JPS6210514B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a cephalosporin compound. More specifically, it has acid stability and is compatible with a wide range of microorganisms (Gram-positive,
It has a strong bactericidal effect against (including Gram-negative pathogens) and is known as an excellent antibiotic. General formula () (In the formula, R ₂ is hydrogen, a methyl group, a carboxymethyl group, or a sulfonic acid methyl group) It is something.

Until now, the compound represented by the general formula () has been
It was produced in two steps using 7-aminocephalosporanic acid as a raw material. Target compound of the present invention ()
For example, 7-mandelamidocephalosporanic acid was obtained from 7-aminocephalosporanic acid and mandelic acid (Japanese Patent Publication No. 52-31879).
For example, 1-methyl-tetrazole-
Reacting 5-thiols (JP-A-49-117487
7-aminocephalosporanic acid and 7-aminocephalosporanic acid.
For example, 7-amino-3-(1-methyl-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid is synthesized by reacting 1-methyl-tetrazole-5-thiols (Japanese Patent Publication No. 49-197-
45880), and then reacted with mandelic acid to obtain the desired compound of the general formula () (Japanese Patent Publication No. 1973-
45880) method, etc.

These methods are a combination of two completely independent reactions. That is, one is an acylation reaction of the amino group at the 7-position of 7-aminocephalosporanic acid, and the other is a substitution reaction between the acetoxy group and the tetrazolethio group at the acetoxymethyl group at the 3-position. The reaction conditions for these two reactions are different, and even if the reactions are performed continuously, interruption of the reaction due to a change in conditions is unavoidable. Furthermore, the cephalosporin compound is subjected to harsh conditions regarding its stability, such as pH 6.5 and 60°C, for 3 to 6 hours in the pre-step and 4 to 8 hours in the post-step of the two-step reaction. Decrease in reaction yield is a big problem from an economic standpoint. Furthermore, when purifying a target product that has been continuously reacted, 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. Furthermore, the acid chloride method, mixed acid anhydride method, and DCC condensation method, which are usually used for the 7-position acylation reaction in conventional methods, are susceptible to decomposition due to the moisture inherent in these acylating agents and the human body. It has significant drawbacks in terms of workability and safety, such as skin irritation.

The present inventors have conducted extensive studies on a method for safely and efficiently producing a compound represented by the general formula () or a pharmaceutically acceptable salt thereof by overcoming the drawbacks of these conventional methods. () (R ₂ in the formula is hydrogen, a methyl group, a carboxymethyl group, or a sulfonic acid methyl group) is reacted with a 7-aminocephalosporanic acid derivative or a salt thereof to achieve the desired purpose. We have now invented a method for easily and safely producing the general formula (). This method is an extremely excellent method for simultaneously and efficiently introducing substituents at the 7- and 3-positions of the target compound represented by the general formula () under a single condition.

That is, the present invention has the general formula () (R ₁ in the formula is a halogen, an azide group, an acetoxy group, or a benzimidazole thio group) or a salt thereof, and a general formula () (R ₂ in the formula is hydrogen, a methyl group, a carboxymethyl group, or a sulfonic acid methyl group) By reacting a compound represented by the general formula () The present invention provides a method for producing a cephalosporin compound represented by the formula (wherein R ₂ is the same as above) or a pharmaceutically acceptable salt thereof.

To explain in more detail, it is expressed by the general formula ()
Among the halogen, azide group, acetoxy group, or benzimidazole thio group for R ₁ , particularly preferred in terms of efficiency and the like are an acetoxy group and a benzimidazole thio group.

The novel compound represented by the general formula () and unknown in the literature is not just an acylating agent. A single compound has a reactive group for both the 7-position acylation reaction and the 3-position substitution reaction of cephalosporanic acid, and has extremely high activity, allowing the reaction to proceed efficiently and producing the desired compound of the general formula (). It has the great advantage of being able to be obtained in high yield and safely.

