JPS6047276B2 - Method for producing 7-aminocephalosporanic acid derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula 1OOC--X2(CH2)3C()N-Niko(
However, X represents an acetate group, a hydroxyl group, a terminal residue, or hydrogen), or a derivative thereof, or a salt thereof (hereinafter abbreviated as a cephalosvorin compound) is generally treated in the presence of hydrogen peroxide. React with an α-ketone aldehyde derivative represented by the formula RCOCHO (where R represents a hydroxyl group, an amino group, or a phenyl group) or a salt thereof (hereinafter abbreviated as an aldehyde derivative), and then react with thiosulfuric acid or a salt thereof. Then, the general formula H00C-(CH2)0~℃
ONH death'SN] (n)ノ 4←Ndoor H2X (However,
The present invention relates to a method for selectively obtaining a 7-aminocephalosboranic acid derivative represented by (same as above).

The aim is to use 7-aminocephalosboran as an intermediate raw material for the synthesis of 3-acetoxymethyl and 7β-aminocephalosboranic acid, which are raw materials for the synthesis of cephalosborin C antibiotics, which have low toxicity and a wide range of medicinal efficacy. The object of the present invention is to provide a method for industrially producing acid derivatives (■) at low cost and easily. Conventionally, as a method for producing a 7-aminocephalosboranic acid derivative (■), for example, a cephalosporin compound obtained by a fermentation method,
Aspergillus, Penicillium, Neurosvora,
7-
Method for obtaining aminocephalosboranic acid derivatives (■) (Belgium Patent No. 736934, Japanese Patent Application Publication No. 1986-395)
No. 95) is known.

In these methods, a large amount of the α-ketoadipate derivative of 7-aminocephalosporin C (hereinafter abbreviated as α-keto derivative) shown in (■) below is produced as a side reaction product. A method has been reported in which an enzyme inhibitor such as sodium azide is present in the reaction system in order to suppress the production of α-keto derivatives, which are these side-reactants. (However, x is the same as above.) However, these methods require a huge amount of industrial equipment to produce D-amino acid oxidase, and use enzyme inhibitors such as sodium azide, which is extremely harmful to the human body. It is necessary to use a large amount of the agent. -In particular, these methods are not necessarily advantageous as industrial methods because they have drawbacks such as the difficulty in stably producing the desired product.

In addition, in view of these drawbacks, the present inventors reacted cephalosporin compound (1) with an aldehyde derivative,
Completed a method for efficiently producing 7-aminocephalosboranic acid derivatives (Special Publication No. 55-1291, Special Publication No. 5, No. 5)
9-2959 eel).

However, even in the method of the above invention, it is not possible to completely suppress the formation of by-products during isolation and purification 4, and therefore the desired 7-aminocephalosboranic acid derivative (■
) had the disadvantage of lowering the production rate. For this reason, for the purpose of suppressing the production of side reactions, the addition of a chemical commonly called a reducing agent is effective in reducing the amount of cephalosporin compound (1), which is the starting material, and 7-aminocephalosboranic acid, which is the target product. It has the disadvantage that it involves a reduction reaction to the derivative and easily causes chemical changes in the cefem nucleus.
The present inventors have conducted intensive research on the above method invented by the present inventors, and as a result, the cephalosporin compound (1
) is treated with an aldehyde derivative in the presence of hydrogen peroxide, and then isolated in the coexistence of thiosulfuric acid or its salts to obtain the desired 7-aminocephalosboranic acid derivative (■). It has been found that the method of the present invention can be obtained selectively and in extremely high yield, and the method of the present invention has been completed as a method that can be implemented industrially. The method of the present invention is a method for obtaining a 7-aminocephalosboranic acid derivative by reacting an aldehyde derivative in an aqueous solution containing a cephalosporin compound in the presence of hydrogen peroxide, and then reacting it with thiosulfuric acid or a salt thereof. It is.

