KR870001984B1 - Process for preparing cephem derivatives - Google Patents

Abstract

Title compds. I [R1=H, metal salts; R2=H, acetoxymethyl, (1methyl-1H- tetrazol-5-yl) thiomethyl, etc. , useful as an antimicrobial agent, are prepd. Thus, a mixt. contg. 5.44g 7aminocephalosporanic acid, 100ml H2O, 40ml N,N-dimethyl-foramide, and 2.4g NaHCO3 is stirred for 10min, cooled to 10≰C, and treated with 7.87g 1-[α -syn-methoxyimino-α-(2-amino-thiazol-4-yl)acetyl -benzotriazol-3-oxide in 40ml N,N- dimethyl formamide. After 4h stirring, the reaction mixt. is reacted with 150ml ethylacetate twice to give 7.98g 7-[[2-2-(2-amino-thiazol-4- yl)-2-synmethoxyimino acetamido! cephalosporanic acid.

Description

Simple Method of Making Cemfe Derivatives

The present invention relates to a novel process for preparing β-lactam derivatives having the following structural formula (I) useful as an antimicrobial agent.

In the above formula,

R ¹ means hydrogen or a metal salt,

R ² is hydrogen, acetoxymethyl, (1-methyl-1H-tetrazol-5-yl) thiomethyl or (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-tri Azin-3-yl) thiomethyl.

The present invention relates to a novel method for the preparation of cephalosporan acid derivatives, including a wide range of strains (eg Streptopococcus, Escherichia coli, Furoteus, Shigella, Salmonella, Klebsiella, Serata, Neisseria, etc.). An economical method for producing β-lactam derivatives exhibiting strong anti-microbial effects against) is provided.

Various methods for the preparation of semi-synthetic β-lactam antibiotics have been published in the literature and patents, and include 7-aminodeoxycephalosporranic acid (7-ADCA) and 7-aminocephalosporranic acid (7-ACA). The derivatives have been condensed with reactive derivatives of organic acids to form peptide bonds to produce various β-lactam antibiotics.

Existing methods for preparing acylates of structural formula (I) have been introduced into the structural formula (II) to protect the amine groups, and then convert organic acids to reactive derivatives to carry out acylation reactions. Reactive esters and reactive amides.

Methods for preparing acid chlorides of organic acids (II) are reported in Japanese Patent Application Laid-Open Nos. 77-102293, 78-68796, 78-34795, 79-52096, 79-157596 and British Patent 2025933. (II) was prepared using the thionyl chloride (SOCl ₂ ), phosphorus pentachloride (PCl ₅ ), phosphorus oxychloride (POCl ₃ ) and the like to prepare an acid chloride of organic acid (II), and then using 7-ADCA or 7 After the acylation reaction with -ACA, the protecting group R was removed to prepare a compound of formula (I). However, these methods are difficult to react, require more amino protecting step and amino protecting group removal process, and have the disadvantage that the acid chloride is not stable.

As a method for preparing a compound of structural formula (I) by preparing a reactive ester of an organic acid (II) to undergo an acylation reaction, it has been reported in Japanese Patent Application Laid-Open Nos. 79-95593, 77-102293, 81-152488, and the like. According to the formula (II), 2-pyridine thiester, 2-benzo thiazole ester, and 1-hydroxybenzotriazole ester of the compound of formula (II) were prepared as a reactive derivative to undergo acylation reaction. Although it has been prepared, there are drawbacks with side reactions and low yields in the preparation of esters, and it takes a long time for the acylation reactions. There is also a method using acid amide and mixed acid anhydride, but has the same problem as the above method. When the acylation reaction is carried out using such a conventional reactive derivative, the amine group of the structural formula (II) compound is first protected by R, and a reactive derivative such as an acid chloride or a reactive ester is prepared. There is a hassle to remove.

The present invention provides a method of selectively preparing only a solvate of a new reactive amide immediately without protecting the amine group of the compound of formula (II), and simply providing an acylation reaction in a high yield. A method of using 1-hydroxybenzotriazole ester and its amide is reported in Japanese Patent Laid-Open No. 79-95593, in which the reactive ester of the structural formula and the compound of the structural formula Generated and the reactive ester of formula (V) is very unstable and readily decomposes into the acid of formula (II) and the alcohol of formula (V), which makes it difficult to separate and acylate.