Further, the reactivity of the new compound represented by the general formula () is almost equal to that of the acid chloride method and the mixed acid anhydride method, which are conventionally said to have the highest acylation reactivity. It is known that the drawback of conventional methods is that if the temperature is not strictly controlled, side reactions occur and the efficiency decreases, but with the general formula (), the temperature range that can be easily implemented is usually from room temperature to 80℃.
No side reactions, including polymerization reactions, decomposition reactions, etc., occur within this range. There is also a conventionally known active thioester method, such as the phenyl thioester method of carboxylic acid, but in this method, the reaction conditions are harsh, such as strongly alkaline conditions, high temperature, and several hours. cannot be applied to On the other hand, if the reaction is carried out under mild conditions, the acylation reaction will not proceed. Although the general formula () is a type of thioester, the fact that it is the most reactive reagent under mild conditions is completely unexpected and truly surprising.

In the case of the general formula () which is the raw material compound of the present invention, for example, an acetoxy group bonded to the 3-methyl group of 7-aminocephalosporanic acid, in a water-containing organic solvent, pH 6.0 to 8.5, reaction temperature 50 ° C. At 80°C, it becomes the highest leaving group. Other halogens and azide groups bonded to the 3-position can also be removed under similar conditions.

Also, 7-amino-3-(benzimidazole-2
-yl)thiomethyl-3-cephem-4-carboxylic acid is characterized in that the benzimidazol-2-yl-thio group bonded to its 3-position methyl group is an extremely reactive leaving group in the presence of protons. be. The elimination reaction is thought to be catalyzed by protons, and the protons of thiols present in the reaction system are utilized, so it is not necessarily necessary to add a new acid catalyst. Similar substituents that bond to the 3-position methyl group include benzthiazolethio group and benzoxazolethio group, and in fact, the reaction proceeds even with these substituents, but benzimidazole-thio group is particularly effective in terms of stability and reactivity. The 2-yl-thio group exhibits excellent effects. Since this substituent undergoes an extremely fast substitution reaction in the stable acidic region of the cephalosporin compound, it is 1.5 times more effective in terms of yield than, for example, an acetoxy group.

General formula (), for example 7-aminocephalosporanic acid, is easily available commercially. In addition, 7-amino-3-(benzimidazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid is already used as a polymer deterioration inhibitor with commercially available 7-aminocephalosporanic acid and is commercially available at low cost. There 2
-obtained by reacting mercaptobenzimidazole by known methods. Or 7-
(Glutaramide)-cephalosporanic acid and 2-mercaptobenzimidazole are reacted, and then the amide bond at the 7-position side chain is cleaved using Comamonas acylase, which is disclosed in JP-A-50-101584. You can get it even if you twist it.

The other raw material, the compound represented by the general formula (), is the compound represented by the general formula () ( _R2 in the formula is hydrogen, methyl group, carboxymethyl group, or sulfonate methyl group) Mandelic acid, 1-substituted or unsubstituted tetrazole-5-thiols, or derivatives thereof; Alternatively, it can be produced in high yield by reacting with a derivative thereof in a solution at -50°C to 100°C.

The thus obtained compound represented by the general formula () or its salt is reacted with the compound represented by the general formula () in a solvent to easily and efficiently produce the target compound represented by the general formula (). A cephalosporan compound or a pharmaceutically acceptable salt thereof can be derived.

The amount of the compound represented by the general formula () may be at least equimolar to the compound represented by the general formula (), and is preferably from 1.0 mol to 2.0 mol from the economic point of view.

Examples of solvents include amides such as N·N-dimethylformamide, N·N-diethylformamide, N·N-dimethylacetamide, and N·N-diethylacetamide, alcohols such as methyl alcohol and ethyl alcohol, acetone, methyl ethyl ketone, etc. fatty acid ketones, ethers such as methyl cellosolve, halogenated hydrocarbons such as dichloromethane and chloroform, acetonitrile,
There are nitriles such as propionitrile, sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide, and these can be used alone or as a mixed solvent, or as a water-containing solvent. Among these solvents, 7-aminocephalosporan In the case of acids, in particular the use of acetone, acetonitrile, methyl alcohol or their aqueous solvents, and in the case of 7-amino-3-(benzimidazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid, in particular N・N-dimethylformamide, N・N
- Use of amides such as dimethylacetamide or their water-containing solvents is particularly preferred in terms of solubility, reaction rate, and economy.