That is, hydrogen peroxide is co-dissolved in an aqueous solution containing a cef-allosporin compound, an aldehyde derivative is added thereto, the reaction is allowed to take place for a certain period of time, and then thiosulfuric acid or its salts are added to the reaction solution. In this way, 7-aminocephalosboranic acid derivatives can be selectively obtained. The method of the present invention is characterized by reacting a cephalosporin compound with an aldehyde derivative in the presence of hydrogen peroxide,
By then reacting with thiosulfuric acid or salts thereof, 7-aminocephalosboranic acid can be selectively obtained without producing any side reaction products.

In the method of the present invention, thiosulfuric acid or its salts that are added and coexisting in the reaction system are determined by adjusting other reaction conditions, such as the amount of hydrogen peroxide added to the reaction solution, the hydrogen ion concentration, the reaction temperature, and the use as a starting material. Although it varies slightly depending on the type of cephalosporin compound or their concentration, the amount is at least equimolar, preferably at most 3@mol, per mole of the cephalosporin compound used as a starting material.

Adding a larger amount of thiosulfuric acid or its salts than necessary has no particular effect on the reaction, but is not economical. The amount of hydrogen peroxide added and coexisting in the reaction system varies slightly depending on other reaction conditions, such as the hydrogen ion concentration of the reaction solution, the reaction temperature, the type of cephalosporin compound used as a starting material, and their concentration. , cephalosporin compound 1 used as starting material
The amount is equal to or more than one mole, preferably less than two times the mole. The starting material, the cephalosporin compound, and the target product, the 7-aminocephalosboranic acid derivative, easily undergo decomposition of their cefem rings through an oxidation reaction.
It is not desirable to coexist an unnecessarily large amount of hydrogen peroxide in the reaction system.

Furthermore, the order in which hydrogen peroxide or a compound that produces hydrogen peroxide in the reaction system and the aldehyde derivative are added to the aqueous solution containing the cephalosporin compound does not have any influence on the result of the reaction, but preferably, After adding the aldehyde derivative, it is preferable to add hydrogen peroxide or a compound that generates hydrogen peroxide into the reaction system. In addition, the amount of the aldehyde derivative used in the method of the present invention may be stoichiometrically equal to or more than equimolar to the cephalosporin compound as the starting material, but other reaction conditions, such as the type of cephalosporin compound, the reaction temperature, etc. , is increased as appropriate depending on the type and amount of coexisting impurities. Using a larger amount of aldehyde derivative than necessary
Although it has no particular effect on the reaction, it is not economical. The cephalosporin compound used in the method of the present invention or hydrogen peroxide coexisting in the reaction system is unstable to alkaline aqueous solutions. Therefore, the hydrogen ion concentration of the reaction solution in the method of the present invention is preferably maintained at pH 3 to 8. In the method of the present invention,
As shown above, by coexisting hydrogen peroxide in the reaction system, the desired 7 can be obtained from the cephalosporin compound.
The present invention is directed to the selective production of -aminocephalosboranic acid derivatives.

In the method of the present invention, the reaction rate of the reaction to obtain a 7-aminocephalosboranic acid derivative by the reaction of a cephalosporin compound and an aldehyde derivative is determined by, for example,
Particularly effective is the addition of salts of iron, copper, cobalt, nickel, zinc, manganese, aluminum, etc. with organic or inorganic acids such as acetic acid, propionic acid, sulfuric acid, or hydrochloric acid. .

Furthermore, when using these metal compounds together with, for example, tertiary cyclic amines such as pyridine, lutidine, and picoline, secondary cyclic amines such as imidazole and piperidine, or chain organic amines such as triethylamine, Furthermore, the reaction time is shortened and the formation of side reactants is suppressed, giving good results. The amount of these metal compounds to be added is appropriately determined depending on the type of these metal compounds and other reaction conditions. Using a larger amount of metal compound than necessary makes it difficult to purify and isolate the desired 7-aminocephalosboranic acid derivative, and is not necessarily preferable. The reaction temperature in the method of the present invention is generally in the range of 0°C to 50°C.

