JPH0322391B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION TECHNICAL FIELD The present invention relates to a method of producing cephalosporin, an antibiotic used in human and veterinary medicine.
The present invention relates to a method for producing an aminocephalosporanic acid solution.

BACKGROUND ART A known method for producing a 7-aminocephalosporanic acid solution that is used industrially is to react the above acid with a tertiary amine, preferably triethylamine, in an aqueous medium of water-acetone or methylene chloride. It becomes more.

The use of water-organic solvent miscible systems has the following disadvantages.

1 The acylating agent, acid chloride anhydride or mixed anhydride, undergoes partial hydrolysis.

2. Antibiotics are difficult to isolate and require more or less complex extraction procedures.

3. Relatively extensive purification is required to separate the contaminated starting materials.

4. Some cephalosporins form gels when precipitated in aqueous media as acids, while other cephalosporins are well soluble in water and require large amounts of organic solvents for isolation.

Attempts have been made to solve these problems by techniques that allow the use of organic solvents.

Dichloromethane, the most common such solvent, has become widely used industrially in the case of 7-aminocephalosporanic acid. However, when dichloromethane is used, at least two equivalents of triethylamine per equivalent of acid are required to obtain a solution. The amount of tertiary amine required is significantly higher than when using 1,2-dichloromethane.

In the case of 6-aminopenicillanic acid Stolberg (Grunenthal)
1159449], the limitations of organic solvents on the one hand and the excess of base on the other hand were overcome, and the use of this technique was extended to the case of 7-aminocephalosporanic acid. This implementation is well known to those skilled in the art, and the number of patents in this field is too numerous to list here.

It is also known that 7-amino-desacetoxycephalosporanic acid does not form a solution in dichloromethane with the most effective base for this purpose, the tertiary amine, triethylamine.
Therefore, the solution is made by using 2 equivalents of amine and 2 equivalents of trimethylchlorosilane. Generally, when operating with the 7-aminocephalosporanic acid group, two equivalents of silylating agent are required to form the N,O-bistrimethylsilyl derivative and obtain the desired solution.

A very special property of the compounds integrating the 7-aminocephalosporanic acid group, related to the purity of such compounds, is that triethylamine can be dissolved in dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile and many other solvents. It cannot be generated.

Thus, for example, extremely impure 7-amino-3
-(5-methyl-1,3,4-thiadiazolyl-
When using 2-thiomethyl)-3-cephem-4-carboxylic acid, a degraded solution is formed with triethylamine; is necessary. However, it has not been possible to produce such solutions in the case of pure substances. Literature (DeMarinis et al.: J.Med.Chem., 19 , 754, 1976)
The same thing happens with similar derivatives, as described in .

It has been shown that the use of 7-aminocephalosporanic acid, which undergoes acyl reactions, creates very complex problems in obtaining pure antibiotics, and the yields are generally low.

Besides the above-mentioned difficulties, another special fact is that the acylation reaction between mixed anhydrides of amino acid enamine salts and pivaloyl chloride and silylated derivatives is not possible, which makes this technology suitable for 6-aminopenicillanic acid. limited to when used. West German patent no.
No. 2,263,861 discloses the difficulty of producing triethylamine salts of such acids and proposes methanol as a suitable solvent for bringing the triethylamine salt into solution during acylation. Although the yield is good, the cephalosporin isolation technique is complicated by the need to evaporate the methanol under reduced pressure. The German patent mentioned above also describes the preparation of a methanol solution of the triethylamine salt of 7-amino-3-(5-methyl-1,3,4-thiadiazolyl-2-thiomethyl)-3-cephem-4-carboxylic acid. It is being unveiled. Swiss patent no.
No. 535261 also discloses in Example 1 that a dichloromethane solution of the triethylamine salt of this acid is prepared, and in Example 2, 7-amino-3-(1-
Methyl-tetrazolyl-5)-3-cephem-4
- Demonstrates the preparation of solutions corresponding to carboxylic acids. This compound and its triethylamine salt solution are also available in the literature (Nanni et al., Arzneim-Forsch./
Drug.Res., 27(1) 2352 (1977)), and similar heterocyclic compounds are described in the literature (DeMarinis et al., J.Med.Chem., 19 , 754 (1976)).
It is described in.

West German Patent Application No. 2758000 contains, in some examples, 7 in the triethylamine salt form.
-Using a solution of aminocephalosporanic acid in dichloromethane is described. Example 1 (2)
In Example 6, 7-amino-3-(2-amino-1,3,
A similar statement has been made in the case of 4-thiadiazolyl-5-thiomethyl)-3-cephem-4-carboxylic acid. DE 2163514 discloses that, because of the difficulties and complications in the acylation reaction of triethylamine salts, it is preferable to use reagents for the silylation of 7-aminocephalosporanic acid. are doing. A chlorosilane derivative and a corresponding equivalent of a tertiary amine are used. Usually, it is necessary to use a reactant in consideration of the moisture content in the solvent and the raw materials used. US Patent No.
No. 3,741,965 uses 3 equivalents of trimethylchlorosilane and a tertiary base per equivalent of 7-amino-3-(3-methylisoxazolyl-5)carbonylthiomethyl-3-cephem-4-carboxylic acid. Such silyl reactions are commonly carried out by heating the mixture, especially the mixture with 3-thionyl substituted 7-aminocephalosporanic acid. If pure compounds are used, silylation requires prolonged heating to the reaction temperature followed by cooling.