When using a compound represented by the general formula (), for example, 7-amino-3-(benzimidazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid, there is a characteristic that the reaction system contains a compound generated from this compound. Since there are thiol compounds and thiol compounds generated by the substitution reaction, it is not necessarily necessary to add a new acid catalyst, but it is better to add an acid catalyst from the viewpoint of shortening the reaction time and improving the reaction yield. good. 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-mercapto-tetrazole. Mineral acids and thiols are preferred from the viewpoint of yield and shortening reaction time.

It is sufficient that the amount of the acid catalyst is substantially 0.05 times mole or more relative to 7-amino-3-(benzimidazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid.

The reaction temperature varies depending on the type of solvent, etc.
A temperature in the range of 10°C to 100°C is usually sufficient, and a range of 40°C to 80°C is particularly preferable in view of the reaction rate, stability of the cephalosporin skeleton, etc.

The reaction time varies depending on the type of R ₁ bonded to the 3-position methyl group in general formula (), the type of solvent, etc., but a range of 30 minutes to 10 hours is usually sufficient. For example, 7-amino-3-(benzimidazole-2
-yl)thiomethyl-3-cephem-4-carboxylic acid, the reaction at 60°C under an acid catalyst in water-containing N/N-dimethylformamide takes 30 minutes to 30 minutes.
Time is enough. Conventionally, when the 7-position acylation reaction and the 3-position substitution reaction were performed consecutively, it required 8 to 18 hours, but considering the side reactions with the reaction reagent and the decomposition of the product, the method of the present invention is extremely simple and economical. Excellent in sex.

In the present invention, the thus obtained cephalosporin compound represented by the general formula () is
It can be converted into a pharmaceutically acceptable salt if desired. This conversion into salts can be conducted to alkali metal salts, ammonium salts, and alkaline earth metal salts by conventional methods. These salts exhibit excellent pharmaceutical properties, for example, in terms of solubility in water.

The compound of the general formula () in the present invention is a light brown crystal, and is not hygroscopic, irritating, or corrosive, so it is extremely easy to handle during production, and it improves the safety of the working environment and workers, as well as the safety of equipment. Extremely high security. Therefore, only the compound of the present invention is a truly excellent compound in practical use, and the compound of the general formula () is an excellent antibiotic having strong antibacterial activity by the method of the present invention.
The cephalosporan compound represented by or a pharmaceutically acceptable salt thereof can be safely produced in high yield.

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

Example 1 7-
Amino-3-(benzimidazol-2-yl)
Thiomethyl-3-cephem-4-carboxylic acid 18.1
g, N・N-dimethylformamide 500ml and water 500ml
ml, heat to 60℃ and stir. Then 14.2 g of mandelic acid-1H-tetrazol-2-yl-thiol ester are added. Further, 20 ml of 0.5N hydrochloric 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 by high performance liquid chromatography, the reaction rate was 88%. After the reaction solution was cooled and impurities were removed with ether in a conventional manner, the pH was lowered to 1.5 with 1N hydrochloric acid and extracted three times with ethyl acetate (1). The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure, yielding 7-mandelamide-3-
(1H-tetrazol-2-yl)thiomethyl-3
-Cefem-4-carboxylic acid 15.7 g of white powder (purity 97%) was obtained.

