JP4659074B2 - Method for producing 3-alkenylcephem compound - Google Patents

Description

  The present invention relates to the preparation of 7-amino-3-[(E / Z) -2- (4-methylthiazol-5-yl) vinyl] -3-cephem-4-carboxylic acid or an alkali metal salt thereof. It is related with the method of improving the content rate of Z body compared with a body.

  7-Amino-3- [2- (4-methylthiazol-5-yl) vinyl] -3-cephem-4-carboxylic acid or an alkali metal salt thereof is useful as an intermediate for the production of cephalosporin antibiotics. It is a substance. In this compound, there are two types of isomers, that is, the steric structure of the alkenyl group at the 3-position is a Z configuration and an E configuration. Among these two types of isomers, it is known that a cephalosporin antibiotic using the same as a raw material expresses an excellent antibacterial action as a pharmaceutical antibacterial agent. Therefore, when synthesizing cephalosporin antibiotics from 7-amino-3- [2- (4-methylthiazol-5-yl) vinyl] -3-cephem-4-carboxylic acid or an alkali metal salt thereof, It is important that only the Z isomer is present in the reaction system and that the E isomer is not present as much as possible.

  From this viewpoint, in Patent Document 1, 7-amino-3- [2- (4-methylthiazol-5-yl) vinyl] -3-cephem-4-carboxylic acid in which a Z form and an E form are mixed or It has been proposed that a high porous polymer or activated carbon is allowed to act on the aqueous solution of the alkali metal salt to increase the content of the Z-form. Examples of the high porous polymer used in this method include acrylic resins, phenolic resins, and styrene resins. On the other hand, as the activated carbon, general activated carbon such as zinc chloride charcoal or steam charcoal is used.

  According to the method described in the above document, 7-amino-3- [2- (4-methylthiazol-5-yl) vinyl] -3-cephem-4-carboxylic acid having an increased Z-form content or The alkali metal salt is obtained. However, in order to use this compound as an intermediate for producing a cephalosporin antibiotic, it is desired to further improve the content of the Z isomer.

JP 2005-343854 A

  Accordingly, the object of the present invention is to provide 7-amino-3- [2- (4-methylthiazol-5-yl) vinyl] -3-cephem-4-carboxylic acid that can eliminate the various disadvantages of the prior art described above. Another object is to provide a method for producing an alkali metal salt thereof.

The present invention relates to 7-amino-3-[(E / Z) -2- (4-methylthiazol-5-yl) vinyl] -3-cephem-4-carboxylic acid represented by the following formula (1): The alkali metal salt is treated with a mineral acid to form a mineral acid salt, and an iodine adsorption performance measured according to JIS K-1474 is an aqueous solution in a low pH region containing the mineral acid salt is 1200 mg / g or more, 7-amino-3-[(Z) -2- (4-methylthiazole) represented by the following formula (2), which is treated by contacting with activated carbon having a methylene blue adsorption performance of 250 ml / g or more. -5-yl) vinyl] -7-amino-3-[(E / Z) -2- represented by the formula (1) in which the content of the 3-cephem-4-carboxylic acid or its alkali metal salt is improved (4-Methylthiazol-5-yl) vinyl] -3-cef The object is achieved by providing a method for producing em-4-carboxylic acid or an alkali metal salt thereof.

  According to the present invention, in the production of 7-amino-3-[(E / Z) -2- (4-methylthiazol-5-yl) vinyl] -3-cephem-4-carboxylic acid or an alkali metal salt thereof. , The content of the Z body can be improved as compared with the conventional case.

  In the present invention, a specific activated carbon is allowed to act on the compound represented by the formula (1) including the Z-form and the E-form or an alkali salt thereof, and the E-form is selectively adsorbed on the activated carbon. And is characterized by increasing the content of the Z-form. The alkali salt here means a pharmacologically acceptable alkali salt. In the following description, the compound represented by the formula (1) and its alkali metal salt are collectively referred to as “alkenyl cephem compound”.

