JPS5923316B2 - Method for producing cephalosporin derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing cephalosporin derivatives.

We found that the bonded benzimidazole thio group is an extremely reactive leaving group under acidic conditions that stabilizes the cephaloskeleton.

That is, the general formula [) = More specifically, the present invention has acid stability,
In addition, it has a strong bactericidal effect against a wide range of microorganisms (including gram-positive and gram-negative pathogens), and is an excellent antibiotic with the general formula (11) (wherein R is hydrogen or , a methyl group), or a pharmaceutically acceptable salt thereof, in an extremely safe and efficient manner.

Until now, methods for producing the compound represented by the general formula (11) include a method in which 7-(1H-tetrazol-1-ylacetamido)cephalosporanic acid and 1,3,4-thiadiazole-5-thiols are reacted ( Special Publication No. 46-14736) is known.

However, this reaction is a substitution reaction between an acetoxy group and a thiazolethio group at the acetoxymethyl group at the 3-position, and PH6
．． It is necessary to expose the cephalosporin skeleton for 4 to 8 hours under conditions of 60°C, which is harsh for the cephalosporin skeleton, and a decrease in reaction yield cannot be avoided. A decrease in reaction yield is a big problem from an economic standpoint. Furthermore, when purifying a target product, the influence of impurities such as unreacted raw material compounds and compounds generated by decomposition cannot be ignored, which may result in problems with the purity of the product. The present inventors have conducted intensive studies to overcome the drawbacks of these conventional methods and to invent a method for safely and efficiently producing the compound represented by the general formula (11) or a pharmaceutically acceptable salt thereof. As a result of overlapping, 71 (1H-tetrazole-
1-ylacetamido)-3-(benzimidazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid, or a salt thereof, at the 3-position methyl group (R in the formula is hydrogen or a methyl group) ) has been found to be able to be obtained extremely efficiently.

That is, the present invention provides 7-(IH-tetrazole-1-
ylacetamido)-3-(benzimidazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid or a salt thereof, and the general formula () (R in the formula is hydrogen or a methyl group) The present invention relates to a method for producing a cephalosporin derivative represented by the general formula (n (wherein R is the same as above) or a salt thereof, which is characterized by reacting a compound represented by the formula (n) in a solvent.

In the present invention, the compound represented by the chemical formula (I) (hereinafter referred to as compound (1), the same hereinafter) used as a raw material is:
The benzimidazole thio group bonded to the 3-position methyl group is a leaving group with extremely high reactivity in the presence of protons.

It is thought that protons act as a catalyst for the elimination reaction.
Since the protons of thiols present in the reaction system are utilized, it is not necessarily necessary to add a new acid catalyst. 3
There are benzthiazole thio groups, benzoxazole thio groups, etc. as substituents of the same type that bond to the methyl group at the position, and in fact, the reaction proceeds even with these substituents, but in terms of stability and reactivity, benzimidazole thio groups, etc. The group exhibits excellent effects.

Since this substituent undergoes an extremely fast substitution reaction even in the acidic region where the cephalocompound is stable, it exhibits about twice as much effect in terms of yield as the acetoxy group in the conventional method. Compound (I) can be easily obtained by a method known per se.

For example, the known 71 (IH-tetrazole-1-
ylacetamide) cephalosporanic acid and 2-, which is already used as a polymer deterioration inhibitor and is commercially available at low cost.
It is obtained by reacting mercaptobenzimidazole by a known method. Or, the known 7-amino-3-(benzimidazol-2-yl)thiomethyl-
3-Cefem-4-carboxylic acid or its salt and IH
It can also be obtained by reacting reactive derivatives of -tetrazole acetic acid. The other raw material, Compound H), can be used as it is commercially available.

The compound obtained in this way or its salt, and the compound ()
can be reacted in a solvent to easily and efficiently lead to the target compound, a cephalosporin derivative represented by the general formula (Tfj) or a pharmaceutically acceptable salt thereof.

The amount of compound () may be at least equimolar to compound (1), and from the economic point of view, it is 1.0 to 2.0 mole.
Moles are preferred.

As reaction medium, N,N-dimethylformamide, N
, N-diethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide, or their aqueous solvents.