However, the cephalosporin compound used as a starting material or the 7-aminocephalosboranic acid derivative, which is the target substance, is chemically susceptible to oxidation reactions and is unstable, especially in the coexistence of hydrogen peroxide. It is not recommended to carry out the process at high temperatures. Most economically, it is preferable to carry out the reaction at around room temperature. The reaction time in the method of the present invention is appropriately determined depending on other reaction conditions, such as the presence or absence of addition of a metal compound or organic amino, the hydrogen ion concentration of the reaction system, and the reaction temperature. More than 1 space and less than 2 spaces is sufficient. The 7-aminocephalosboranic acid derivative obtained by the method of the present invention is relatively stable under the above reaction conditions,
Although a long reaction time does not particularly adversely affect the nature of the reaction, it is not necessarily preferable to carry out the reaction for an unnecessarily long time. The 7-aminocephalosboranic acid derivative obtained by the method of the present invention is extracted and purified from the reaction solution using an organic solvent such as ethyl acetate, n-butyl acetate or n-butanol. It can be purified by different methods.

Another feature of the method of the invention is that it can be carried out in aqueous solution. Therefore, for example, the desired 7-aminocephalosboranic acid derivative can be obtained by directly applying the method of the present invention from a culture solution of cephalosporin compounds "θ" without purifying and isolating these cephalosporin compounds. This is a very advantageous point when the method of the present invention is carried out industrially.The 7-aminocephalosboranic acid derivative obtained by the method of the present invention can be in chloride solvent,
Glutaric acid bound to the amino group at the 7-position of a 7-aminocephalosboranic acid derivative is produced by the so-called iminoether method, in which the iminochloride derivative is treated with phosphorus oxytrichloride, and then an alcohol is added. 3-monosubstituted methyl-7, useful as a pharmaceutical raw material by cleaving the residue
β-Aminocephalosboranic acid, for example 3-acetoxymethyl-7β-aminocephalosboranic acid, can be obtained. Hereinafter, the present invention will be explained in detail with reference to Examples.

However, these Examples show one example of the method of the present invention, and do not limit the method of the present invention. Example 1 Cephalosporin C (hereinafter referred to as C) with a purity of 74.2%
4f crystals of the sodium salt of Ceph-C (abbreviated as Ceph-C) (i.e., 2.97f as Ceph-C sodium salt) and 3.3q of copper acetate were dissolved in 120 TLt of water.

In this case, the pH of the reaction solution was 3.9. While stirring the reaction solution at room temperature, 120 mL of an aqueous solution containing 6.249 TFLt of glyoxylic acid and 5.5 TFLt of pyridine was added dropwise over 1 hour. The pH at the end of the reaction was 4.6. Then, with 1N sulfuric acid, pH 3. After adding 60 cc of 15% hydrogen peroxide solution dropwise over 1 hour and continuing stirring for 1 hour, sodium thiosulfate pentahydrate 21.9
After adding y and stirring for another minute, sulfuric acid was added and PHL. 5, and the reaction was terminated. Analysis using this method revealed that 3-acetoxymethyl-7β-. The production rate of (4-carboxybutanamide) 3-cefemu-4-carboxylic acid was 92%. 3-acetoxymethyl-7β-(5-
Carboxy 5-oxopentanamide) 3-cephemu 4-carboxylic acid was not detected.

This reaction solution was extracted three times with 50011 t of ethyl acetate, and the collected ethyl acetate extracts were concentrated under reduced pressure at 40° C. or lower to about 200 TnL, and then dried overnight using anhydrous sodium sulfate.

After filtering this liquid, the residue was washed with a small amount of ethyl acetate, further concentrated under reduced pressure at below 40°C to 10ml, and then mixed with 200ml of petroleum ether while stirring vigorously.
1 was added dropwise. The resulting precipitate was centrifuged, the supernatant liquid was removed by decantation, petroleum ether was added to suspend the precipitate, and the mixture was centrifuged again. After removing the supernatant liquid by decantation, 3-acetoxymethyl-7β-(4-carboxyptamide)3-cefemu-4- was quickly dried on alumina in vacuo.
2.43y of a pale yellow solid of carboxylic acid was obtained. Crystal acquisition efficiency: 91.8% (purity: 98.9%). Example 2 Ceph-C sodium salt O with a purity of 74.2%
1.5y of crystals (i.e. 1.11y as Ceph-C sodium salt) and 406m9 of copper sulfate in 100m
1 dissolved in water.