  The alkenyl cephem compound used in the present invention consists of a mixture of Z-form and E-form. Both Z-form and E-form are known compounds. There is no particular limitation on the abundance ratio of the Z form and the E form in the alkenyl cephem compound, and this abundance ratio depends on the production conditions of the alkenyl cephem compound. In view of the object of the present invention, it is desirable that the abundance ratio of the Z isomer is sufficiently higher than the abundance ratio of the E isomer. However, by using the method of the present invention, the Z isomer can be obtained easily and with a high yield. Is possible. The proportion of the E form in the alkenyl cephem compound is generally 0.3 to 20% by weight, particularly 2 to 12% by weight in the state before the treatment with activated carbon.

  In the present invention, the alkenyl cephem compound is brought into contact with activated carbon in the form of an aqueous solution. In order to make the alkenyl cephem compound into an aqueous solution, for example, the alkenyl cephem compound may be treated with an alkali to form a corresponding salt (for example, an alkali metal salt). Examples of the alkali include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide; alkali metal hydrogen carbonates such as sodium hydrogen carbonate; alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; Can be used. By mixing the aqueous solution containing these alkalis with the alkenyl cephem compound, the alkenyl cephem compound can be made into an aqueous solution.

The concentration of the salt before Symbol alkenylcephem compound contained in the aqueous solution of, not critical in the present invention may be a low concentration to the extent that crystals of the salt does not precipitate.

As a method for the aqueous solution alkenylcephem compound, the alkenyl cephem compounds, and treated with a mineral acid, a method in the form of the corresponding mineral acid salts. Examples of the mineral acid include hydrochloric acid, sulfuric acid, nitric acid and the like. By mixing these mineral acids and the alkenyl cephem compound, an aqueous solution in which the compound is in the form of a mineral salt can be obtained.

  The pH of the aqueous solution containing the mineral acid salt may be in a low pH region so that the mineral acid salt does not precipitate, and is generally 0.5 to 1.7, particularly 0.8 to 1.4. It is preferable to do. Further, the concentration of the mineral acid salt contained in the aqueous solution is not critical in the present invention, and may be any level as long as the mineral acid salt does not precipitate.

  When the alkali metal salt and the mineral acid salt are compared, it is preferable to use the mineral acid salt. This is because the adsorption removal of phenylacetic acid or a derivative thereof (which will be described in detail later), which is a by-product generated when the alkenylcephem compound is synthesized, can be performed simultaneously with the adsorption removal of the E form. . Of the mineral acid salts, the use of hydrochloride is particularly preferable because the purity of the Z form can be further increased.

  The present inventors diligently investigated activated carbon for selectively adsorbing and removing E-forms from alkenyl cephem compounds, and it is effective to use activated carbon having a large pore diameter peak and a small pore diameter peak. found. Furthermore, as the inventors proceeded with investigations, activated carbon having such a pore size distribution was identified with iodine adsorption performance measured according to JIS K-1474 and methylene blue adsorption performance measured according to JIS K-1474. It was found to be within the range. In the present invention, by using activated carbon having such specific iodine adsorption performance and methylene blue adsorption performance, it is possible to selectively adsorb and remove E form from the alkenyl cephem compound.

  About the specific iodine adsorption | suction performance mentioned above, the value is 1200 mg / g or more. In addition, since it is extremely difficult to industrially obtain activated carbon having an iodine adsorption performance exceeding 1600 mg / g and having the methylene blue adsorption performance described below, the upper limit of the iodine adsorption performance of the activated carbon used in the present invention is 1600 mg / g. Therefore, the range of iodine adsorption performance is preferably 1200 to 1600 mg / g, and more preferably 1400 to 1600 mg / g. However, the higher the value of iodine adsorption performance, the better. Therefore, there is no problem in using activated carbon having an iodine adsorption performance of more than 1600 mg / g.