The present inventors have conducted a long study, and reacted the dialkyl (or diaryl) chlorothio phosphate of formula (IV) with 1-hydroxybenzotriazole of formula (V) to make a compound of formula (VI) By reacting the organic acid of formula (II), only the reactive amide of formula (V) can be selectively obtained in high yield in the form of a solvate, and the solvate of the reactive amide is reacted with the compound of formula (III) at room temperature. The present invention has been accomplished by finding a method for preparing acylate (I) in high yield and for easy separation.

Accordingly, it is an object of the present invention to provide compounds of formula (VI) resulting from the reaction of dialkyl (diaryl) chlorothiophosphate of formula (IV) with 1-hydroxybenzotriazole of formula (V). A new acylation method is prepared by reacting an organic acid to prepare a solvate of a compound of formula (IV), which is a novel reactive amide, and reacting the solvate with a compound of formula (III) to produce a compound of formula (I) in high yield. It is.

Examples of the alkyl group represented by R ⁴ in this specification are ethyl, and an example of an aryl group is phenyl.

The process of the present invention is represented by the following scheme.

Wherein R ¹ , R ² , R ⁴ are as described above.

Among these reactions, solvents for preparing the dialkyl (or diaryl) 1-hydroxybenzotriazolylthiophosphate of formula (VI) include tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide And the like are preferred, of which tetrahydrofuran is most suitable. Bases used include triethylamine, trimethylamine, pyridine and the like, of which triethylamine is most suitable. The new dialkyl (or diaryl) 1-hydroxybenzotriazolylthiophosphate of formula (VI) is unstable and is reacted with a solution of the organic acid of formula (II) without separation in solution, where a solvent is used to dissolve the organic acid. Suitable examples are N, N-dimethylformamide and N, N-dimethylacetamide. Bases used include triethylamine, trimethylamine, pyridine and the like, of which triethylamine is most suitable. The reaction usually proceeds at room temperature and within 1-2 hours solvates of the reactive amides are obtained by precipitation.

Next, the acylation reaction for preparing compound (I) is carried out in a mixed solution of a basic aqueous solution and an organic solvent, and bases used include sodium bicarbonate, potassium bicarbonate, triethylamine, sodium carbonate, potassium carbonate, and the like. It is preferable to use double sodium bicarbonate. As the organic solvent, acetonitrile, acetone, ethyl acetate, tetra hydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, dioxane, etc. are used, among which acetonitrile, acetone, tetrahydro Furan and N, N-dimethylformamide are suitable. In the reaction performance method, the structural formula (III) compound is dissolved in the basic aqueous solution, an organic solvent is added thereto, and then a reactive amide solvate is added to a crystalline state and stirred at room temperature for 1-5 hours to proceed quantitatively.

Next, the organic solvent was distilled off under reduced pressure, the by-product 1-hydroxybenzotriazole was removed by adjusting the pH of the water layer to 4.0, the water layer was saturated with salt, and then the pH was adjusted to an isoelectric point by adding ethyl acetate and stirring. The lower surface of the compound of formula (I) is obtained by precipitation. The amount of water and organic solvent used in this reaction is 10 to 30 times as appropriate for the compound of formula (III), and the ratio of water and organic solvent is 2: 1 to 1: 2.

The present invention has the following advantages compared to the conventional acylation method.

1. A novel, low-cost, readily available dialkyl (or diaryl) dialkyl (or diaryl) 1-hydride of the formula (VI) produced by the reaction of 1-hydroxybenzotriazole with dialkyl (or diaryl) chlorothiophosphate. The solvate of the reactive amide is prepared in high yield using oxybenzotriazolylthiophosphate,

2. Since the solvate of this reactive amide is extremely soluble in various organic solvents, the acylation reaction proceeds uniformly and the reaction is completed in a short time.

3. Unlike acid chlorides or mixed acid anhydrides, solvates of reactive amides are very stable at room temperature and can be commercialized.

4. There is an advantage that the reaction can be carried out at room temperature,

5. Since the reaction proceeds almost quantitatively without side reactions without protecting the amino group, there is no inconvenience of protecting the amine group of the amino acid and then removing the protecting group again.