The pH of the reaction solution was 3.9. While stirring at room temperature, 100 ml of an aqueous solution containing 2.3 q of glyoxylic acid and 1.5 ml of triethylamine was added in 20 ml portions at 3 times a day.
Added to each powder. Furthermore, after each addition, 20% after one powder has passed.
Hydrogen peroxide solution was added in 3ml portions. Further, three powders were stirred and reacted. The pH at the end of the reaction was 3.5. After stirring for another 30 minutes, sodium thiosulfate 5
After adding 6.29y of hydrate and continuing stirring for another 1 min, sulfuric acid was added to the reaction solution and PHL. 5, and the reaction was terminated. According to this analysis, the production rate of 3-acetoxymethyl-7β-(4-carboxybutanamide)3-cephemu-4-carboxylic acid was 87.8%.
This reaction solution was treated with 3-acetoxymethyl-7β-(4-carboxybutanamide)3 by the method shown in Example 1.
-Cefemu 0.88y of pale yellow solid of 4-carboxylic acid was obtained. Crystal acquisition efficiency 87.5% (purity 97.1%)
. Example 3 A fermented liquid of Cephalosborium acremonium was sterilized by filtering, and then treated with acid (pH 2.8) to decompose the penicillin N contained therein, and then filtered once to wash the residue. Combine the washing liquid and Oki liquid and make Ceph-C3223γ/M.
A liquid 4.6e containing L was obtained.

This was adsorbed by passing through an activated carbon column, and after washing with water, 3
Elution was performed with 7% n-butanol and the desired fractions were collected. This has a pH of 6. 275 ml of a pale yellow solution containing Ceph-C4Om9/ml was obtained by concentration under reduced pressure below 40°C. 100 ml of this solution was adjusted to pH 6.5 with sodium hydroxide, and 2.0 ml of zinc acetate was added to it.
Add 1y of glyoxylic acid and add 4.6% of glyoxylic acid while stirring at room temperature.
500 ml of an aqueous solution containing y and γ-picoline 9.4 ml
1 was added dropwise over an hour and a half. For the reaction, the pH is 5.
．． Sodium hydroxide was added so that the concentration was 0. At this time, a part of the reaction solution was collected and analyzed by fuchi paper vapor chromatography. It was found that 3-acetoxymethyl-7β-(5-
carboxy5-oxopentanamide) 3-cephemu-4-carboxylic acid and 3-acetoxymethyl-7β-
The production rates of (4-carboxybutanamide) 3-cefemu-4-carphonic acid were found to be 61% and 15%, respectively. 1. The reaction was further stirred for 30 minutes, and the pH was adjusted to 3. After lowering the temperature to O, 60 mt of 35% hydrogen peroxide solution was added dropwise, and
After continued stirring, sodium thiosulfate pentahydrate 37
．． 9y and continued stirring for an additional 3 minutes, sulfuric acid was added and PHL. 5, and the reaction was stopped. According to this analysis, the production rate of 3-acetoxymethyl-7β-(4-carboxybutanamide)3-cephemu-4-carboxylic acid was 76.1%. 3-acetoxymethyl-7β-
(5-carboxy5-oxopentanamide)3-ceph5em-4-carboxylic acid was not detected.

This reaction solution was treated with 3-acetoxymethyl-7β-(4-carboxybutanamide)3 by the method shown in Example 1.
3.48y of pale yellow solid of -cefemu-4-carboxylic acid was obtained. Crystal acquisition efficiency 75.1% (purity 80.2%)
. Example 4 The fermentation liquid of Cephalosborium/Acremonium was sterilized by filtration, and then treated with acid (pH 2.8) to decompose the penicillin N contained therein, and then filtered again, and the residue was washed and washed. Ceph-C4762γ/ML by combining liquid and Oki liquid
A solution 3e containing was obtained.