  For the methylene blue adsorption performance, those having a value of 250 ml / g or more are used. In addition, since the methylene blue adsorption performance is over 500 mg / g and it is extremely difficult to industrially obtain activated carbon having the above iodine adsorption performance, the upper limit of the methylene blue adsorption performance of the activated carbon used in the present invention is 500 ml / g. And Therefore, the range of methylene blue adsorption performance is preferably 250 to 500 ml / g, more preferably 280 to 500 ml / g. However, the higher the value of the methylene blue adsorption performance, the better. Therefore, there is no problem in using activated carbon having a methylene blue adsorption performance of more than 500 ml / g.

  Normally, the physical properties of activated carbon used in water treatment have iodine adsorption performance of 1200 mg / g or less and methylene blue adsorption performance of 200 ml / g or less (“Applied technology of activated carbon”, supervised by Hideki Tachimoto, Kunio Abe. , Issued by Techno System Co., Ltd., July 25, 2000, pages 409 and 555), these physical properties of the activated carbon used in the present invention are much higher than those of ordinary activated carbon. It is expensive. This is because large pores and small pores are distributed. In general, iodine adsorption performance is an indicator of small pore distribution (that is, an index of adsorptivity of a compound having a low molecular weight), and methylene blue adsorption performance is an indicator of distribution of a large pore (that is, an adsorptivity of a compound having a large molecular weight). Index).

  Examples of the activated carbon that satisfies the iodine adsorption performance and methylene blue adsorption performance described above include water vapor activated activated carbon using coconut shell, coal, wood material, or the like as a raw material. In this case, the above-described physical property values are satisfied by appropriately controlling the activation conditions and appropriately controlling the granulation conditions. The activated carbon may be in the form of powder, granules or fibers, or may be a molded body. It is also possible to use a commercial product as activated carbon that satisfies the above physical property values. Examples of such commercially available products include unitica activated carbon fiber Adol A-20 (trade name), which is activated carbon available from Unitika Ltd., and liquid phase activated carbon CL-KP (product), which is activated carbon available from Ajinomoto Fine Techno. Name).

  There is no restriction | limiting in particular in the method of making the above-mentioned activated carbon and an alkenyl cephem compound contact. For example, a method of adding the above-mentioned activated carbon to an aqueous solution of an alkenyl cephem compound, or a method of adding an aqueous solution of an alkenyl cephem compound to the above-mentioned activated carbon can be employed. Alternatively, the above-mentioned activated carbon is packed in a column, and an aqueous solution of the alkenyl cephem compound is fed to the column with a pump or the like, passed through the column, and further circulated through the column a plurality of times, or activated carbon is applied to a molded body such as a filter. A method in which an aqueous solution of the alkenyl cephem compound is brought into contact with the contained one can also be adopted. The ratio between the amount of activated carbon and the amount of alkenyl cephem compound is not particularly limited. For example, 0.1 to 3 parts by weight of activated carbon, particularly 0.5 to 0.5 parts by weight with respect to 100 parts by weight of alkenyl cephem compound contained in the aqueous solution. It is preferable to make contact with 2 parts by weight because the loss rate of the Z form can be reduced and the E form and phenylacetic acid can be efficiently removed.

  There are no particular restrictions on the conditions under which the activated carbon is brought into contact with the alkenyl cephem compound. For example, the temperature at the time of contact can be 0-20 degreeC. By making the temperature at the time of contact within this range, the loss rate of the Z form can be reduced, and the E form and phenylacetic acid can be efficiently removed, which is preferable. The contact time is preferably 0.5 to 3 hours, particularly 1 to 2 hours, provided that the temperature at the time of contact is in the above range. While the two are in contact with each other, the reaction system may be in a stirred state or may be left in a stationary state.

  The above method may be performed only once, or may be repeated two or more times for the purpose of increasing the purity of the Z form.