The following results have been obtained when 0.01 mole of 3-substituted-7-amino-3-cephem-4-carboxylic acid is dissolved in 15 ml and 20 ml of organic solvent: 3
-acetoxymethyl: when using 1 equivalent of triethylamine, dichloromethane, 1,2-
Solutions cannot be made in dichloromethane, acetonitrile, dimethylformamide, dimethylacetamide, chloroform, isopropanol and methanol. When using 2 equivalents of triethylamine, no solution forms in 1,2-dichloroethane, chloroform, dimethylacetamide and isopropanol. Solutions formed in nitromethane and methanol.

3-azidomethyl: When using 1 equivalent of triethylamine, no solution is formed in any of the above mentioned solvents. When using 2 equivalents, solutions were formed only in dimethylformamide, nitromethane, acetonitrile and methanol.

3-Methyl: When more than 3 equivalents of triethylamine were used, it was poorly soluble in all the solvents mentioned above except methanol.

3-thiomethyl derivative: When using a tertiary base, no solution was formed in any of the above mentioned solvents.

3-heterocycloyl-2 derivative: This derivative contains 1,3, It includes derivatives having a 4-thiazole ring or a 1,3,4-oxazole ring. No triethylamine solution was formed. No solution was formed in any case where a compound having a heterocycle fused to a 7-membered ring was used.

Other common tertiary amines were completely ineffective. The above results were obtained using industrially pure compounds. In some cases, solutions or simulated solutions are produced from impure raw materials, and the use of such solutions or simulated solutions may lead to acylation, as disclosed in several patents, such as the patents and scientific publications mentioned above. The yield in the reaction will be lower,
A complex cephalosporin purification process is required later.

DISCLOSURE OF THE INVENTION In the present invention, the preparation of a solution of a compound belonging to the group consisting of 7-aminocephalosporanic acid is carried out by the following general formula: (In the formula, R ₁ is a hydrogen atom and R ₂ is a methyl group, an acetoxymethyl group, a thiadiazolylthiomethyl group, or a tetrazolylthiomethyl group). : (In the formula, x is an integer of 3 to 5, y is an integer of 2 to 4) and is reacted with a bicyclic amidine represented by the following general formula: This is achieved by producing a salt represented by the formula (in which R ₁ , R ₂ , x and y are the same as those described above).

The products resulting from the above-mentioned reactions are salts that are soluble in various organic solvents.

The bicyclic amidine represented by the formula is a known compound whose properties and examples of its use in synthesis can be found in the literature (Oediger, Moller and Eiter: Synthesis,
591, 1972). Among such bicyclic amidines, 1,5-diazabicyclo(4,
3,0) nonene-5 (DBN) and 1,8-diazabicyclo(5,4,0) undecene-7
(DBU) is a commercial product, in particular DBU is manufactured on an industrial scale.

C-7 methoxy derivatives of 7-aminocephalosporanic acid of the formula, e.g. 7β-amino-7α-methoxy-3-(1-(1H)tetrazolyl-5)thiomethyl-3-cephem-4-carboxylic acid and 7β-amino-7α-methoxycephalosporanic acid, French Patent Application No. 75 35-009
It is manufactured by the method described in the specification for the purpose of making a solution using DBU and DBN.

Literature (DeMarinis et al.: J.Med.Chem., 19 , 754,
Another 7-amino-3-heterocyclo-thiomethyl-3-cephem-4-carboxylic acid described in 1976) was prepared by the method of Spanish Patent No. 461,095. One example is 7-amino-3-(4-
Methyl-1,2,4-triazolyl-3-thiomethyl)-3-cephem-4-carboxylic acid.

To carry out the method of the invention for preparing a solution, the corresponding 7-aminocephalosporanic acid of the formula is suspended in the chosen solvent at a temperature of 5° C. to ambient temperature, and then a solution is obtained. A bicyclic amidine of the formula is slowly added with thorough stirring. The amount of DBN or DBU used essentially depends on the stoichiometry of the reaction, which is usually a 1:1 ratio, and the purity of the starting materials.

An acylation reagent is added to the solution of the compound represented by the formula thus obtained, and the solution is then treated in a conventional manner. Control of time, temperature and PH are adjusted in each case to match the particular reaction characteristics to obtain the desired cephalosporin.

Under the conditions described above, the mixed anhydrides of P-hydroxyphenylglycine and the optically active enamine salt of phenylglycine act with the corresponding chlorides of pivaloyl chloride and tetrazolylacetic acid. These acids are also activated with dimethylforminium chlorosulfite, commonly anhydrides, and other reagents commonly used in the art.

Suitable solvents for the purposes of the present invention include dichloromethane, 1,2-dichloroethane, dimethylacetamide, acetonitrile, dimethylformamide and mixtures of these solvents with methyl isobutyl ketone. Chloroform and nitromethane are also suitable.

