol is usually used in a molar ratio of 1 to 30 to cefatridine, although a 3 to 10 molar ratio is often appropriate. When 2-methoxyethanol is added in excess, the recovery rate of the adduct can be improved even when the concentration of cefatridine is low or when the liquid nature of the solution tends to be acidic (for example, pH 1.5). For example, if a 30 molar ratio of 2-methoxyethanol is added to a 0.01% aqueous solution of cefatridine, most of the cefatridine in the solution can be recovered as a solid adduct. Utilizing the properties of the adduct of cefatridine and 2-methoxyethanol of the present invention, it is possible to efficiently purify cefatridine or recover cefatridine from a dilute solution. Cefatridine is usually produced by acylating 7-amino-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid with a D-P-hydroxyphenylglycine derivative, and the reaction The usual method is to add a large amount of methanol to the solution to precipitate and recover the methanol adduct of cefatridine. When attempting to recover cefatridine dissolved in the mother liquor by resin adsorption, it is first necessary to distill off methanol. 2- of the present invention
When the methoxyethanol adduct is used, most of the remaining cefatridine in the mother liquor can be recovered by simply adding 2-methoxyethanol without requiring operations such as distilling off methanol or further concentrating the mother liquor. Considering that cefatridine is not necessarily stable when heated and concentrated,
The method of recovering cefatridine using the 2-methoxyethanol adduct of the present invention is extremely advantageous. In addition, as mentioned above, this 2-methoxyethanol adduct can be precipitated with a good recovery rate even from a weakly acidic solution (about PH 1.5), so it can be -3-(1・
2,3-triazol-5-ylthiomethyl)-
It can also be used for the purpose of removing 3-cephem-4-carboxylic acid. The table shows the recovery rate of each adduct when the indicated amount of 2-methoxyethanol, propylene glycol, or methanol was added to a 1.6% aqueous solution of cefatridine. This result also makes it clear that by using the compound of the present invention, recovery of cefatridine from a dilute solution can be performed much more efficiently and economically than when it goes through other adducts.