6. When the reaction is completed, the target compound can be easily separated in aqueous solution.

The manufacturing facility is simpler than the existing method and there is no complicated process, thus providing an economical and new method of acylation.

The following examples illustrate the method of the invention in more detail, and these examples do not limit the invention.

Example 1

13.5 g (0.1 M) of 1-hydroxybenzotriazole is completely dissolved in 80 ml of tetrahydrofuran and 16.8 ml (0.12 M) of triethylamine, and 20.8 g (0.11 M) of diethylchlorothiophosphate is added thereto. As the reaction proceeds, triethylamine hydrochloride precipitates as crystals. The reaction solution was stirred at room temperature for 1 hour, and the precipitate formed was filtered and washed with 20 ml of tetrahydrofuran. 20.1 g (0.1 M) of 2- (2-aminothiazol-4-yl) -2-syn-methoxyiminoacetic acid in 100 ml of N, N-dimethylformamide and 13.9 mg (0.1 M) of triethylamine Was added dropwise to the tetrahydrofuran solution prepared above for 10 minutes.

After stirring the reaction solution at room temperature for 1 hour, crystals start to form. After stirring for 1 hour at room temperature and stirring for 2 hours at 0-5 ° C, and filtered, the reactive amide 1- [α-syn-methoxyimino-α- (2-aminothiazol-4-yl) acetyl]- Obtain a DMF solvate of benzotriazole-3-oxide.

Yield: 36.0 g (92%)

IR (KBr, cm ^-1 ): 1730

NMR (DMSO-d ₆ , δ, ppm): 2.27 (3H, s, -N-CH ₃ ), 2.90 (3H, s, -N-CH ₃ ),

3.90 (3H, s, -OCH ₃ ), 7.07 (1H, s, chiazole-H), 7.13 (2H, s, -NH ₂ ), 7.5-8.5 (4H, m, benzotriazole-H), 7.97 (1H, s,

mp (° C): 156-159 (decomposition)

Example 2

Instead of tetrahydrofuran, the reaction was carried out in the same manner as in Example 1 using N, N-dimethylformamide (DMF) as a solvent, and the reactive amide 1- [α-syn-methoxyimino-α- ( DMF solvate of 2-aminothiazol-4-yl) -acetyl] -benzotriazole-3-oxide is obtained.

Yield: 34.4 g (88%)

IR and NMR data are the same as in Example 1.

Example 3

The reaction was carried out in a manner similar to that of Example 1, using 31.3 g (0.11 M) of diphenylchlorothiophosphate instead of diethylchlorothiophosphate to give 1- [α-syn-methoxyimino-α- (2-amino Obtain a DMF solvate of chiazol-4-yl) -acetyl] -benzotriazole-3-oxide.

Yield: 36.4 g (93%)

IR and NMR data are the same as in Example 1.

Example 4

Instead of tetrahydrofuran and N, N-dimethylformamide, the reaction was carried out in the same manner as in Example 1 using N, N-dimethylacetamide in the same amount, and 1- [α-syn-methoxyimino-α- ( A DMA solvate of 2-aminothiazol-4-yl) -acetyl] -benzotriazole-3-oxide is obtained.

Yield: 34.4 g (85%)

IR (KBr, cm ^-1 ): 1730 (amide carbonyl), 1655 (DMA carbonyl)

, 2.30(3H,s,-N-CH₃), 2.95(3H,s,-N-CH₃), 3.95(3H,s,-OCH₃), 7.10(1H, 치아졸-H), 7.20(2H,s,-NH₂), 7.4-8.4(4H, m, 벤조트리아졸-H)NMR (DMSO-d ₆ δ, ppm):

, 2.30 (3H, s, -N-CH ₃ ), 2.95 (3H, s, -N-CH ₃ ), 3.95 (3H, s, -OCH ₃ ), 7.10 (1H, chiazole-H), 7.20 ( 2H, s, -NH ₂ ), 7.4-8.4 (4H, m, benzotriazole-H)

mp (℃): 157-160 (decomposition)

Example 5

5.4 g of 7-aminocephalosporranic acid was turbid in 100 ml of water and 200 ml of acetonitrile, 2.4 g of sodium bicarbonate was added thereto, and stirred at room temperature for 10 minutes to dissolve completely.