Pure 7-aminocephalosporanic acid of the formula, when treated with triethylamine, has been shown in the literature (DeMarinis et al.: J.Med.Chem., 19 , 754, 1976 and Gericke et al.: Arzneim.-Forsch., Drug.
Res., 29 () 362, 1979), it becomes completely insoluble in any of these solvents.

An alternative to the process of the invention produces a solution of impure 7-aminocephalosporanic acid. Impurities are precipitated as a solid or pasty product by slow addition of methyl isobutyl ketone or 1,2-dimethoxyethane under controlled conditions.
The clear solution is decanted and acetic acid is added to precipitate white highly pure 7-aminocephalosporanic acid. Also, 1,2-dimethoxyethane can be used to precipitate the salt, leaving impurities in solution. In this case salt is preferably
Separate the DBU salt.

In another alternative method of the present invention, the amount of bicyclic amidine DBN, DBU, etc. is adjusted, and then triethylamine salt of a weak carboxylic acid such as pivalic acid, 2-ethylhexanoic acid, isononanoic acid, etc.
Addition of equivalent amounts produces a solution at a temperature of -20 to 0<0>C. Salts of these acids with tertiary bases such as N-methylmorpholine, N-ethylpiperidine, n-tributylamine, and the like can be used.

A clear, light-colored solution is obtained under such conditions, which can be used for the next acylation step. A special property of such solutions is that when impure 7-aminocephalosporanic acid is used, they become dark in color, which indicates that the raw materials used are of low quality.

The advantages achieved by the process according to the invention are: 1. Wide selection range for the production of stable solutions.

2. Use highly purified 7-aminocephalosporanic acid.

3. The temperature in the solution manufacturing process is between -20°C and room temperature.

4 Use of bicyclic amidines, which are cheaper compounds than silylating agents.

5. There are no siloxanes present in the reaction mixture that would make subsequent solvent recovery difficult.

6. It is a relatively simple technique as it eliminates the need for humidity maintenance and the use of inert ambient air in chemical processing.

7 Acylation reactions can be carried out over a wide temperature range.

8 There are no restrictions on the use of any known form of activated carboxylic acid.

The above results 2, 3, 4, 5, 6 and 8 are not possible when using a silylating agent by a conventional method, and in result 1, methanol and isopropanol are not included because they are incompatible solvents, Moreover, in the case of silyl ester, the solution is unstable with respect to humidity, contrary to the stable solution of result 1.

Another important advantage of the method of the invention relates to the isolation of antibiotics. A number of examples show mixtures of water and miscible organic solvents for making triethylamine solutions. The most common are acetone and tetrahydrofuran. Despite the disadvantage of partial hydrolysis of the acylation reagent, the resulting cephalosporin is soluble. Therefore, the common steps in all cases are vacuum distillation of the solvent and different
In a continuous extraction process at PH, these steps are technically complex processes and lead to yield losses. All of this is known in the art and is reflected in patents.

A solution of the salt of a bicyclic amidine and 7-aminocephalosporanic acid also shows the presence of an amino group with an activity at least similar to that of the ester and greater than that of the N,O-bis-trimethylsilylated compound in the solvent. clearly shows. Increased activity is determined by relative acylation capacity and temperature sensitivity. The conversion time can therefore be adjusted in each case to obtain the best yield. Example 22 shows that the reaction can be carried out effectively at moderate temperatures and the yield is better than Example 17 of West German Patent No. 2263861. German Patent No. 2,263,861 carries out the reaction at -35°C for 1 hour and then at -20°C for 3 hours and uses a complex and time-consuming isolation method. West German Patent No. 2758000 is 7
An acylation reaction using a solution of -aminocephalosporanic acid and triethylamine is presented, and Example 6 shows that a solution that cannot be reproduced is obtained when using technically pure materials. The following 1-(α-syn-methoximino-α(2-
The reaction with amino-thiazole-4)acetoxy)-benzotriazole takes place with low efficiency. On the other hand, using solutions obtained by the method of the invention, yields are obtained that are better than those shown in these examples. Similarly, the use of such bicyclic amidine salts gives better yields than those reported in Swiss Patent No. 535,261 and in the scientific literature (eg Nannini et al., supra).

These solutions can be effectively used on an industrial scale in the reaction to form acylamine derivatives of 7-aminocephalosporanic acid by adding them as side chains at the C-7 position by acylation with activated carboxylic acids. can. Therefore, depending on the acid to be incorporated, the active forms include anhydrides and mixed anhydrides of weak or strong acids, such as carboxylic acids, alkyl or arylsulfonic acids and hindered acids such as trimethylacetic acid, trichloroacetic acid and diphenylacetic acid ( It is a monoester of (hindered acid). Furthermore, azides, active esters or active thioethers of acids (e.g. P-nitrophenol, 2,4
-dinitrophenol, thiophenol, N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxybezothiazole); the acid itself is dimethylformiminium chlorosulfite, N,N-carbonylimidazole or N,
N'-carbonylditriazoles and carbodiimides (particularly N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide or N-cyclohexyl-N'-(2-morpholineethyl)carbodiimide; Sheehan and
Hess: J. Amer. Chem. Soc., 77 , 1067 (1955), or alkyl reactants (Buijili and Viehe:
Angew.Chem.Inter.Ed:. , 3, 582 (1964)) or ketene imine (Stevens and Munk: J.
Amer.Chem.Soc., 80 , 4065 (1958)) or reactive salts of isoxazolonium (Woodward,
Olofson and Mayer: J.Amer.Chem.Soc., 83 ,
1010 (1961)). azolides or active amides in which the nitrogen atom is one member of a semi-aromatic five-membered ring containing at least two nitrogen atoms, such as imidazoles, pyrazoles, triazoles, benzimidazoles, bezotriazoles and fused Activated amides such as substituted derivatives thereof such as heterocyclics can be used. The active form of carboxylic acid includes mixed anhydrides of phosphorus compounds. All these compounds are widely known;
Described in scientific and technical literature.