Add 200 mt of this solution to pH 7. 350m9 of cobalt sulfate and 194m9 of piperazine.
9 was added, the mixture was heated to 3rC, and 3.41 glyoxal of phenylglyoxal was added dropwise over 1 hour while stirring. On this occasion,
The pH of the reaction solution was adjusted to 5.0 using sodium hydroxide and sulfuric acid. Further, after stirring the three powders at 37°C, the reaction was made to pH 3 with sulfuric acid. After adding 43.9 mL of saturated sodium perborate solution dropwise and continuing stirring for one more powder, 2.84 y of sodium thiosulfate pentahydrate was added and stirring for one more powder. Add PHL. 5, and the reaction was terminated. When analyzed using this method, 3-acetoxymethyl-7β-(4-carboxybutanamide)3-
The production rate of cefhemu-4-carboxylic acid was 70.1%. This reaction solution was converted into 3-acetoxymethyl-7β-(4-carboxybutanamide) by the method shown in Example 1.
3-cefemu-4-carboxylic acid yellow solid 1123m9
was gotten.

Crystal acquisition efficiency 66.9% (purity 75.3%). Example 5 1.25y crystals of Ceph-C sodium salt with a purity of 74.2% (i.e. 928m9 as Ceph-C sodium salt) and 791mg of nickel sulfate were
It was dissolved in 50 mt of water and 2.16 y of glyoxylic acid and 204 m9 of imidazole were added with stirring at 5°C.

The reaction is carried out at pH 5.0 by appropriately adding an aqueous sodium hydroxide solution. It was set as O. After the reaction was allowed to stir for 2 hours, 53.0 ml of saturated potassium perborate solution was added dropwise, and stirring was continued for an additional 3 minutes. After that, 7.37 grams of sodium thiosulfate pentahydrate was added, and the mixture was further stirred for 1 hour. After continuing, add hydrochloric acid and
Hl. 5, and the reaction was terminated.

When analyzed using this method, 3-acetoxymethyl-7β-(4
-carboxybutanamide) 3-cephemu-4-carboxylic acid production rate was 81.4%. This reaction solution was treated with 3-acetoxymethyl-7β- by the method shown in Example 1.
(4-Carboxybutanamide) 809 mg of pale yellow solid of 3-cefemu-4-carboxylic acid was obtained. Crystal acquisition efficiency: 81.0% (purity: 82.0%). Example 6 Ceph-C sodium salt' with a purity of 74.2%
2.3y of crystals (i.e. 1.71g as Ceph-C sodium salt) were added to M phosphate buffer (pH 4.6
) containing 4.7y of glyoxylic acid sodium salt dissolved in 300mL and stirred at 5°C. Phosphate buffer (
300 mL of pH 4.6) was gradually added dropwise over 30 minutes.

5 After stirring and reacting this for another 2 hours, 33 ml of 15% hydrogen peroxide solution was added continuously, then stirred once, and 11.0 y of sodium thiosulfate pentahydrate was added.
After continuing stirring for another 30 minutes, sulfuric acid was added to PHL. The reaction was stopped by lowering the concentration to 5.

When analyzed with Oko), 3-acetoxymethyl-7β-(
The production rate of 3-cephemu (4-carboxybutanamide) 4-carboxylic acid was 76.4%. This reaction solution was treated with 3-acetoxymethyl-7β by the method shown in Example 1.
-(4-carboxybutanamide)3-cefemu 4-
1.67 y of a pale yellow solid of carboxylic acid was obtained. Crystal acquisition efficiency 73.6λ (purity 70.0%). Example 7 Instead of using Ceph-C sodium salt in Example 1, deacetyl Cep with a purity of 56.3% was used.
It was treated in exactly the same manner except that crystal 3y of h-C sodium salt (ie, 1.689y as deacetyl Ceph-C sodium salt) was used.