  By the above operation, the E form is selectively adsorbed and removed from the alkenyl cephem compound including the Z form and the E form by activated carbon, and the content of the Z form is increased. After that, the activated carbon and the treatment liquid are separated, and acid such as hydrochloric acid, nitric acid, sulfuric acid (when made water-soluble with alkali) or alkali such as sodium hydroxide (when made water-soluble with mineral acid) is added to the treatment liquid. In addition, the pH of the liquid is adjusted to a weakly acidic region of 3.8 to 4.8 to precipitate crystals of the compound represented by formula (2). The obtained crystals are separated by filtration or centrifugation, and washed with water and an organic solvent such as methanol. By adjusting the pH of the treatment liquid to the above range and precipitating the compound represented by the formula (2) in the pH within the range, the target product can be recovered with high purity and high yield.

  Prior to recovering the compound represented by formula (2) by the above-described precipitation operation, phenylacetic acid contained in the treatment liquid treated with activated carbon is removed, and the purity of the compound represented by formula (2) is obtained. You may perform operation which raises further. Specifically, the activated carbon and the treatment liquid are separated, and an acid (when made water-soluble with alkali) or alkali (when made water-soluble with mineral acid) is added to the treatment liquid, and the pH of the liquid is preferably 2 or less More preferably, the solvent is extracted from this aqueous solution using an organic solvent. By repeating the solvent extraction a plurality of times, the concentration of phenylacetic acid in the treatment liquid gradually decreases.

  Organic solvents used for solvent extraction include (a) lower alkyl esters of lower carboxylic acids, (b) ketones, (c) ethers, (d) substituted or unsubstituted aromatic hydrocarbons, (e) ) Halogenated hydrocarbons, (f) aliphatic hydrocarbons, and (g) cycloalkanes. These organic solvents can be used alone or in combination of two or more. Examples of the lower alkyl esters of the lower carboxylic acid (i) include methyl formate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, and ethyl propionate. . Examples of (b) ketones include methyl propyl ketone, methyl butyl ketone, methyl isobutyl ketone, and diethyl ketone. Examples of (iii) ethers include diethyl ether, ethyl propyl ether, ethyl butyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methyl cellosolve, dimethoxyethane and the like. Examples of the substituted or unsubstituted aromatic hydrocarbons of (d) include benzene, toluene, xylene, chlorobenzene, anisole and the like. Examples of the halogenated hydrocarbons of (e) include dichloromethane, chloroform, dichloroethane, trichloroethane, dibromoethane, propylene dichloride, carbon tetrachloride and the like. (F) Aliphatic hydrocarbons pentane, hexane, heptane, octane and the like. Examples of (g) cycloalkanes include cyclopentane, cyclohexane, cycloheptane, cyclooctane and the like.

  By performing the above solvent extraction a plurality of times, the concentration of phenylacetic acid in the treatment liquid can be suitably reduced to 0.1% by weight or less. After the solvent extraction, an alkali such as sodium hydrogen carbonate is added to the treatment liquid and isoelectric point precipitation is performed to precipitate crystals, which are collected.

  In the present invention, an alkenylcephem compound used as a starting material is, for example, a 7-substituted acylamino-3-[(E / Z) -2- (4-methylthiazol-5-yl) represented by the following formula (3). It is obtained by subjecting a salt of vinyl] -3-cephem-4-carboxylic acid to an enzyme reaction to deprotect the 7-position amide bond. If this salt is water-soluble, there will be no restriction | limiting in particular in the kind. Examples of water-soluble salts include alkali metal salts and ammonium salts.