In the case of active acids that release equivalent amounts of acid in the acylation process, the action of the acid is abolished when using the solutions presented in this invention or by incorporating a further equivalent amount of bicyclic amidine into the medium. .

The mixtures obtained from acylation reactions carried out using these solutions require only simple processing to isolate the corresponding cephalosporins. This point is illustrated in some examples. On the other hand, the isolation methods described in publications (e.g., page 352 of the above-mentioned document of Nannini et al. and British Patent No. 1319173) are extremely time-consuming, and their practical use in industry is limited to 3. It is difficult to obtain cephalosporins substituted with a thiomethyl heterocycle.

Next, the present invention will be explained with reference to Examples and Reference Examples. The operation for isolating the compound from the 7-aminocephalosporanic acid solution produced in the example is as follows:
Solvent evaporation was unsuccessful due to the formation of a hygroscopic solid material. Therefore, confirmation tests were conducted on the solution itself. Confirmation tests included measurements of the specific optical rotation [α] ²⁰ _D and stability tests of 7-aminocephalosporanic acid in solution by high performance liquid chromatography (HPLC), as well as Examples 1 and 12.
The final antibiotic was produced from this solution. Note that the purity of the raw materials and products is shown in Example 3 because Example 3 relates to the purification of low-purity raw materials (purity 86.5%). In all other examples and reference examples, commercially available pure reagents (purity 97 to 98%) were used as raw materials.

Example 1 7-amino-3-(5-methyl-1,3,4-
Thiadiazolyl-2-thiomethyl)-3-cephem-4-carboxylic acid A suspension of 34.44 g of the title compound in 600 ml of dichloromethane was stirred at room temperature (20°C) until a complete solution was obtained. , DBU was added slowly. Approximately 16 ml of bicyclic amidine was required. The resulting solution was then cooled to 5°C and made available for further processing.

[α] ²⁰ _D = -37° (C = 1%, dichloromethane) HPLC (equipment: Hewlett-Packard 1090): [Conditions] Column:
Hypersyl ODS (product name); 10cm,
5 micron; Mobile phase: 93% phosphate buffer PH50.7
% methanol; Flow rate: 1.5ml/min; Wavelength:
254nm; retention time: 8.6 minutes.

[Result] (after storing the solution for 2 hours at 5°C) 99.3% of starting material.

7-(1(1H)-tetrazolylacetamide)-
Synthesis of 3-[2-(5-methyl-1,3,4-thiadiazolyl)thiomethyl]-3-cephem-4-carboxylic acid (cefazoline) 7-Amino-3-(5-methyl obtained in Example 1) -1,3,4-thiadiazolyl-2-thiomethyl)-3-cephem-4-carboxylic acid (7-ACA
-TD) solution was kept at 5°C in advance, then -
20% stoichiometric excess of the mixed anhydride solution (obtained by reacting the triethanolamine salt of tetrazolylacetic acid with pivaloyl chloride at -10°C) cooled to 30/-35°C for 20 minutes. dripped. The resulting mixture was stirred at -30/35°C for 3 hours. Cefazolin was obtained in a yield of 83.2% by conventional separation procedures.

Confirmation: Same as reference standard IR spectrum Purity: 98.7% Water content: 3.7% (Karl Fitscher) Example 2 7-Amino-3-desacetoxycephalosporanic acid 21.42 g of the title compound was mixed with 200 ml of methyl isobutyl ketone and dimethyl formamide. If the suspension is suspended in a mixture with 200 ml and stirred at 20 °C.
16 ml of DBU was added. A solution formed immediately.
The solution was cooled to 0°C and ready for use.

[α] ²⁰ _D = 66.7゜ (C = 1%, MIBK/DMF1:
1) HPLC (apparatus: same as Example 1); [Conditions] Column, mobile phase, and flow rate are the same as Example 1; Wavelength: 235 nm; Retention time: 1.7 minutes.

[Result] (after storing the solution for 2 hours at 0°C) 99.7% of starting material.

Example 3 7-Amino-3-desacetoxycephalosporanic acid A suspension of 21.42 g (purity 86.5%) of the title compound in the solvent mixture described in Example 2 at a temperature of 0-5°C A sufficient amount of 100-200 ml of methyl isobutyl ketone was added to separate the impurities. Decant the liquid and check the pH
When DBU is neutralized by adjusting with acetic acid, a white 7
-ADCA crystals were precipitated. Separately, after acetone washing and drying, this precipitate (97.8% purity) was treated as in Example 2.