6.40 g of a DMF solvate of 1- [α-syn-methoxyimino-α- (2-aminothiazol-4-yl) -acetyl] -benzotriazole-3-oxide prepared in Example 1 was added thereto. After the addition and stirring at room temperature for 4 hours, the reaction is completed. The acetonitrile in the solution was distilled off under reduced pressure, the mixture was adjusted to pH 4.0 with 2N hydrochloric acid while cooling to 0-5 ° C, stirred for 1 hour, and the crystals were filtered off. Saturate the filtrate with salt, add 120 ml of ethyl acetate and adjust to pH 2.5 with 2N hydrochloric acid under vigorous stirring to produce an off-white precipitate. After stirring for 1 hour, the mixture was filtered and dried to give the desired 7-[[2- (2-aminothiazol-4-yl) -2-syn-methoxy imino] acetamido] cephataxanoic acid (cefotaxime). Get

Yield: 8.65 g (95%)

IR (KBr, cm- ¹ ): 1780 (β-lactamcarbonyl)

, 3.53(2H,d,C₂-H), 4.02 (3H,s, -OCH₃), 4.84(2H,d,3-CH₂-), 5.20(1H,d,C₆-H), 5.82(1H,d,C₇-H), 6.97(1H,s, 치아졸-H).NMR (D ₂ O / NaHCO ₃ , δ, ppm):

, 3.53 (2H, d, C ₂ -H), 4.02 (3H, s, -OCH ₃ ), 4.84 (2H, d, 3-CH _2- ), 5.20 (1H, d, C ₆ -H), 5.82 (1H, d, C ₇ -H), 6.97 (1H, s, chiazole-H).

Example 6

Tetrahydrofuran was used in place of acetonitrile and reacted in the same manner as in Example 5 to obtain the desired 7-[[2- (2-aminothiazol-4-yl) -2-syn-methoxyimino] acetamido. Get cephalosporan acid.

Yield: 8.44 g (93%)

IR and NMR are the same as in Example 5.

Example 7

Using the same amount of acetone instead of acetonitrile, the reaction was carried out by the method of Example 5 to obtain the desired 7-[[2- (2-aminothiazol-4-yl) -2-syn-methoxyimino] acetamido] Obtains palosporranic acid.

Yield: 8.26 g (91%)

IR, NMR are the same as in Example 5.

Example 8

5.44 g of 7-aminocephalosporranic acid was turbid in 100 ml of water and 40 ml of N, N-dimethylformamide, 2.4 g of sodium bicarbonate was added thereto, stirred at room temperature for 10 minutes, dissolved, and cooled to 10 ° C or lower. 7.87 g of DMF solvate of 1- [α-syn-methoxyimino-α- (2-aminothiazol-4-yl) acetyl] -benzotriazole-3-oxide was added to N, N-dimethylformamide. The solution dissolved in 40 ml was added dropwise over 10 minutes.

When the above solution is stirred at room temperature for 4 hours, the reaction is completed. 150 ml of ethyl acetate was extracted twice with N, N-dimethylformamide in the reaction solution, and the water layer was saturated with sodium chloride. The solution was cooled to 5 ° C., adjusted to pH 4.0 with 2N-HCl, stirred for 1 hour, the insolubles were filtered off, and the filtrate was adjusted to pH 2.5 again to obtain an off-white precipitate. After stirring for 1 hour, filtered, washed with a small amount of water and dried to obtain 7-[[2- (2-aminothiazol-4-yl) -2-syn-methoxyimino] acetamido] cephalosporonic acid Get

Yield: 7.98 g (88%)

IR, NMR are the same as in Example 5.

Example 9

Instead of N, N-dimethylformamide, the same amount of N, N-dimethylacetamide was used as the reaction of Example 8 to react with the desired 7-[[2-2-aminothiazol-4-yl) -2-syn -Methoxyimino] acetamido] cephalosporan acid is obtained.

Yield: 7.96 g (88%)

IR, NMR are the same as in Example 5.

Example 10

The reaction was carried out for 3 hours in the same manner as in Example 5 using 8.10 g of the DMA solvent prepared in Example 4 to obtain 7-[[2- (2-aminothiazol-4-yl) -2-syn-methoxy. Mino] Acetamido] Obtain cephalosporanic acid.