During the process, 3-hydroxymethyl-7β-(4-
The production rate of 3-cephemu-4-carboxylic acid (carboxybutanamide) was 90%. 1.3 q of pale yellow solid of 3-hydroxymethyl-7β-(4-carboxybutanamide)3-cefemu-4-carboxylic acid was obtained.

Crystal acquisition efficiency: 84.4% (purity: 93.1%). Example 8 Instead of using Ceph-C sodium salt in Example 1, deacetoxyCeph with a purity of 83% was used.
The procedure was carried out in exactly the same manner except that crystals 5q of -C sodium salt (ie, 4.15 g as the theacetoxyCeph-C sodium salt) were used.

During the reaction, the production rate of 3-methyl-7β-(4-carboxybutanamide)3-cefemu-4-carboxylic acid in the reaction solution was 95.2%. 3.05 g of pale yellow solid of 3-methyl-7β-(4-carboxybutanamide)3-cefemu-4-carboxylic acid was obtained.

Crystal acquisition efficiency: 87.9% (purity: 97.8%). Example 9
In Example 1, Ceph-C sodium salt. Instead of using N-[7-D-
The treatment was carried out in exactly the same manner except that crystal 3y of (5-aminoadipinamide)3-cefem-3-ylmethyl]pyridinium-4-carboxylic acid was used.

N-[7-(4-carboxybutanamide)3-cefem-3-ylmethyl]pyridinium-4- in the reaction solution
The production rate of carboxylic acid was 82.0%. N-[7-
2.14y of pale yellow solid of (4-carboxybutanamide)3-cefem-3-ylmethyl]pyridinium-4-carboxylic acid was obtained. Crystal acquisition efficiency 79.9% (purity 87.9%). Example 10 The same procedure as in Example 6 was carried out except that glyoxylic acid amide 4.6y was used instead of glyoxylic acid sodium salt.

During the reaction, the production rate of 3-acetoxymethyl-7β-(4-carboxybutanamide)3-cefemu-4-carboxylic acid in the reaction solution was 75.9%. 1.654 y of pale yellow solid of 3-acetoki5dimethyl-7β-(4-carboxybutanamide)3-cephemu-4-carboxylic acid was obtained.

Crystal acquisition efficiency 71.9% (purity 69.3%). Example 1
1.3y of Ceph-C sodium salt crystals with a purity of 074.2% (i.e. 965 mg as Ceph-C sodium salt) were dissolved in 250ml of water, 441ml of copper acetate was added and the pH was adjusted to 5.0. 506 mg of glyoxylic acid was added while stirring at room temperature.

5 After further stirring for 2 hours, the pH was adjusted to 3.0 with 1N sulfuric acid. O
Then, 1.9 ml of 15% hydrogen peroxide solution was added.

After further stirring the powder, add sulfuric acid to PHL. 5, and the reaction was terminated. According to this analysis, the production rate of 3-acetoxymethyl-7β-(4-carboxybutanamide)73-cefemu-4-carboxylic acid was 77.3%.
This reaction solution was treated with 3-acetoxymethyl-7β-(4-carboxybutanamide)3 by the method shown in Example 1.
884 mg of pale yellow solid of -cefemu-4-carboxylic acid was obtained.

Crystal acquisition efficiency 73.7% (purity 71.1%). Example 1
2 1.9 y of Ceph-C sodium salt crystals with a purity of 74.2% (i.e. 1.4 y as Ceph-C sodium salt) were dissolved in 350 ml of water and pyridine 2
ml and 736 m9 of glyoxylic acid were added while keeping the pH at 4.6 and stirring at room temperature.

Claims (1)

[Claims] 1. General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (However, X
is an acetate group, a hydroxyl group, a nucleophilic residue, or hydrogen), or a derivative thereof, or a salt thereof, is mixed with the general formula RCOCHO (where R is a hydroxyl group, an amino basis,
By reacting glyoxylic acid or its derivatives or salts thereof represented by phenyl group), and then reacting with thiosulfuric acid or their salts, the general formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) A method for producing a 7-aminocephalosboranic acid derivative, which comprises selectively obtaining a 7-aminocephalosboranic acid derivative represented by (where X is the same as above).