Example 4 7-amino-3-(5-methyl-1,3,4-
Thiadiazolyl-2-thiomethyl)-3-cephem-4-carboxylic acid The procedure of Example 1 was carried out using 12 ml of DBN instead of DBU to obtain a solution.

Reference example 1 7β-amino-7α-methoxy-3-(1H-tetrazolyl-5-thiomethyl)-3-cepheme-4
-Carboxylic acid A suspension of 17.18 g of the title compound in 300 ml of dichloromethane was stirred at room temperature.
18 ml of DBU was added slowly until a complete solution was obtained. The solution was then cooled to 5°C for later use.

Reference example 2 7-amino-3-(4-methyl-1,2,4-
(Triazolyl-3-thiomethyl)-3-cephem-4-carboxylic acid 16.36 g of the title compound was dissolved in dimethylacetamide.
To the suspension in 200 ml, 6 ml of DBN was slowly added with stirring at 10° C. until a complete solution was obtained. The solution was then cooled to -5°C for later use.

Example 5 7-Aminocephalosporanic acid A suspension of 27.22 g of 7-ACA in 200 ml of acetonitrile was stirred at 20°C.
Approximately 12 ml of DBN was slowly added. A solution formed immediately. The solution was filtered as required and then cooled to 0-5°C.

[α] ²⁰ _D = 60.3° (C = 1%, acetonitrile) HPLL (equipment: same as Example 1): [Conditions] Column,
Mobile phase, flow rate and wavelength are the same as in Example 1; retention time: 1.9 min. Results: 99.0% of starting material (after storing the solution for 2 hours at 0°C).

Example 6 7-Amino-3-desacetoxycephalosporanic acid About 16 ml of DBU was slowly added to a suspension of 21.42 g of the title compound in 200 ml of 1,2-dichloroethane while stirring at 20°C. did. A complete solution was formed in 10 minutes.

[α] ²⁰ _D = 106.6° (C = 1%, 1,2-dichloromethane) Example 7 7-Aminocephalosporanic acid The procedure of Example 7 was carried out using 16 ml of DBU instead of DBN. A solution formed almost immediately.

Example 8 7-amino-3-(5-methyl-1,3,4-
Thiazolyl-2-thiomethyl)-3-cephem-
4-Carboxylic acid 34.44g of the title compound was dissolved in dimethylacetamide.
Approximately 16 ml of DBU was added to the mixture in 200 ml while stirring at 20°C. A solution formed.

[α] ²⁰ _D = -130° (C = 1%, dimethylacetamide) Reference example 3 7β-amino-7α-methoxy-3-(acetoxymethyl)-3-cephem-4-carboxylic acid 15g of the title compound was dissolved in dichloroethane. Add to the suspension in 200ml while stirring at room temperature.
7.5 ml of DBU was added and then final adjustments were made until a complete solution was obtained. This solution was then heated to 5°C.
It was then cooled for later use.

Example 9 7-aminodesacetoxycephalosporanic acid A suspension of 18.9 g of the title compound in 150 ml of dichloromethane was stirred at 10°C.
14.8 ml of DBU was added. A solution formed in 5 minutes at 10°C, then the solution was cooled to -35°C.

[α] ²⁰ _D = 112.4° (C = 1%, dichloromethane) 7-(D-α-aminophenyl acetamide)-
Synthesis of desacetoxycephalosporanic acid (cephalexin) The 7-aminodesacetoxycephalosporanic acid (7-ADCA) solution obtained in Example 9 was preliminarily diluted with -35
A solution of a 3% stoichiometric excess of mixed anhydrides (potassium salt of N-(1-ethoxycarbonylpropenyl-2)-α-aminophenyl acetic acid and pivaloyl chloride) cooled to (obtained by reacting at -20℃) to 20
It was dripped over several minutes. -55/
The mixture was stirred at -40°C for 1 hour and then at -30/-40°C for 3 hours. Cephalexin was obtained in a yield of 89.3% by conventional separation procedures.

Confirmation: IR spectrum same as reference standard Purity: 98.3% (anhydrous standard) [α] ²⁰ _D : 154.9° (C = 1%, water) Water content: 6.3% (Karl Fitscher) 7-(D-α-amino Synthesis of -4-hydroxyphenylacetamide)-desacetoxycephalosporanic acid (cephadroxil) The 7-ADCA solution obtained in Example 9 was prepared in advance at -35°C.
A solution of mixed anhydride (N-(1-ethoxycarbonylpropenyl-2)α-amino-4) with 5% stoichiometric excess cooled to
-obtained by reacting the potassium salt of hydroxyphenylacetic acid with pivaloyl chloride at -20°C) over 20 minutes. The resulting mixture was heated at -50/-40°C for 1 hour, -40/-30
The mixture was stirred for 1 hour at ℃ and then for 2 hours at -30℃. Cephadroxil was obtained in a yield of 80.3% by conventional separation procedures.

Confirmation: IR spectrum same as reference standard Purity: 97.9% (anhydrous standard) [α] ²⁰ _D : 172.8° (C = 1%, water) Water content: 5.1% (Karl Fitscher) Example 10 7-Aminocephalo 27.22g of the compound labeled sporanic acid was mixed with methyl isobutyl ketone.
200 ml of dimethylformamide and 200 ml of dimethylformamide at 22°C with vigorous stirring.
12 ml of DBN was added slowly. The resulting solution was filtered after 10 minutes as required and the resulting liquid was
Cooled to ℃.