  As the solvent for the enzyme reaction, water is preferably used from the viewpoint of maximizing enzyme activity. The pH of the enzyme reaction is a factor that affects the activity of the enzyme. Although depending on the type of enzyme, it is preferable to maintain the pH at 7.5 to 8.5 from this viewpoint. Various alkali aqueous solutions, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal hydrogen carbonates such as sodium hydrogen carbonate; alkali metal carbonates such as sodium carbonate and potassium carbonate; An aqueous solution can be used. The temperature of the enzyme reaction is also a factor that affects the activity of the enzyme. Although depending on the type of enzyme, the temperature of the reaction system is preferably maintained at 25 to 35 ° C. from this viewpoint. The reaction time is not critical in the present invention. In general, the reaction may be carried out until the compound represented by the formula (3) disappears from the reaction system. In general, the reaction time can be 1 to 3 hours, provided that the pH and temperature are within the above ranges.

  As the enzyme to be used, a conventionally known penicillin G acylase can be used without particular limitation. For example, Penicillin G amidase PGA-150, PGA-300, PGA-450 manufactured by Boehringer Mannheim; Penicillin G acylase manufactured by Dallas Biotech Limited; Penicillin G amidase manufactured by Roche Molecular Biochemicals; Biological Technology Co., Ltd. IPA-750; Atlas Biologics Co., Ltd. SynthaCLEC-PA, etc. can be used.

  The amount of the enzyme used depends on the type, but is 0.3 to 1.5 parts by weight, particularly 0.5 to 1 part by weight, based on 100 parts by weight of the compound represented by formula (3). preferable.

  The salt of an alkenyl cephem compound is obtained by the above enzyme reaction. In this enzymatic reaction, phenylacetic acid or a derivative thereof (hereinafter collectively referred to as “phenylacetic acids”) is a by-product by deprotection of the amide protecting group at the 7-position in the compound represented by formula (3) Generate as This phenylacetic acid or the like is a 7-amino-3- [2- (4-methylthiazol-5-yl) vinyl] -3-cephem-4-carboxylic acid having a high content of Z form, which is an object of this production method. Since it is an impurity for acid, it is necessary to eliminate its existence as much as possible. For the purpose, the present inventors diligently studied. Surprisingly, when the activated carbon is brought into contact with the alkenyl cephem compound in the strongly acidic region, the E-form is adsorbed and removed by the activated carbon. It was also found that phenylacetic acids were also adsorbed. Also from this point, the method of the present invention is superior to the method of the prior art.

  Thus, in the present invention, a by-product of the deprotection reaction produced by subjecting the salt of the compound represented by the formula (3) to an enzyme reaction to deprotect the amide bond at the 7-position. It is preferable to use an alkenylcephem compound containing phenylacetic acid or a derivative thereof as a raw material.

  In order to efficiently remove phenylacetic acids with the above-mentioned activated carbon, it is preferable to set the pH of the aqueous solution to 0.5 to 1.7, particularly 0.8 to 1.4, which is a strongly acidic region. From this viewpoint, it is preferable that the alkenyl cephem compound is present in the aqueous solution in the form of a mineral salt thereof, and the aqueous solution is in a strongly acidic region.

  The compound represented by formula (3) can be synthesized by a known method. For example, a 7-substituted acylamino-3-[(E / Z) -2- (4-methylthiazol-5-yl) vinyl] -3-cephem-4-carboxylic acid compound represented by the following formula (4) A compound represented by the formula (3) can be obtained by deprotecting the 4-position carboxylic acid protecting group. As a deprotection reaction, various methods known as a deprotection reaction of a carboxylic acid protecting group in a β-lactam compound can be employed. For example, the deprotection reaction in phenols described in JP-A No. 61-263984 can be employed.

In the formula (4), examples of the carboxylic acid protecting group represented by R ² include a benzyl group optionally substituted with an electron donating group, a diphenylmethyl group optionally substituted with an electron donating group, and the like. Is mentioned. Examples of the electron donating group include an alkyl group having 1 to 6 carbon atoms; a hydroxy group, and an alkoxy group having 1 to 6 carbon atoms.

  The present invention has been described above based on the preferred embodiments. However, the present invention is not limited to the above-described embodiments, and appropriate modifications within the scope of ordinary creation ability of those skilled in the art belong to the scope of the present invention. It is.

