JPS60161990A - Method for purifying oxacephalosporin - Google Patents

Abstract

PURPOSE:To remove neutral substances, low-molecular weight substances, etc. efficiently and obtain the titled substance of high purity, by adjusting an aqueous solution of oxacephalosporin to a pH below pKa, and treating the adjusted aqueous solution with a specific macroporous high polymer adsorbent. CONSTITUTION:An aqueous solution of oxacephalosporin having carboxyl group adjusted to a pH below pKa, e.g. 1.5pH, (in 0.1-30wt% concentration at 0-50 deg.C) is brought into contact with a macroporous high polymer adsorbent, e.g. styrene- divinylbenzene copolymer nonionic adsorbent resin, having >=1.05 true specific gravity and >=60mg/ml saturated adsorption capacity for the cephalosporin C and >=1.2 times that of the conventional adsorbent to separate the oxacephalosporin from nonadsorbable impurities, and the adsorbed oxacephalosporin is eluted with an aqueous solution of a hydrophilic organic solvent, e.g. methanol. The aimed oxacephalosporin is then extracted, concentrated, precipitated, distributed, crystallized, freeze-dried, etc. from the eluate to recover the purified oxacephalosporin. The amount of the adsorbent resin to be used is preferably 5-100 times that of the raw material.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for purifying oxacephalosporin useful as an antibacterial agent, in particular, an aqueous solution of oxacephalosporin having a carboxyl group and having a true specific gravity of 1.05, adjusted to a pH below pKa. The oxacephalosporin is not adsorbed by contacting it with a macroporous polymer adsorbent that has a saturation adsorption capacity of 60 m&ha or more for cephalosporin C, which is more than 162 times that of conventional ones. The present invention relates to a method for purifying the oxacephalosporin by separating it from sexual contaminants and then separating it from non-eluting contaminants by elution with an aqueous solution of a hydrophilic organic solvent.

In the known synthesis process of oxacephalosborin free acid,
During post-treatment, extraction, distribution, precipitation, crystallization, conventional synthetic adsorbents (Amberlite XAD-2゜XAD-4, XAD-
7, XAD-8, Diaion HP-10, HP-20
, HP-30, HP-40, HP-50, etc.) and elution are repeated to remove impurities.

After considering various ways to streamline this process, we found that the true specific gravity was 1.
．． 05 or more, and the saturated adsorption capacity for cephalosporin C is 60 mg or 2 or more.
．． It was discovered that a purification method using a macroporous polymer adsorbent, which exhibits a value more than double, is suitable, and this invention was completed.

Japanese Patent Publication No. 52-50799 and Japanese Patent Publication No. 54-1 disclose a method of using a macroporous polymeric pretensioning agent to remove neutral substances, low molecular weight substances, etc. from an aqueous solution of cephalosporins.
6922, JP 50-106996, JP 51-1
10587, etc. However, the adsorbents used in these methods have drawbacks such as a low adsorption capacity of /J%, a cloudy eluent, and a low specific gravity.

However, the present invention has a true specific gravity of 1.05 or more and a saturated adsorption capacity of 60 mg/C for cephalosporin C.
The macroporous polymer adsorbent, which has a value of d or more, which is 1.2 times higher than conventional ones, does not have such drawbacks and is suitable for purifying unstable oxacephalosporin 332-isolated carboxylic acids. There is. Examples of such macroporous nonionic polymer adsorbents include styrene/divinylbenzene copolymer resin Amberlite XAD-2000 manufactured by Rohm & Haas and styrene/divinylbenzene copolymer resin 5P manufactured by Mitsubishi Chemical Corporation. -206,5P
-207 etc.

The oxacephalosporin purified by this invention is 7
Acylamino group at β position, hydrogen or methoxy group at 7α position, R group or CH2R group (co, 1: 4: R
1-dethia 1-oxer 3- having a nuclear group such as halogen, alkyl, carbamoyl, carboxy, hydroxy, alkoxy, acyloxy, alkylthio, haloalkylthio, arylthio, heterocyclic thio, pyridinium, substituted pyridinium, etc. It is cephem-4-carboxylic acid or a derivative thereof having one or more carboxy groups.

The acyl of the acylamino group is the acyl group of the amide side chain in the chemistry of penicillins and cephalosporins.

- The heterocyclic group is a monocyclic or bicyclic heterocyclic group having one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and may have an alkyl-substituted alkyl group.

Each of the above moieties may have an R group or other substituents commonly used in cephalosporin chemistry.