Example 11 7-amino-3-(5-methyl-1,3,4-
Thiadiazolyl-2-thiomethyl)-3-cephem-4-carboxylic acid 34.44 g of the title compound was added to 250 ml of 1,2-dichloroethane, and while stirring the mixture at room temperature, 16 ml of DBU was slowly added until a complete solution was obtained. Added. The solution was then cooled to 5°C for later use.

[α] ²⁰ _D = -143.7° (C = 1%, 1,2-dichloroethane) Example 12 7-amino-3-(5-methyl-1,3,4-
Thiadiazolyl-2-thiomethyl)-3-cephem-4-carboxylic acid 34.44 g of the title compound was added to 250 ml of 1,2-dichloroethane, and while stirring the mixture at room temperature, 12 ml of DBU was slowly added. The amount added was adjusted to the amount necessary to obtain a complete solution. The solution was then cooled to 5°C for later use.

Example 13 Example 11 was repeated using dimethylacetamide in place of 1,2-dichloroethane. A solution formed in a short time.

Example 14 7-Aminodesacetoxycephalosporanic acid A suspension of 21.42 g of the title compound in 200 ml of chloroform was stirred at room temperature.
16 ml of DBU was added slowly. The amount added was adjusted as required. A solution formed almost immediately.
The solution was cooled to 5°C and ready for use.

[α] ²⁰ _D = 113.6° (C = 1%, chloroform) Example 15 7-Aminodesacetoxycephalosporanic acid A suspension of 21.42 g of the title compound in 200 ml of nitromethane was stirred at room temperature. While
16 ml of DBU was added slowly. The amount of PBU added was adjusted so that a complete solution was generated in 5 minutes. The solution was cooled to the desired temperature for later use.

Reference example 4 7β-amino-7α-methoxy-3-(acetoxymethyl)-3-cephem-4-carboxylic acid 15 g of the title compound instead of cephalisporanic acid
The operation of Example 11 was carried out using the following. A solution formed in a short time.

Reference example 5 7-amino-3-(5-methyl-1,2,4-
Triazolyl-3-thiomethyl)-3-cephem-4-carboxylic acid The title compound instead of cephalosporanic acid
The procedure of Example 11 was carried out using 17.18 g. A solution formed in a short time.

Reference example 6 7-amine-3-(3-methylisoxazolyl-5)-carbonylthiomethyl-3-cepheme-
4-Carboxylic acid A suspension of 3.79 g of the title compound in 50 ml of dichloromethane and 1 ml of methanol was heated at -10°C.
and 1.50 ml of DBH was added thereto. Upon stirring, the mixture immediately went into solution. At this time, the solution was adjusted with a few drops of DBU depending on the purity. Then 1 equivalent of triethyl pivalate was added. No precipitate was formed.

Example 16 7-amino-3-(1-methyl-1,2,3,
4-Tetrazolyl-5-thiomethyl)-3-cephem-4-carboxylic acid A suspension of 3.28 g of the title compound in 50 ml of dichloromethane was cooled to -10°C and then
1.60 ml of DBU was added. A solution formed immediately.
[α] ²⁰ _D = -134.3℃ (C = 1%, dichloromethane)
To this solution was added 1 equivalent of triethylamine 2-ethylhexanoate. No precipitate was formed.

Example 17 Example 16 was repeated using 30 ml of methanol instead of dichloromethane. A solution formed.
No precipitate formed when triethylamine pivalate was added.

Example 18 Example 16 was repeated using 30 ml of acetonitrile instead of dichloromethane and 1.20 ml of DBN instead of DBU. A solution formed. No precipitate was formed when triethylamine pivalate was added to this solution.

Example 19 Example 16 was repeated using 40 ml of 1,2-dichloroethane instead of dichloromethane and 1.2 ml of DBN instead of DBU. A solution formed. No precipitate formed when triethylamine 2-ethylhexanoate or triethylamine pivalate was added.

Example 20 7-amino-3-(2-amino-1,3,4-
Thiadiazolyl-5-thiomethyl)-3-cephem-4-carboxylic acid Add 3.45 g of the title compound to a suspension of -10°C in 20 ml of methanol while stirring.
1.55 ml of DBU was added. A solution formed after 10 minutes. The solution was adjusted as required using a few drops of DBU. [α] ²⁰ _D = -81.3° (C = 1%, methanol) No precipitate was formed when triethylamine pivalate was added.

Example 21 1,2-dichloroethane40 instead of methanol
ml and 8 ml of methanol. A solution formed.

Example 22 Example 27 was repeated using a mixture of 40 ml of dichloromethane and 8 ml of methanol instead of methanol. A solution formed. No precipitate formed when triethylamine pivalate was added.

Reference example 7 7-amino-azidomethyl-3-cephem-4
-Carboxylic acid 1.20 ml of DBN was added to a suspension of 2.51 g of the title compound in 20 ml of dichloromethane at a temperature of -10°C, and adjustments were made using additional amounts of base depending on the purity. A solution formed within a short time. No precipitate formed when triethylamine 2-ethylhexanoate was added.