  Hereinafter, the present invention will be described in more detail with reference to examples. However, the scope of the present invention is not limited to such examples. Unless otherwise specified, “%” means “% by weight”.

Prior to describing the examples and comparative examples, the analysis method used will be described. High performance liquid chromatography (HPLC) was used for the analysis. The details are as follows.
Column: Unison UK-C18, 3 μm, 250 mm × 4.6 mm
-Column temperature: 30 ° C
Mobile phase (volume ratio): acetonitrile 13%, 10 mM sodium heptanesulfonate aqueous solution 87%
・ Flow rate: 0.8ml / min
・ Detection wavelength: 254 nm
・ Injection volume: 10 μL
-Z body retention time: 29.0-30.0 minutes-E body retention time: 31.0-32.0 minutes-E body content: E body area value / (Z body area value + E body area value) x 100 (%)

The method for analyzing the content of phenylacetic acid is as follows.
Column: SUPELCO ODS HYPERSIL 5 μm 250 × 4.6 mm
-Column temperature: 25 ° C
Mobile phase (volume ratio): acetonitrile 20%, 50 mM potassium dihydrogen phosphate 80%
・ Flow rate: 1.0ml / min
・ Detection wavelength: 225 nm
・ Injection volume: 10 μL
-Z-form + E-form retention time: 2.5-3.5 minutes-Phenylacetic acid retention time: 8.5-9.5 minutes-Phenylacetic acid content calculation formula [Phenylacetic acid area value / ((Z + E) form Area value + phenylacetic acid area value)] x 100 (%)

[Example 1]
(1) First step A compound represented by the following formula (5) (content of E form: 3.5%) is weighed into a 10.0 g four-necked flask, and 240 g of 6% aqueous sodium hydrogen carbonate solution is added to the sodium salt. It became an aqueous solution. To this aqueous solution was added 7.0 g of penicillin-G acylase enzyme (PGA-450, manufactured by Dalas Biotech Limited). A 7-position deprotection reaction of the sodium salt of the compound represented by the formula (5) is performed while adding a 5% aqueous sodium carbonate solution at a liquid temperature of 25 to 30 ° C. and controlling the pH to 7.7 to 8.5. Went for hours. After completion of the reaction, 7.0 g of a sodium salt of a compound represented by the following formula (6) containing 3.5% of E form in the solution was contained. Moreover, 16.6% of phenylacetic acid was contained.

(2) Second Step Following the first step, the enzyme was filtered off and adjusted to pH 0.9 with concentrated hydrochloric acid while keeping the liquid temperature at 20 ° C. or lower. This obtained the aqueous solution of hydrochloride of the compound represented by Formula (6). Next, 6.2 g of activated carbon (Unitika activated carbon fiber Adol A-20 (trade name) manufactured by Unitika Ltd.) was added to this aqueous solution and allowed to stand for 1 hour. The activated carbon had an iodine adsorption performance measured in accordance with JIS K-1474 of 1580 mg / g and a methylene blue adsorption performance of 310 ml / g. Thereafter, the activated carbon was filtered off, and a 1N aqueous sodium hydroxide solution was added to the aqueous solution to adjust the pH to 4.3, followed by aging for 1 hour. By this aging, crystals of the compound represented by the formula (1) were precipitated. The precipitated crystals were collected by filtration, washed with water and methanol, and dried. The analysis result of the obtained crystal was as follows.
-Z body yield: 92.0%
-E body content: 0.28%
-Phenylacetic acid content (after activated carbon filtration): 3.9%
¹ H-NMR (D ₂ O / DCl) ppm from TSP
_{2.52 (s, 3H, CH 3} ), 3.56~3.60 (d, 1H, S-CH (H), 18.3Hz), 3.75~3.78 (d, 1H, S- CH (H), 18.6 Hz), 5.25-5.26 (d, 1H, S-CH, 5.2 Hz), 5.44-5.45 (d, 1H, N-CH, 5.2 Hz) ), 6.78 (s, 2H, CH = CH), 9.78 (s, 1H, S-CH = N)