Yield: 8.92 g (98%)

IR, NMR are the same as in Example 5.

Example 11

3.28 g of 7-amino [3- (1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cepem-4-carboxylic acid was turbid in 35 ml of water, and 2.0 g of sodium hydrogencarbonate was added thereto at room temperature. After stirring for 20 minutes to dissolve, 40 ml of acetonitrile were added and cooled to 10 ° C. 4.68 g of a DMF solvate of 1- [α-syn-methoxyimino-α- (2-aminothiazol-4-yl) -acetyl] -benzotriazole-4-oxide prepared in Example 1 was added thereto. Add Stirring at room temperature for 5 hours results in a clear solution and completes the reaction. The acetonitrile in the solution was distilled off under reduced pressure, 40 ml of water was added to the water layer, and the mixture was adjusted to pH 3.8 with 2N-HCl, stirred for 1 hour, and then the crystals were filtered off. The filtrate is saturated with sodium chloride and adjusted to pH 2.7 with 2N-HCl to precipitate in the crystals. Stir at 5 ° C. for 2 hours and filter to give the desired 7-[[2- (2-aminothiazol-4-yl) -2-syn-methoxyimino] acetamido] -3-[(1- Methyl-1H-tetrazol-5-yl) thiomethyl] -3-cepem-4-carboxylic acid (Cefmenoxime).

Yield: 4.65 g (91%)

IR (KBr, cm- ¹ ): 1780 (β-lactamcarbonyl)

NMR (D ₂ O / NaHCO ₃ , δ): 3.84 (2H, d, C ₂ -H), 4.01 (3H, s, -OCH ₃ ), 4.05 (3H, s, N-CH ₃ ), 5.20 (1H , d, C ₆ -H), 5.77 (1H, d, C ₇ -H), 7.01 (1H, s, chiazole-H)

Example 12

40 ml of ethyl acetate instead of acetonitrile was reacted in the same manner as in Example 11 to obtain the desired 7-[[2- (2-aminothiazol-4-yl) -2-syn-methoxyimino] acetamido] Obtain 3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cefe-4-carboxylic acid.

Yield: 4.60 g (90%)

IR, NMR are the same as in Example 11.

Example 13

4.05 g of the DMA solvate prepared in Example 4 was reacted for 3 hours in a similar manner to Example 11 to obtain 7-[[2- (2-aminothiazol-4-yl) -2-syn-methoxyimino Acetamido] -3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cefe-4-carboxylic acid.

Yield: 4.97 g (94%)

IR, NMR data are the same as in Example 11.

Example 14

7-amino-3- (2,5-dihydro-2-methyl-6-hydroxy-5-oxo-as-triazin-3-yl) thiomethyl-3-cepem-4-carboxylic acid 3.71 g Was dissolved in 40 ml of water and 30 ml of tetrahydrofuran and dissolved by adding 2.7 g of sodium bicarbonate to obtain a clear solution of pH 8.0-8.2. To this was added 4.68 g of a DMF solvate of 1- [α-syn-methoxyimino-α- (2-aminothiazol-4-yl) -acetyl] -benzotriazole-3-oxide and 1 hour at 5 ° C. After stirring, the temperature was raised to 25 ° C. and stirred for 5 hours to complete the reaction. Tetrahydrofuran in solution was evaporated under reduced pressure, and 30 ml of water was added thereto and cooled to 5 ° C. The mixture was adjusted to pH 4.2 with 2N-HCl, stirred for 30 minutes, and the produced insolubles were removed by filtration. Saturate the filtrate with sodium chloride and adjust again to pH 2.9-3.0 with 2N-HCl to form a precipitate. Stirring at constant pH for 2 hours, filtered and dried to give the desired 7-[[2- (2-aminothiazol-4-yl) -2-syn-methoxyimino] acetamido] -3- [(2,5-Dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thiomethyl] -3-cepem-4-carboxylic acid is obtained.