As mentioned above, the true specific gravity used in this invention is 1.05.
1. of the conventional method, which is above and has a saturated adsorption capacity of 60ffIg/111 for cephalosporin C.
The appropriate amount of the macroporous polymer adsorption resin showing a value of 2 times or more is 5 to 100 times the amount of the raw material.

As the aqueous solution of oxacephalosporin, an aqueous solution that does not contain adsorption-interfering substances such as organic solvents in excess of an interfering amount is suitable. Concentration: 0.1 to 30% by weight, temperature: 0°C to 50°C
°C is appropriate.

For adsorption, the aqueous solution of oxacephaosporin is brought into contact with the macroporous polymer adsorbent using a conventional method such as a batch method, a column method, or a chromatography method.

In order to remove non-adsorbable substances from adsorbates, the Oxasefa 0 sporin is added to a liquid that can wash away non-adsorbable substances without eluting the target substance, such as water, a buffer solution, an aqueous salt solution, an aqueous surfactant solution, etc. Wash the absorbed adsorbent. Conventional methods such as batch method, column method, chromatography method, and gradient method can be applied here as well. The amount of washing liquid can also be determined by measuring the impurity content in the washing liquid. Temperature is θ℃~50
°C is appropriate.

Next, to elute the adsorbed target substance, ester,
Aqueous solutions of organic solvents (especially lower alcohols) such as ketones, alcohols, and ether-based industrial solvents are preferred. This can contain substances that are unrelated to elution ability or that control elution ability (eg, inorganic salts, acids, bases, anionic surfactants, etc.). Elution is also carried out by conventional methods such as batch method, column method, chromatography method, and gradient method. A suitable temperature is 0°C to 50°C.

In this manner, the elution operation is terminated when the target substance is eluted and non-eluting impurities remain.

After the elution of the target substance has been completed, the adsorbent is evaporated using a conventional method.
It can be regenerated using an aqueous alkaline solution, an aqueous solution of acetone, methanol, impropatul, or a combination of these solutions containing an acid.

To recover oxacephalosporin from the eluate, conventional methods such as extraction, concentration, precipitation, distribution, crystallization, and freeze-drying are applied.

Each of the above steps is usually performed at room temperature (temperature is 0° C. to 50° C.), and the required time is usually 30 minutes to 50 hours.

Oxacephalosvorin produced in this manner with low energy has a high yield and high purity.

The present invention will be explained in detail by describing examples below.

Example 1 Hydrochloric acid was added to a 0.11% crude latamoxef sodium aqueous solution obtained by removing the organic solvent from the reaction solution obtained by hydrolyzing latamoxef benzhydryl ester with aluminum chloride. p) 11.5 Adjust to.

Macroporous nonionic polymer adsorbent (styrene/divinylbenzene copolymer adsorption M resin Amberlite XAD-2000 manufactured by Rohm & Haas) was placed in a glass tube with an inner diameter of 32 mm and a length of 350 mm and a height of 200 d and a height of 2701 cm.
1111, and 2780 g of the above solution was passed through to adsorb latamoxef. Water this resin column with 13
Wash with 60 nQ to remove non-adsorbable impurities such as salt,
Then, after washing with 50% methanol 125-, 70%
Elute Latamoxef through methanol 5QQnA. This eluent contains the target substance at a concentration of 0.46%, calculated from the ultraviolet absorbance.

After concentrating the eluate under reduced pressure, it is neutralized with aqueous sodium hydroxide and freeze-dried to obtain pure tamoxef sodium.

Yield: 86%.

Example 2 A 0.19% crude rattan aqueous solution is adjusted to pH 2.9.

A glass tube with an inner diameter of 2211 nm was filled with a macroporous nonionic polymer adsorbent (styrene, manufactured by Rohm and Haas).
Divinylbenzene copolymer resin Amberlite XAD-
2000) I Q QnQ was filled to a height of 255 m, and the target substance was adsorbed through 4800 inches of the above solution (containing 8.02 g of the above compound). The resin column is washed with water 24 B 011i and then the purified target product is eluted through 50-80% methanol 81011Q. The eluent contained 68.7% of the amount of the compound charged, as calculated from the ultraviolet absorbance.

Example 3 A 0.94% crude rattan aqueous solution is adjusted to pH 2-3.