[Example 2]
In the first step of Example 1, the first step was performed in the same manner as in Example 1 except that the compound represented by formula (5) had an E-form content of 4.6%. After completion of the reaction, 7.0 g of the sodium salt of the compound of the formula (6) containing 4.6% of E isomer was contained in the solution. Moreover, 16.7% of phenylacetic acid was contained. Thereafter, the enzyme enzyme was filtered off and the second step was performed. In the second step, the pH was adjusted to 0.9 with concentrated hydrochloric acid while keeping the liquid temperature at 20 ° C. or lower. This obtained the aqueous solution of hydrochloride of the compound represented by Formula (6). Next, 5.6 g of activated carbon (CL-KP (trade name) manufactured by Ajinomoto Fine-Techno) was added to this aqueous solution and stirred for 1 hour. The activated carbon had an iodine adsorption performance of 1620 mg / g and a methylene blue adsorption performance of 280 ml / g. Thereafter, the activated carbon was filtered off, and a 1N aqueous sodium hydroxide solution was added to the aqueous solution to adjust the pH to 4.3, followed by aging for 1 hour. By this aging, crystals of the compound represented by the formula (1) were precipitated. The precipitated crystals were collected by filtration, washed with water and methanol, and dried. The rest was the same as in Example 1. The analysis result of the obtained crystal was as follows.
-Z body yield: 91.9%
-E body content: 0.25%
-Phenylacetic acid content (after activated carbon filtration): 3.9%

Example 3
In the first step of Example 2, the first step was performed in the same manner as in Example 2 using the compound represented by formula (5) having an E-form content of 3.5%. After completion of the reaction, 7.0 g of the sodium salt of the compound of formula (6) containing 3.5% of E form in the solution was contained. Moreover, 16.7% of phenylacetic acid was contained. Next, 15% sulfuric acid was used in place of concentrated hydrochloric acid in the second step of Example 2. Except for these, crystals of the compound represented by the formula (1) were obtained in the same manner as in Example 2. The rest was the same as in Example 2. The analysis result of the obtained crystal was as follows.
-Z body yield: 93.3%
-E body content: 0.15%
・ Phenylacetic acid content (after activated carbon filtration): 4.1%

Example 4
In the first step of Example 2, the first step was performed in the same manner as in Example 2 using the compound represented by formula (5) having an E-form content of 3.5%. After completion of the reaction, 7.0 g of the sodium salt of the compound of formula (6) containing 3.5% of E form in the solution was contained. Moreover, 16.7% of phenylacetic acid was contained. The pH of this aqueous solution was between 7.7 and 8.5. Next, 4.6 g of the same activated carbon used in Example 2 was added to this aqueous solution, and the mixture was stirred for 1 hour while maintaining at 20 ° C. Thereafter, the activated carbon was filtered off, and 3N hydrochloric acid was added to the aqueous solution to adjust to pH 4.3, followed by aging for 1 hour. By this aging, crystals of the compound represented by the formula (1) were precipitated. The precipitated crystals were collected by filtration, washed with water and methanol, and dried. The rest was the same as in Example 2. The analysis result of the obtained crystal was as follows. In this example, the content of phenylacetic acid was higher than in Example 2 due to the pH of the aqueous solution when activated carbon was in the alkaline range.
-Z body yield: 92.5%
-E body content: 0.20%
-Phenylacetic acid content (after activated carbon filtration): 17.0%

Example 5
In the first step of Example 2, the first step was performed in the same manner as in Example 1 except that the compound represented by formula (5) had an E-form content of 3.5%. After completion of the reaction, 7.0 g of the sodium salt of the compound of formula (6) containing 3.5% of E form in the solution was contained. Further, 16.8% of phenylacetic acid was contained. Subsequently, the same operation as the 2nd process of Example 2 was performed. However, the amount of activated carbon used was 4.6 g. Except for these, crystals of the compound represented by the formula (1) were obtained in the same manner as in Example 2. The analysis result of the obtained crystal was as follows.
-Z body yield: 93.7%
-E body content: 0.12%
-Phenylacetic acid content (after activated carbon filtration): 4.0%