Elemental analysis value Actual value Theoretical value C 45.7% 45.5% H 3.3% 3.6% N 18.7% 18.8% S 14.1% 14.3% NMR spectrum (in D ₂ O-NaHCO ₃ ) δppm 3.5 (s 2H) 4.5 (s 2H) 5.0 (d 1H) 5.6 (d 1H) 6.1 (s 1H) 7.3 (m 5H) 9.2 (s 1H) 10.7 (s 1H) Example 2 Into a three-necked flask equipped with a thermometer, add 7-
Aminocephalosporanic acid 27.2g, acetone 1.1
Add 0.9 g of water and heat to 60℃ with stirring. Then 28.3 g of mandelic acid-1H-tetrazol-2-yl-thiol ester are added. Heat the reaction solution to 60℃
The reaction was completed by stirring for 4.5 hours. When the reaction solution was quantified using high performance liquid chromatography,
The reaction rate was 57%. After cooling the reaction solution and removing impurities with ether in a conventional manner, the pH was lowered to 1.5 with 1N hydrochloric acid and extracted three times with ethyl acetate (2). The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to yield 7-mandelamide-3-(1H-tetrazol-2-yl).
Thiomethyl-3-cephem-4-carboxylic acid 20.4
g of white powder was obtained (purity 96%).

Example 3 Into a three-necked flask equipped with a thermometer, 7-
Amino-3-(benzimidazol-2-yl)
Thiomethyl-3-cephem-4-carboxylic acid 36.2
g, N.N-dimethylformamide 1 and water 1
and stir to heat to 60℃. Next, mandelic acid-
Add 30.0 g of 1-methyl-tetrazol-2-yl-thiol ester. Further, 100 ml of 0.5N hydrochloric acid water was added as a reaction catalyst, and the mixture was stirred at 60°C for 3 hours to complete the reaction. When the reaction solution was quantitatively determined using high performance liquid chromatography, the reaction rate was 93%. After cooling the reaction solution and removing impurities with ether in a conventional manner, the pH was lowered to 1.5 with 1H-hydrochloric acid and extracted three times with ethyl acetate (2). The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to yield 7-mandelamide-3-(1
33.1 g of white powder (purity 97%) was obtained.

Elemental analysis value Actual value Theoretical value C 46.5% 46.8% H 3.7% 3.9% N 18.5% 18.2% S 14.1% 13.9% NMR spectrum (in D ₂ O-NaHCO ₃ ) δppm 3.5 (s 2H) 5.6 (d 1H) 3.8 (s 3H) 6.1 (s 1H) 4.5 (s 2H) 7.3 (m 5H) 5.0 (d 1H) 10.7 (s 1H) Example 4 Into a three-necked flask equipped with a thermometer, add 7-
Aminocephalosporanic acid 27.2g, acetone 1.1
Add 1 part of water and heat to 60°C with stirring. Next, 30.0 g of mandelic acid-1-methyl-tetrazol-2-yl-thiol ester is added. reaction solution
The reaction was completed by stirring at 60°C for 4 hours. When the reaction solution was quantified by high performance liquid chromatography, the reaction rate was 53%. After cooling the reaction solution and removing impurities with ether in a conventional manner, the pH was lowered to 1.5 with 1N hydrochloric acid and extracted three times with ethyl acetate (2). The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 7-mandelamide-3-(1-methyl-tetrazole-2).
18.4 g of white powder (purity 98%) was obtained.

Example 5 In a 300ml three-necked flask equipped with a thermometer, 7
-amino-3-(benzimidazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid
Add 3.62 g, 100 ml of N.N-dimethylformamide and 100 ml of water, and heat and stir at 60°C. Next, mandelic acid-1-carboxymethyl-tetrazole-
Add 3.5 g of 2-yl-thiol ester.
Furthermore, 10ml of 0.5N hydrochloric acid was added as a reaction catalyst.
The reaction was completed by stirring at 60°C for 2.5 hours. When the reaction solution was quantified by high performance liquid chromatography, the reaction rate was 89%. After cooling the reaction solution and removing impurities with ether in a conventional manner,
The pH was lowered to 1.5 with hydrochloric acid water and extracted three times with 200 ml of acetic acid ethyl ester. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure, yielding 3.5 g of 7-mandelamido-3-(1-carboxymethyl-tetrazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid. A white powder was obtained (purity
98%).