Reference Example 8 The operation of Reference Example 7 was carried out using 1,2-dichloroethane instead of dichloromethane. A solution formed.

Reference Example 9 The operation of Reference Example 7 was carried out using acetonitrile instead of dichloromethane. A solution formed.

Reference Example 10 The operation of Example 30 was carried out using dimethylacetamide in place of dichloromethane. A solution formed.

Reference Example 11 The operation of Reference Example 7 was carried out using dimethylformamide instead of dichloromethane and an equivalent amount of DBU instead of DBN. A solution formed.

Reference Example 12 The operation of Reference Example 7 was carried out using nitromethane instead of dichloromethane and an equivalent amount of DBU instead of DBN. A solution formed.

Reference Example 13 The operation of Reference Example 7 was carried out using chloroform instead of dichloromethane. A solution formed.

Example 32 7-Amino-3-(1-phenyl-tetrazolyl-2-thiomethyl)-3-cephem-4-carboxylic acid Suspension of 3.90 g of the title compound in 20 ml of dichloromethane at a temperature of -10°C 1.55 ml of DBU was added to the solution. This mixture was adjusted depending on the purity of the base used. A solution formed immediately. No precipitate formed when triethylamine 2-ethylhexanoate was added.

Example 24 Example 23 was repeated using 40 ml of acetonitrile instead of dichloromethane and 1.20 ml of DBN instead of DBU. A solution formed. No precipitate was formed when triethylamine pivalate was added to this solution.

Reference Example 14 7-Amino-3-azidomethyl-3-cephem-4-carboxylic acid 1.20 ml of DBN of a suspension of 2.54 g of the title compound in 20 ml of isopropanol was added.
At this time, adjustments were made depending on the purity of the base used. A solution formed in a short time. No precipitate was formed when triethylamine pivalate was added to this solution.

Example 25 7-Amino-3-acetoxymethyl-3-cephem-4-carboxylic acid 13.6 g of the title compound was dissolved in 100 ml of isopropanol.
6.0 ml of DBN was added to the suspension, and adjustments were made depending on the purity of the base used. about 15
A solution formed after stirring for a few minutes. No precipitate was formed when triethylamine pivalate was added to this solution.

Example 26 7-amino-3-(5-methyl-1,3,4-
Thiadiazolyl-2-thiomethyl)-3-cephem-4-carboxylic acid 12.0 ml of DBU was added to a suspension of 17.2 g of the title compound in 100 ml of methanol at a temperature of -20°C. A solution formed immediately.

Reference Example 15 7-Amino-3-(1,2,3-triazolyl-5-thiomethyl)-3-cephem-4-carboxylic acid 3.13 g of the title compound was suspended in 30 ml of dichloromethane at a temperature of -15°C. 1.55 ml of DBU was added to the suspension. A solution formed. One equivalent of triethylamine pivalate was added to this solution, but no precipitate formed.

Example 27 7-Amino-3-(1,3,4-thiadiazolyl-2-thiomethyl)-3-cephem-4-carboxylic acid 3.30 g of the title compound was dissolved in 1,2-dichloroethane.
1.20 ml of DBN was added to the suspension in 30 ml, and adjustments were made depending on the purity of the base used. A solution formed after brief stirring at -5°C. No precipitate formed when one equivalent of isononanoic acid triethylamine salt was added to this solution.

Reference example 16 7-amino-3-acetyl-thiomethyl-3-
Cefem-4-carboxylic acid 1.55 ml of DBU was added to a suspension of 2.88 g of the title compound in 30 ml of dichloroethane at a temperature of -10°C, with adjustment being made depending on the purity of the base used. A solution formed after stirring briefly and no precipitate formed when triethylamine piperate was added to this solution.

Reference Example 17 The procedure of Example 44 was carried out using the corresponding 3-phenylthiomethyl derivative in place of the title compound. A solution formed. No precipitate was formed when triethylamine pivalate was added to this solution.

Reference example 18 7β-amino-7α-methoxy-3-acetoxymethyl-3-cephem-4-carboxylic acid Add 1.0 DBU to a suspension of 3.02 g of the title compound in 30 ml of dichloroform at a temperature of -10°C. 55 ml was added, and adjustments were made at this time depending on the purity of the base used. A solution formed after a short time and no precipitate formed when triethylamine pivalate was added to this solution.

Example 28 7-amino-3-(5-methyl-1,3,4-
Thiadiazolyl-2)-3-cephem-4-carboxylic acid 1.20 mol of DBN were added to a solution of 2.98 g of the title compound in 35 ml of dichloromethane at a temperature of -10°C. At this time, adjustments were made depending on the purity of the base used. A solution formed after a short time. 1 in this solution
No precipitate formed when an equivalent amount of N-ethylpiperazine-2-ethylhexanoate was added.

Reference example 19 7-amino-3-(1(H)-5-methyl-1,
3,4-triazolyl-2)-3-cephem-4
-Carboxylic acid 1.20 ml of DBN was added to a suspension of 2.81 g of the title compound in 30 ml of dichloromethane at a temperature of -5°C, and adjustments were made depending on the purity of the base used. A solution was formed in a short time, and no precipitate was formed when N-methylmorpholine isononanoate was added to this solution.