[Table] The adduct thus obtained is a stable and extremely pure crystal containing cefatridine and 2-methoxyethanol in a molar ratio of 1:1.
It can be easily converted into other crystalline solvent adducts of cefatridine, such as propylene glycol adducts, methanol adducts, or sesquihydrates. For example, if this compound is suspended in a large amount of 75% aqueous propylene glycol, an acid is added to dissolve it, and the isoelectric point is adjusted with a base, a propylene glycol adduct of cefatridine is precipitated. Alternatively, a propylene glycol adduct of cefatridine can also be obtained by adsorbing an acidic aqueous solution of the present compound onto an adsorption resin such as Diaion HP-20 or Amberlite XAD-2, and then eluting this with an aqueous propylene glycol solution. can be obtained. The present invention will be specifically explained below with reference to Examples. Example 1 30g of methanol adduct of cefatridine was added to water.
1.8 and add 2-methoxyethanol to this.
Crystals precipitate shortly after adding 21 ml. After this was left at 0 to 5°C for 20 hours, the precipitated crystals were collected by filtration and dried to obtain 30.1 g (yield: 92%) of a 2-methoxyethanol adduct of cefatridine. This product decomposes at 225-230°C, and according to the results of gas chromatography analysis, it contains one molecule of 2-methoxyethanol. In addition, this product shows lactam absorption at 1770 cm ^-1 in the infrared spectrum (potassium bromide tablet), and nuclear magnetic resonance spectrum data shows that cefatridine and 2-methoxyethanol are 1:1.
It shows that it is contained in a molar ratio of . Elemental analysis value as C ₁₈ H ₁₈ N ₆ O ₃ S ₂・C ₃ H ₈ O ₂ (%) C H N S Calculated value 46.83 4.86 15.60 11.90 Experimental value 46.69 4.70 15.64 11.91 Comparative example Cefatridine as in Example 1 Prepare a solution by dissolving 30 g of methanol adduct in 1.8 g of water. To this solution, instead of 21 ml of 2-methoxymethanol, 1.8 ml of propylene glycol or 1.8 ml of methanol was added and left at 0 to 5°C for 20 hours. 20.7 g (69% recovery) of methanol adduct was recovered. When the amount of propylene glycol or methanol added is halved, the recovery of the adduct decreases significantly. Also, increase the amount of methanol added from 1.8 to
When it was reduced to 0.6, no adducts were precipitated at all. Example 2 1.0 g of a crude methanol adduct of cefatridine (purity about 84%, based on area percentage on high performance liquid chromatography) is dissolved in 100 ml of water, and 0.7 ml of 2-methoxyethanol is added thereto. After this liquid was left at 0 to 5°C for 20 hours, the precipitated crystals were collected by filtration and dried. 0.79 g of 2-methoxyethanol adduct of cefatridine with a purity of 99% (high performance liquid chromatography) (apparent yield 73 %)was gotten. Impurities such as 7-amino-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid and P-hydroxyphenylglycine contained in the crude product were not observed at all. Nakatsuta. Example 3 4 g of 7-amino-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid was suspended in 100 ml of methylene chloride, and 4 ml of hexamethyldisilazane was added. Reflux for 8 hours while stirring. The reaction solution was then cooled to 15-20°C, and 1.3 ml of a 30% (w/v) methylene chloride solution of dimethylaniline hydrochloride and dimethylaniline were added.
Add 2.1ml. This liquid was further cooled to 0 to 5°C, and 0.08 g of imidazole and D-(-)-P-
Hydroxyphenylglycine chloride hydrochloride
Add 4.0g in 5 portions. Thereafter, this liquid was stirred for 5 hours under ice-cooling and further for 6 hours at 20°C, and then 40 ml of methanol was added and stirred for 1 hour. After filtering off insoluble matter, methylene chloride was distilled off, and the resulting concentrated solution was decolorized with charcoal powder. 550 ml of water and 5 ml of 2-methoxyethanol were added, and the pH was adjusted to 5.2 with 28% aqueous ammonia under ice-cooling and stirring. do. After stirring for 5 hours under ice cooling, the precipitated crystals were collected by filtration and dried to yield 4.9 g (71%) of 2-methoxymethanol adduct of cefatridine.
is obtained. The infrared absorption spectrum and nuclear magnetic resonance spectrum of this sample completely match those of the sample obtained in Example 1. Reference Example 1 1.0 g of the 2-methoxyethanol adduct of cefatridine obtained in Example 1 is suspended in 30 ml of 75% water-containing propylene glycol, and 35% hydrochloric acid is added and dissolved while stirring under ice cooling. Next, adjust the pH of this solution to 5.1 with 28% aqueous ammonia, and continue stirring under ice cooling for 3 hours. Filter the precipitated crystals and dry them to obtain 0.84 g of propylene glycol adduct of cefatridine.
(84%). No 2-methoxyethanol was detected in this product by gas chromatography, and the infrared absorption spectrum and nuclear magnetic resonance spectrum completely matched the standard. Reference Example 2 1.8 g of the 2-methoxyethanol adduct of cefatridine obtained in Example 3 was suspended in 30 ml of water,
Add hydrochloric acid to dissolve. Add this liquid to Diamond Ion.
The solution was passed through an HP-20 column to adsorb only cefatridine onto the column, and the column was then washed with water and eluted with a mixture of 5 ml of 3N hydrochloric acid and 50 ml of methanol. The eluate was adjusted to pH 5.1 with 28% aqueous ammonia under ice-cooling and stirring, and after continued stirring under ice-cooling for 5 hours, the product was collected by filtration. After drying, 1.41 g (85%) of methanol adduct of cefatridine is obtained.

Claims (1)

[Claims] 1. 2-methoxyethanol adduct of cefatridine. 2. Claim 1, wherein the molar composition ratio of cefatridine and 2-methoxyethanol is 1:1.
A 2-methoxyethanol adduct of cefatridine as described in 2. 3. 2-methoxyethanol of cefatridine, which is characterized by adding 2-methoxyethanol to a solution containing cefatridine and recovering an adduct of both as a solid.
Method for producing methoxyethanol adduct.