Examples of other solvents include ethers such as methyl cellosolve, fatty acid ketones such as acetone and methyl ethyl ketone, halogenated hydrocarbons such as dichloromethane and chloroform, nitriles such as acetonitrile and propionitrile, dimethyl sulfoxide, diethyl There are sulfoxides such as sulfoxide, and these can be used alone, as a mixed solvent, or as a water-containing solvent to allow the reaction to proceed. Among these solvents, N,N-dimethylformamide is particularly effective. and N,N-
The use of amides such as dimethylacetamide or water-containing solvents such as Amare is particularly preferred in terms of solubility, reaction rate, and economy. A feature of the present invention is that the reaction system contains a compound (n
) and thiol compounds produced by the 3-position substitution reaction, it is not necessarily necessary to add a new acid catalyst, but from the viewpoint of shortening the reaction time and improving the reaction yield, it is recommended to add a replacement catalyst. Better add it.

Examples include mineral acids such as hydrochloric acid and sulfuric acid, sulfonic acids such as para-toluenesulfonic acid and methanesulfonic acid, fatty acids such as propionic acid, and organic acids such as thiols such as 2-mercaptothiadiazole. Mineral acids and thiols are preferred from the viewpoint of reduction in reaction rate and reaction time. It is sufficient that the amount of the acid catalyst is substantially 0.05 mol or more relative to the amount of compound (1). The reaction temperature is
It varies depending on the presence or absence of a catalyst, the type of solvent, etc., but usually 10℃
A range of from 30°C to 100°C is sufficient, and a range of from 30°C to 80°C is particularly preferable in view of reaction rate, stability of the cephalosporin skeleton, etc.

The reaction time varies depending on the presence or absence of an acid catalyst, the type of solvent, etc., but a range of 30 minutes to 10 hours is usually sufficient.

For example, in the case of reaction at 60° C. in aqueous N,N-dimethylformamide in the presence of an acid catalyst, 30 minutes to 3 hours is sufficient. The target compound of the present invention can be extracted from the reaction solution by a conventional method, or in the case of an anhydrous solvent, by a conventional method.
It can be isolated as crystals by converting it into sodium and potassium salts.

In the present invention, the general formula (1
The cephalosporin derivative represented by 1 can be converted into a pharmaceutically acceptable salt as desired.

This conversion into salts can be conducted to alkali metal salts, ammonium salts, and alkaline earth metal salts using conventional methods. These salts exhibit excellent pharmaceutical properties, for example, in terms of solubility in water. According to the method of the present invention, a Cefa.' rosporin derivative represented by the general formula (11), which is an excellent antibiotic having strong antibacterial activity, and its pharmaceutically acceptable salts can be produced safely and well in high yield. Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto.
Example 1 7-(1H-tetrazol-1-ylacetamido)-3-(benzimidazol-2-yl)thiomethyl-3-cepheme-4 was added to a 31-meter three-bottle flask equipped with a thermometer.
-carboxylic acid 46.4 g, 2-methyl-1,3,4thiadiazole-5-thiol 19,89, N,N-dimethylformamide 1.

11 and water 0.911 were added and heated to 60°C.

Further, 100 ml of 0.5N monohydrochloric acid was added as a reaction catalyst, and the mixture was stirred at 60°C for 2 hours to complete the reaction. When the reaction solution was quantified using high performance liquid chromatography, the reaction rate was 93%. This reaction solution was cooled, and by a conventional method,
After removing impurities with ether, the mixture was diluted to a concentration of 1.5 with 1N hydrochloric acid and extracted three times with ethyl acetate 21. After drying over anhydrous magnesium sulfate and removing the solvent under reduced pressure, 7-(1H-tetrazol-1-ylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl was obtained. A white powder of 42.39 g of -3-cephem-4-carboxylic acid was obtained. (Purity 96.8%
) λMax:: 272 nm (3% heavy water) M. p. l97
5-200℃ (decomposition) NMR spectrum (DMSO-Ds) δ Sir 2.68 (S
, 3H) 3.71 (Dd, 2H) 4.39 (Dd, 2
H) 5.12 (D, lH) 5.37 (S, 2H) 5.
73(q′1H)9.33(S,lH) 9.49(D
, 2H) Elemental analysis value Example 2 71 (1
H-tetrazol-1-ylacetamido)-3-(benzimidazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid 2,329, 1,3,4thiadiazole-5-thiol 0.79.9 , N,N-dimethylformamide 1107! Add Ll and 90me of water, 6
Heat to 0°C.