Reference example 20 7-amino-3-(phenyl-thiomethyl)-3
-Cefem-4-carboxylic acid To a suspension of 3.23 g of the title compound in 25 ml of dichloroethane at a temperature of -10°C is added 1 equivalent of the bicyclic amidine DBN, DBU or other similar compound. did. The amount of base used was adjusted depending on its purity. A solution of the corresponding salt was formed after stirring briefly.

Reference Example 21 The operation of Example 49 was carried out using chloroform instead of dichloromethane. A solution of the corresponding salt was produced.

Reference example 22 7-amino-3-(γ-pyridyl-thiomethyl)
-3-Cefem-4-carboxylic acid To a suspension of 3.24 g of the title compound in 30 ml of acetonitrile at a temperature of -10°C is added 1 equivalent of the bicyclic amidine DBN, DBU or other similar compound. was added. The amount of base used was adjusted depending on its purity. A solution of the corresponding salt was produced.

Reference example 23 7-(1-(1H)-tetrazolylacetamide)
-3-[2-(5-methyl-1,3,4-thiadiazolyl)thiomethyl]-3-cephem-4-carboxylic acid Industrially pure 7-amino-3-(5-methyl-1,3, 1,8-diazobicyclo(5,4,
0) Undecene-7 (DBU) was added. A solution formed immediately. Add 1.5 g of pivalic acid to this solution.
Triethylamine pivalate prepared from and 4.0 ml of triethylamine was added. Then 9.5 g of tetrazolylacetic anhydride was added in one portion. This solution was stirred for 90 minutes at a temperature of 0-5°C. The temperature of the reaction mixture was raised to 15° C. and 325 ml of water were added to it along with a few drops of dioctyl sulfosuccinate sodium salt solution. This mixture at PH3.5 (20℃) will rise to PH3.8 (20℃) in 1 minute and after about 15 minutes.
PH decreased to 3.63 (20℃). A slightly brown precipitate (0.50 g) was isolated. The aqueous phase was decanted off and decolorized with 2.5 g of activated carbon for 15 minutes. PH
was 4.48. This mixture was filtered (if aqueous triethylamine solution was used)
A portion of 0.025 g was isolated from the activated carbon). 250 ml of methyl isobutyl ketone was added to this aqueous solution. The PH slowly rose to 3.0 (23°C) and 1.0 g of yellowish product precipitated. The product obtained after decantation became colorless with 1N base.

Claims (1)

[Claims] 1. In producing a 7-aminocephalosporanic acid solution that can be used in the acylation reaction, the following general formula: (In the formula, R ₁ is a hydrogen atom, R ₂ is a methyl group, an acetoxymethyl group, a thiadiazolylthiomethyl group, or a tetrazolylthiomethyl group) is suspended in an organic solvent. The liquid has the following general formula: (In the formula, x is an integer of 3 to 5, y is an integer of 2 to 4) and is reacted with a bicyclic amidine represented by the following general formula: (wherein R ₁ , R ₂ , x and y are the same as those mentioned above) Method for producing aminocephalosporanic acid solution. 2 A suspension of a compound represented by the general formula in an organic solvent is prepared by the following formula: The method according to claim 1, which comprises reacting with a bicyclic amidine represented by: 3 A suspension of the compound represented by the general formula in an organic solvent is prepared by the following formula: The method according to claim 1, which comprises reacting with a bicyclic amidine represented by: 4 The compound represented by the general formula and the compound represented by the general formula are combined into dichloromethane, dimethylacetamide, 1,2-dichloroethane, chloroform, nitromethane, diethylformamide,
A process according to claim 1, characterized in that the reaction is carried out in acetonitrile, methyl isobutyl ketone, methanol, isopropanol or mixtures thereof to obtain a solution of the corresponding salt of 7-aminocephalosporanic acid of the formula. 5 A precipitant selected from the group consisting of methyl isobutyl ketone, 1,2-methoxyethane, and ethyl acetate is added to the organic solvent solution produced by the reaction of the compound represented by the formula and the compound represented by the formula to make it pure. 2. A process according to claim 1 for producing corresponding salts of bicyclic amidines of the formula and salts of the formula. 6 7-Aminocephalosporanic acid in methanol, isopropanol, dichloromethane, 1,2
-The temperature at which the suspension is suspended in an organic solvent selected from the group consisting of dichloroethane, chloroform, acetonitrile, dimethylformamide, dimethylacetamide, nitromethane, etc. or a mixture thereof-
The suspension at 20°C was diluted with 1,5-diazabicyclo(4,
3,0) Nonene-5,1,8-diazabicyclo(5,4,0)undecene-7, etc. to form the corresponding salt of 7-aminocephalosporanic acid by reacting with a bicyclic amidine selected from the group consisting of The subsequent activation of the active form is performed by forming a solution and then adding to this solution a tertiary amine salt, such as a salt of triethylamine with a carboxylic acid selected from trimethylacetic acid, 2-ethylhexanoic acid, isononanoic acid, etc. A method according to claim 1 for obtaining a solution useful for reaction with a carboxylic acid.