JPS5930714B2 - Method for producing cephalosporin derivatives - Google Patents

Description

Detailed Description of the Invention The present invention provides 7-(1H-tetrazol-1-ylacetamido)-3-(benzimidazol-2-yl)thiomethyl-3-cepheme-4-carboxylic acid, represented by the chemical formula (). or a method for producing the salt thereof.

The compound represented by the chemical formula () (hereinafter referred to as compound ()) is one of the cephalosporin derivatives and is useful as an extremely important intermediate for pharmaceutical synthesis.

For example, by reacting with a compound represented by the general formula (V) (wherein R represents hydrogen or a methyl group), the general formula () (wherein R represents hydrogen or a methyl group) can be extremely safely and efficiently produced. (representing a methyl group) can be produced.

This compound (2) is already commercially available as an excellent antibiotic with extremely strong bactericidal activity. The present invention provides compounds (
) provides a new manufacturing method.

That is, the present invention provides 7-amino-3-(benzimidazol-2-yl)thiomethyl-3cephem-4-, which is a compound represented by the chemical formula (T).
Carboxylic acid or its salt and 1H represented by the chemical formula ()
- Chemical formula () characterized by the action of tetrazole acetic acid or its reactive derivative at the carboxyl group
The present invention relates to a method for producing a cephalosporin derivative or a salt thereof.

Examples of reactive derivatives at the carboxyl group of tetrazole acetic acid include acetic acid halides, acid anhydrides, acid azides, acid amides, esters, etc., but particularly frequently used ones include acid chlorides, acid azides, acid anhydrides, Examples include alkyl carbonic acid mixed anhydrides and thiol esters represented by the general formula, but thiol esters, such as 2-methyl-1,3,4-thiadiazol-5-ylthiol ester, are particularly preferred in terms of reaction rate and economy. .

Regarding the preparation of the raw material compound, compound (1) is
For example, it can be easily produced by reacting 7-aminocephalosporanic acid with 2-mercaptobenzimidazole (Japanese Patent Publication No. 3917936).

In addition, 1H-tetrazole acetic acid of compound () is once converted into 1H-tetrazole acetic acid by a known method from glycine ethyl ester hydrochloride.
It can be obtained by converting it into tetrazole acetic acid ethyl ester and further hydrolyzing it. In addition, the active ester represented by the general formula () is a compound that has not been described in the literature, and 1
It can be easily produced with good yield by esterifying H-tetrazole acetic acid and thiadiazole thiol under conventional dehydration conditions (Japanese Patent Application No. 53-25975).
). In the method of the present invention, when using 1H-tetrazole acetic acid after its release or in its salt form, for example, N
The reaction is carried out in the presence of a condensing agent such as -N'-dicyclohexylcarbodiimide.

The reaction of the present invention is usually carried out in a solvent.

Solvents include acetone, ethyl acetate, dioxane, acetonitrile, chloroform, methylene chloride,
Or other general organic solvents that do not participate in the reaction, and among these, hydrophilic solvents can also be used in combination with water. The pH of the solution is preferably neutral, with pH 6. O
It is also good to have a range of 7.5 to 7.5.

The reaction temperature is not particularly limited, but it is usually carried out under cooling or at room temperature.

The reaction product of the present invention can be extracted from the reaction solution by conventional methods or isolated as a powder using a synthetic adsorbent.

The thus obtained cephalosporin derivative represented by the chemical formula () can be safely converted into the general formula (), which is a pharmaceutically excellent antibiotic, in high yield, if desired.

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1 Into a 21 eggplant-shaped flask, 36.27 of 7-amino-3(benzimidazol-2-yl)thiomethyl-3cephem-4-carboxylic acid, 2-methyl-1,3,4- of 1H-tetrazoleacetic acid were added. Thiadiazol-5-ylthiol ester 29.07, N-N/-dimethylformamide 200 ml and pH 7. O, 1M-phosphoric acid buffer -80
0ml was added and stirred at 25°C for 30 minutes to complete the reaction.

When the reaction solution was quantified using high performance liquid chromatography,
The reaction rate was 92.5%. This reaction solution was separated and purified using a synthetic adsorbent column in a conventional manner, resulting in 40. 31 yellow powder was obtained (purity 97.8%)
. λMaxlλMax(H2O) 283nm, 290n
mNMR spectrum (heavy water single methanol) δPpm3
．． 7O (S2H) 4.60 (DlH) 4.80 (S2H) 5.00 (DlH) 5.50 (S2H) 7.30 (M4H) 9.50 (SlH) Elemental analysis value example 2 Calcium chloride tube Add 7 to the attached 2e eggplant flask.
-amino-3-(benzimidazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid 3.627, 1H
After adding 1.547 g of -tetrazole acetic acid and 1.51 g of dry ethyl acetate, 2.067 g of N-N'-dicyclohexylcarbodiimide was added, and the mixture was stirred at 20 DEG C. for 10 hours to complete the reaction.

When the reaction solution was quantified using high performance liquid chromatography,
The reaction rate was 87.2%. This reaction solution is filtered in a conventional manner. ▲The residue was washed three times with 50 TLI of acetic acid ethyl ester, and then the ▲ solution was distilled off under reduced pressure to obtain 71 (1H-tetrazol-1-ylacetamide) as a yellow powder.
-3(benzimidazol-2-yl)thiomethyl-3
-Cefem-4-carboxylic acid 3.27 was obtained (purity 98
．． 2%). Example 3 In a 50 d three-necked flask with a calcium chloride tube, 7
-amino-3-(benzimidazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid 362W! 9,
After adding 20 ml of water and 5 ml of acetone, cool on ice.

Next, a solution of 176η of acid chloride of 1H-tetrazole acetic acid dissolved in 10 ml of acetone was gradually added dropwise using a dropwise load, and the pH was adjusted to 7.0 with 1N sodium monohydroxide.
After controlling the temperature to 0, the reaction was completed by stirring for 10 minutes. When this reaction solution was quantified using high performance liquid chromatography, the reaction rate was 6.5%. This reaction solution was neutralized by a conventional method, and then extracted three times with 30 ml of ethyl acetate. After drying over anhydrous magnesium sulfate and distilling off the solvent under reduced pressure, 180W of 7-(1H-tetrazol-1-ylacetamido)-3(benzimidazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid was obtained.
II! A yellow powder was obtained (purity 97.3%). Reference example
1. In a 500 ml three-bottle flask equipped with a thermometer, 7-(1H tetrazol-1-ylacetamide)-3-(benzimidazol-2-yl)thiomethyl-3-cepheme-4-carboxylic acid obtained in Example 1 was added. 2.327, 1・
3.4thiadiazole 5-thiol 0.79y. N-N
'-dimethylformamide 110Tf11 and water 90m
1 and heat to 60°C.

Claims (1)

[Claims] 1 7-amino-3-(benzimidazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid or its salt (I) and ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I )
Chemical formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼1 indicated by (II)
Chemical formula (III) ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ A method for producing a cephalosporin derivative or its salt represented by (III), in which H-tetrazole acetic acid or its reactive derivative at the carboxyl group acts. 2 1H-tetrazole acetic acid represented by the chemical formula (II) or its reactive derivative at the carboxyl group is the general formula (IV) ▲There are numerical formulas, chemical formulas, tables, etc.▼(IV) (R in the formula is hydrogen or 2. The method according to claim 1, wherein the thiol ester is a thiol ester represented by methyl group. 3. The method according to claim 1, wherein the reaction is carried out in a solvent.