Further, 10 mj of 0.5N monohydrochloric acid was added as a reaction catalyst, and the mixture was stirred at 60°C for 1.5 hours to complete the reaction.
When the reaction solution was quantified using high performance liquid chromatography,
The reaction rate was 89%. After cooling the reaction solution and removing impurities with ether in a conventional manner, 1N hydrochloric acid was added to Pllll. 5 and extracted three times with 200 ml of acetic acid ethyl ester. Dry with anhydrous magnesium sulfate,
When the solvent was distilled off under reduced pressure, 7-(1H-tetrazol-1-ylacetamido)-3-(2-methyl-1,3
, 4-thiadiazole-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.059%) was obtained as a white powder.
(Purity 96%) λMax 273 nm (3% sodium bicarbonate solution) Example 3 In a 100 ml three-loaf flask equipped with a thermometer, 71 (
1H-tetrazol-1-ylacetamide)゛-3
-(benzimidazole-2-ino(ha)thiomethyl-)
Pour 928ヮ of 3-cephem-4-carboxylic acid, 330η of 1,3,4thiadiazole-5-thiol, 22ml of N,N-dimethylformamide, and 18rfL1 of water,
Heat to 80°C.

The reaction was completed by stirring at 80° C. for 30 minutes.

When the reaction solution was quantified using high performance liquid chromatography,
The reaction rate was 94%. After cooling the reaction solution and removing impurities with ether in a conventional manner,
PHL. 5 and extracted three times with 40me acetic acid ethyl ester. Dry with anhydrous magnesium sulfate,
When the solvent was distilled off under reduced pressure, 7-(1H-tetrazol-1-ylacetamido)-3-(2-methyl-1,3
, 4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, 854 m9 of white powder was obtained.
(Purity 95%) Example 4 71 (1
H-tetrazol-1-ylacetamido)-3-(benzimidazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid 928 w, 1,3,4thiadiazole-5-thiol 317 w, acetone 22 ml and water 18
ml and heated to 70°C.

Furthermore, 1111 ml of 0.5M monosulfuric acid water was added as a reaction catalyst, and the mixture was stirred at 70°C for 2 hours. The reaction rate was determined to be 66% by high performance liquid chromatography. This reaction solution was cooled, and after removing impurities with ether in a conventional manner, PHL. 5 and extracted three times with 40 ml of acetic acid ethyl ester.
After drying over anhydrous magnesium sulfate and removing the solvent under reduced pressure, 7(1H-tetrazol-1-ylacetamido)-3-(1,3,4-thiadiazol-5-yl)thiomethyl-3-cepheme-4 was obtained. - A white powder of carboxylic acid 503η was obtained. (Purity 94%) Example 5 71 (1H
-tetrazol-1-ylacetamido)-3-(benzimidazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid 464η, 1,3,4-thiadiazole-5-thiol 158η, dichloromethane 20mf!
Anhydrous hydrochloric acid gas was blown into the reaction solution which was heated to 30° C., and when 0.05 mol of hydrochloric acid gas was blown into the reaction solution, the hydrochloric acid gas was stopped and the mixture was stirred for 5 hours.

Claims (1)

[Claims] 1 Chemical formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ 7-(1H-tetrazol-1-ylacetamide)- shown by (I)
3-(benzimidazol-2-yl)thiomethyl-3
-Cefem-4-carboxylic acid or a salt thereof, and the general formula (
II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼General formula (III) characterized by reacting the compound represented by (II) (in the formula, R is hydrogen or methyl group)▲Mathematical formulas, chemical formulas, tables, etc. ▼(III) (In the formula, R is hydrogen or methyl group) A method for producing a cephalosporin derivative or a pharmaceutically acceptable salt thereof. 2. The method according to claim 1, wherein the reaction is carried out under an acidic catalyst. 3. The method according to claim 2, wherein the acidic catalyst is hydrochloric acid or sulfuric acid. 4. The method according to claim 1, wherein the solvent is a polar solvent or a water-containing polar solvent. 5 The polar solvent is N,N-dimethylformamide or
5. The method according to claim 4, wherein N,N-dimethylacetamide is used.