Elemental analysis value Actual value Theoretical value C 45.5% 45.1% H 3.3% 3.6% N 16.8% 16.6% S 12.9% 12.6% Example 6 In a three-necked flask equipped with a thermometer, 7-
Amino-3-chloromethyl-3-cephem-4-
Add 12.4 g of carboxylic acid, 500 ml of acetone, and 500 ml of water, and heat to 60°C with stirring. Next, mandelic acid-1-
17.6 g of carboxymethyl-tetrazol-2-yl-thiol ester are added. Heat the reaction solution to 60℃
The mixture was stirred for 4 hours to complete the reaction. When the reaction solution was quantitatively determined using high performance liquid chromatography, the reaction rate was 51%. After cooling the reaction solution and removing impurities with ether using a conventional method, the reaction solution was diluted with 1N acid water.
The pH was lowered to 1.5 and extracted three times with ethyl acetate (1). The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure, yielding 10.3 g of 7-mandelamido-3-(1-carboxymethyl-tetrazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid. A white powder was obtained (purity 97%).

Example 7 7-
Amino-3-(benzimidazol-2-yl)
Thiomethyl-3-cephem-4-carboxylic acid 18.1
g, N・N-dimethylacetamide 500ml and water 500ml
ml and heat and stir at 60℃. Then 16.5 g of mandelic acid-1-sulfonic acid methyl-tetrazol-2-yl-thiol ester are added. Furthermore, as a reaction catalyst, 20 ml of 0.5N hydrochloric acid was added and heated to 60°C.
The mixture was stirred for 3 hours to complete the reaction. When the reaction solution was quantified using high performance liquid chromatography, the reaction rate was 91%. After cooling the reaction solution and removing impurities with ether in a conventional manner, the pH was lowered to 1.5 with 1N-hydrochloric acid, and 3% with 1 part of acetic acid ethyl ester.
Extracted twice. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 7-mandelamide-3-(1-methyl-sulfonate methyl-tetrazol-2-yl)thiomethyl-3-cephem-
19.3 g of 4-carvone white powder was obtained (purity 97
%).

Elemental analysis value Actual value Theoretical value C 39.7% 39.9% H 3.1% 3.3% N 15.7% 15.5% S 17.9% 17.7% Example 8 Into a three-neck flask No. 3 equipped with a thermometer, 7-
Amino-3-azidomethyl-3-cephem-4-
25.5 g of carboxylic acid, 1 part of acetonitrile and 0.9 of water
Add and heat to 60℃ with stirring. Next, 33.0 g of mandenic acid-1-sulfonic acid methyl-tetrazol-2-yl-thiol ester are added. The reaction solution was stirred at 60° C. for 5 hours to complete the reaction. When the reaction solution was quantified by high performance liquid chromatography, the reaction rate was 52%. After cooling the reaction solution and removing impurities with ether in a conventional manner,
The pH was lowered to 1.5 with 1N hydrochloric acid and extracted three times with ethyl acetate (2). The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure.
17.6 g of white powder of -mandelamide-3-(1-methyl-tetrazol-2-yl sulfonate) thiomethyl-3-cephem-4-carboxylic acid was obtained (purity 98%).

Claims (1)

[Claims] 1 General formula () (R ₁ in the formula is a halogen, an azide group, an acetoxy group, or a benzimidazole thio group) and a 7-aminocephalosporanic acid derivative or a salt thereof represented by the general formula () ( _R2 in the formula is hydrogen, methyl group, carboxymethyl group, or sulfonic acid methyl group) React with 1-substituted or unsubstituted tetrazol-5-yl-thiol esters of mandelic acid represented by A general formula () characterized by (In the formula, R ₂ is the same as above.) A method for producing a cephalosporin compound or a pharmaceutically acceptable salt thereof.