Yield: 4.70 g (85%)

IR (KBr, cm ^-1 ): 1780

N-CH₃), 3.95(3H, s, -OCH₃), 4.21(2H, d, -S-CH₂-), 5.17(1H, d, C₆-H), 5.72(1H, d, C₇-H), 6.95(1H, s, 치아졸-H)NMR (D ₂ O / NaHCO ₃ , δ): 3.20 (2H, d, C ₂ -H), 3.62 (3H, s,

N-CH ₃ ), 3.95 (3H, s, -OCH ₃ ), 4.21 (2H, d, -S-CH _2- ), 5.17 (1H, d, C ₆ -H), 5.72 (1H, d, C _7- H), 6.95 (1H, s, Chiazole-H)

Example 15

The desired 7-[[2- (2-aminothiazol-4-yl) -2-syn-methoxyimino] acetamido was reacted by the method of Example 14 using 40 ml of acetonitrile instead of tetrahydrofuran. ] -3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) -thiomethyl] -3-cef-4-carboxylic acid Get

Yield: 4.50 g (81%)

IR, NMR are the same as in Example 14.

Example 16

Using 4.05 g of the DMA solvate prepared in Example 4 and reacting for 4 hours by the method of Example 14, 7-[[2- (2-aminothiazol-4-yl) -2-syn-methoxyimino Acetamido] -3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thiomethyl] -3-cepem-4-carboxylic acid Get

Yield: 5.27 g (91%)

IR, NMR data are the same as in Example 14.

Example 17

1.88 g of 7-amino-3-cepem-4-carboxylic acid is turbid in 20 ml of water and 20 ml of tetrahydrofuran, 2.0 g of sodium bicarbonate is added to dissolve, and cooled to 5 ° C. To this was added 3.91 g of a DMF solvate of 1- [α-syn-methoxyimino-α- (2-aminothiazol-4-yl) -acetyl] -benzotriazole-3-oxide over 10 minutes. . Then, the reaction is completed by stirring at 5 ° C for 1 hour and at 25 ° C for 2 hours.

Tetrahydrofuran in solution is evaporated under reduced pressure, and 15 ml of water is further added and cooled to 5 ° C. The mixture was adjusted to pH 4.2 with 2N-HCl, stirred for 30 minutes, and the produced insolubles were removed by filtration. Saturate the filtrate with sodium chloride and adjust again to pH 2.8 with 2N-HCl to form a precipitate. After stirring for 2 hours while maintaining a constant pH under ice cooling, and filtered. After washing with saturated brine and cooling water and drying, the desired 7-[[2- (2-aminothiazol-4-yl) -2-syn-methoxyimino] acetamido] -3-cepem-4-carboxylic acid Get

Yield: 3.48 g (91%)

IR (KBr, cm ^-1 ): 1780, 1695, 1655

NMR (DMSO-d ₆ , δ): 3.60 (2H, broad, C ₂ -H), 3.84 (3H, s, -OCH ₃ ), 5.12 (1H, d, C ₆ -H), 5.84 (1H, dd , C ₇ -H), 6.52 (1H, s, 3-H), 6.76 (1H, s, chizol-H), 7.26 (2H, broad, -NH ₂ ), 9.65 (1H, d, -NH- CO-)

Example 18

20 ml of acetone instead of tetrahydrofuran was reacted by the method of Example 17 to obtain the desired 7-[[2- (2-aminothiazol-4-yl) -2-syn-methoxyimino] acetamido] Obtain -3-cefe-4-carboxylic acid.

Yield: 3.40 g (90%)

IR, NMR are the same as in Example 17.

Example 19

Using 4.05 g of the DMA solvate prepared in Example 4, the reaction was carried out for 3 hours in the same manner as in Example 17 to obtain 7-[[2-aminothiazol-4-yl) -2-syn-methoxyimino] acetami Fig.]-3-cepem-4-carboxylic acid is obtained.

Yield: 5.27 g (94%)

IR and NMR data are the same as in Example 17.

Claims (1)

(Correction) By reacting the dialkyl (or diallyl) chlorothio phosphate of formula (IV) with 1-hydroxybenzotriazole of formula (V) and the organic acid of formula (II) A method of producing the compound of formula (I) by subjecting the solvate of the reactive amide of formula (III) to an acylation reaction with the compound of formula (III).

In the above formula, R ¹ is hydrogen or alkali metal or alkaline earth metal: R ² is hydrogen, acetoxymethyl, (1-methyl-1H-tetrazol-5-yl) thiomethyl or (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-tri Azin-3-yl) thiomethyl. R ⁴ means ethyl or phenyl