Macroporous nonionic polymer adsorbent (styrene/divinylbenzene copolymer resin SP-207 manufactured by Mitsubishi Chemical Corporation) 4Q1m11 was placed in a glass tube with an inner diameter of 1911111.
Filled with 200 d of the above solution to a height of 115 m.
(containing 1.88 g of the above compound) to adsorb the target substance. The resin column was washed with water 2QQnQ, then 5
Elute the purified target product through 0% acetone. The eluent contains 93.3% of the amount of the compound charged, as calculated from the high performance liquid chromatogram.

Similarly, the above eluent, 50% acetone, was changed to 70%
Even if you change to Improper Tools, you can still produce the same purified product at a high yield.

Example 4 Crude 7β-difluoromethylthioacetamide-3-[1
A 1.0% aqueous solution of -(2-hydroxyethyl)tetrazol-5-ylkothiomethyl-7α-methoxy-1-tethia-1-oxer-3-cephem-4-carboxylic acid was added to p
Adjust to H approximately 2.

A glass tube with an inner diameter of 22IIITl was filled with macroporous nonionic polymer adsorbent (styrene-divinylbenzene copolymer resin 5P-207 manufactured by Mitsubishi Chemical Industries, Ltd.) 4Qnll to a height of 10511F, and the above solution 210
d (containing 2.0 g of the above compound) to adsorb the target substance. The resin column was washed with water 1001Q, then
The purified target product is eluted through 140 nu% inproper tool. The eluent contained 871% of the amount of the compound charged, as calculated from the ultraviolet absorption rate.

Example 5 Crude 7β-difluoromethylthioacetamide-3-[1
A 1.0% aqueous solution of -(2-hydroxyethyl)tetrazol-5-ylcothiomethyl-7α-methoxy-1-dethia-1-oxer-3-cephem-4-carboxylic acid was added to p
Adjust to H approximately 2.

A glass tube with an inner diameter of 12 holes was filled with a macroporous non-ironant polymer adsorbent (styrene-divinylbenzene copolymer resin Amberlite XAD-20 manufactured by Rohm and Haas).
00) 30111 was filled to a height of 275 m, and the target substance was adsorbed through the solution 206d (containing 2.0 g of the compound). Add this resin column to 300 d of water.
The purified target product is then eluted through 70% Improper Tools 80r&Q. Calculated from the ultraviolet absorption rate, the eluent is 99.4% of the amount of the compound charged.
%including.

Example 6 Crude 7β-[2-(2-carbamoyl-2-fluorovinylthio)acetamide]-3-[1-(2-hydroxyethyl)tetrazol-5-ylcothiomethyl-α-
Methoxy-1-dethia-1-oxer-3-cephem-4
-Adjust a 0.15% aqueous solution of carboxylic acid to a pH of about 2.

A glass tube with an inner diameter of 16III11 was filled with macroporous nonionic polymer adsorbent (styrene/divinylbenzene copolymer resin 5P-207 manufactured by Mitsubishi Chemical Corporation) 3QnQ to a height of 132cm, and the above solution 200iQ (
(containing 0.6 g of the above compound) to adsorb the target substance. This adsorption resin column was washed with water 2QQnQ, and then
Elute the purified target product through 0% Improper Tools 1501111.

The eluent contains 77.5% of the amount of the compound charged, as calculated from the ultraviolet absorbance.

Patent Applicant Shionogi & Co., Ltd. Representative Patent Attorney Written amendment (spontaneous) April 4, 1980 Patent Application No. 17699 2, Title of Invention Purification of Oxacef 70 Sporin Law 3, Relationship with the person making the amendment Patent applicant address 3-12 Doshomachi, Higashi-ku, Osaka-shi, Osaka Prefecture Name (1
92) Shionogi & Co., Ltd. Representative: Yu 4, Geely, Agent address: Honmachi Building, 2-10 Honmachi, Higashi-ku, Osaka-shi, Osaka Prefecture” 7. The following parts of the detailed statement of amendments will be amended.

1) On page 5, line 1, insert 1-1 or more after rmg/mNJ.

2) Page 8, line 2, “500JJ has been corrected to l-535+JJ.

3) Same line 4, io,, i6%" to ro, 5u+/v%"
Corrected.

4) On page 12, line 2, ro, 6gJ was corrected to rO, 3gJ.

that's all

Claims (1)

[Claims] (1) An aqueous solution of oxacephalosporin having a carboxy group adjusted to a pH below pKa with a true specific gravity of 1.0
5 or more and has a saturated adsorption capacity of 60 mg/nΩ or more for cephalosporin C to separate it from non-adsorbable impurities, and then remove the aqueous hydrophilic organic solvent. A method for purifying oxacephalosporin, which comprises separating it from non-eluting impurities by elution with a solution.