[Comparative Example 1]
The same operation as in the first step of Example 1 was performed. After completion of the reaction, the solution contained 6.9 g of a sodium salt of the compound of formula (6) containing 3.5% of E form. Moreover, 16.7% of phenylacetic acid was contained. Subsequently, the same operation as the 2nd process of Example 1 was performed. However, CL-H (trade name) manufactured by Ajinomoto Fine Techno was used as the activated carbon. This activated carbon had an iodine adsorption performance measured in accordance with JIS K-1474 of 980 mg / g and a methylene blue adsorption performance of 180 ml / g. The amount of activated carbon used was 4.6 g. Except for these, crystals of the compound represented by the formula (1) were obtained in the same manner as in Example 1. The analysis result of the obtained crystal was as follows. The phenylacetic acid content was 6.2%.
-Z body yield: 94.2%
E content: 3.0%

[Comparative Example 2]
The same operation as in the first step of Example 1 was performed. After completion of the reaction, 7.0 g of the sodium salt of the compound of formula (6) containing 3.5% of E form in the solution was contained. Moreover, 16.7% of phenylacetic acid was contained. Subsequently, the same operation as the 2nd process of Example 1 was performed. However, BA-WD (trade name) manufactured by Ajinomoto Fine Techno was used as the activated carbon. This activated carbon had an iodine adsorption performance measured according to JIS K-1474 of 970 mg / g and a methylene blue adsorption performance of 180 ml / g. The amount of activated carbon used was 4.6 g. Except for these, crystals of the compound represented by the formula (1) were obtained in the same manner as in Example 1. The analysis result of the obtained crystal was as follows. The phenylacetic acid content was 5.8%.
-Z body yield: 93.0%
-E body content: 2.8%

  As is clear from the above results, the E-form can be selectively removed by using activated carbon having specific iodine adsorption performance and methylene blue adsorption performance according to the present invention. Phenylacetic acid can also be removed.

Claims (4)

7-amino-3-[(E / Z) -2- (4-methylthiazol-5-yl) vinyl] -3-cephem-4-carboxylic acid represented by the following formula (1) or an alkali metal salt thereof Is treated with a mineral acid to form a mineral acid salt, and an aqueous solution in the low pH region containing the mineral acid salt has an iodine adsorption performance measured according to JIS K-1474 of 1200 mg / g or more, and a methylene blue adsorption performance of 250 ml. 7-amino-3-[(Z) -2- (4-methylthiazol-5-yl) represented by the following formula (2), characterized by being contacted with activated carbon that is at least / g 7-amino-3-[(E / Z) -2- (4-methylthiazole) represented by the formula (1) with an improved content of vinyl] -3-cephem-4-carboxylic acid or an alkali metal salt thereof -5-yl) vinyl] -3-cephem-4-ca A process for producing rubonic acid or an alkali metal salt thereof.

The production method according to claim 1, wherein the mineral acid is hydrochloric acid. A salt of 7-substituted acylamino-3-[(E / Z) -2- (4-methylthiazol-5-yl) vinyl] -3-cephem-4-carboxylic acid represented by the following formula (3) is enzyme A compound represented by the above formula (1) containing phenylacetic acid or a derivative thereof, which is a byproduct of the deprotection reaction, produced by subjecting the reaction to a deprotection reaction of the 7-position amide bond. The manufacturing method of Claim 1 or 2 used as.

The production according to any one of claims 1 to 3, wherein a pH of the treatment liquid after the treatment with the activated carbon is adjusted to 3.8 to 4.8 to precipitate crystals of the compound represented by the formula (2). Method.