KR810000235B1 - Process for preparing cephalosporin antibiotic derivatives - Google Patents

Abstract

Title compds. (I; R1 = phenyl, 2-thienyl, phenxoxy, R2 = H, lower alkyl, phenyl etc.; R3 = H, lower alkyl, substd. low alkyl; A = single bond, alkylene, alkenylene) and their salts are prepd. by reacting 7-acylamidocephalosporanic(II) or its carbonate with thiol compds.(III) or its carbonate. The final products(I) are broad spectrum antibiotics with low toxicity and exhibit more powerful antibacterial activity against gram negative bacteria such as Proteus vulgaris, Salmonella typhi than Cephalothin or Cefazoline.

Description

Method for preparing cephalosporin antibiotic derivative

The present invention relates to a method for producing a new cephalosporin antibiotic derivative or salt thereof represented by the following general formula (I).

Wherein R ₁ is a phenyl group or 2-thienyl group or

Phenoxy,

R ₂ is hydrogen, lower alkyl, phenyl, substituted lower alkyl or substituted phenyl;

R ₃ is hydrogen, a lower alkyl group, or a substituted lower alkyl group,

A is an alkylene group or an alkynylene group which represents a single bond or is branched or branched.

The compound obtained by the present invention has excellent antimicrobial activity, which is characteristic of the cephalosporin antibiotics conventionally commercially available.

It has a good value as a broad range of medical antibiotics.

The present inventors explored the relationship between the chemical structure of the cephalosporin antibiotic and the antimicrobial activity, and as a result of repeated studies for the purpose of producing a cephalosporin antibiotic having excellent antibacterial and low toxicity, Acylamido has a chemical structure substituted with a substituted mercapto group in a heterocyclic thionyl compound having a special structure represented by the following general formula (III) in the acetoxy methyl group of the cephalosporinic acid New cephalosporin derivatives were synthesized into various types.

For example, the new cephalosporin derivative having the chemical structure represented by the above general formula (I) has a broad antimicrobial spectrum against Gram-positive and negative bacteria, especially Protius. The present invention has been found to exhibit strong antimicrobial activity against Gram-negative fungi, which have very few effective cephalosporin antibiotics, such as Proteus Vulgaris and Salmonella typhi, and are also stable and extremely low in toxicity. To complete.

The cephalosporin antibiotic of the general formula (I) obtained in the present invention is preferably used in the form of a salt, for example, an alkali salt, in the same manner as a conventionally known cephalosporin antibiotic, and the same formulation or administration method as in the prior art. It is effective for use in the treatment of diseases caused by a wide range of Gram-negative and positive bacteria, and is used in the treatment of diseases caused by the above-mentioned Bulgari bacteria and Salmonella bacteria, and has particularly effective characteristics not presently known.

The target compound (I) of the present invention is synthesized by the synthesis method described below.

First, the first method of the present invention is a known compound obtained by acylating the primary amino group of 7-amino cephalosporranic acid, such as phenylacetylation, 2-thienylated acetylation, or phenoxyacetylation. A compound of the general formula (II), for example, 7-phenylacetamido cephalosporanic acid or 7- (2-thienylacetamido) cephalosporanic acid or the like, or a carboxylate thereof It is a method of making the compound represented by this, or the carboxylate of this compound, or its corresponding mercaptide compound react.

Where R ² is hydrogen, a lower alkyl group such as

An alkyl group, phenyl group, substituted lower alkyl group or substituted phenyl group having 1 to 4 carbon atoms,

R ³ is hydrogen, lower alkyl group or substituted lower alkyl group A is a single bond or a linear or branched alkylene group or alkenylene group.

Specific examples of the thiol compound represented by the general formula (III) used in this reaction are as follows.

2-mercapto-1,3,4-triazole-5-carboxylic acid,

2- (2-mercapto-1,3,4-triazol-5-yl) -alkancarboxylic acid,

Especially 2- (2-mercapto-1,3,4-triazol-5-yl) -acetic acid,

3- (2-mercapto-1,3,4-triazol-5-yl) -propionic acid,

2- (2-mercapto-1,3,4-triazol-5-yl) -propionic acid,

1-alkyl-2-mercapto-1,3,4-triazole-5-carboxylic acid,

2- (1-alkyl-2-mercapto-1,3,4-triazol-5-yl) -acetic acid,

3- (1-alkyl-2-mercapto-1,3,4-triazol-5-yl) -propionic acid,

2- (1-alkyl-2-mercapto-1,3,4-triazol-5-yl) -propionic acid,

3- (1-alkyl-2-mercapto-1,3,4-triazol-5-yl) -acetic acid,

4- (1-alkyl-2-mercapto-1,3,4-triazol-5-yl) -valerianic acid,

1-phenyl (or substituted phenyl) -2-mercapto-1,3,4-triazole-5-carboxylic acid,

3- (2-mercapto-1,3,4-triazol-2-yl) -acrylic acid,

3- (2-mercapto-1-alkyl-1,3,4-triazol-2-yl) -acrylic acid,

3- [1-phenyl (or substituted phenyl) -2-mercapto-1,3,4-triazol-2-yl] -acrylic acid,

2- [1-phenyl (or substituted phenyl) -2-mercapto-1,3,4-triazol-5-yl] -acetic acid,

3- [1-phenyl (or substituted phenyl) -2-mercapto-1,3,4-triazol-5-yl] -propionic acid,

2- [1-phenyl (or substituted phenyl) -2-mercapto-1,3,4-triazol-5-yl] -propionic acid,

3- [1-phenyl (or substituted phenyl) -2-mercapto-1,3,4-triazol-5-yl] -butyric acid,

4- [1-phenyl (or substituted phenyl) -2-mercapto-1,3,4-triazol-5-yl]-valeric acid etc. are mentioned.

The corresponding carboxylic acid esters obtained by condensing the free carboxylic acids enumerated above with alcohols represented by the general formula R ³ OH (wherein R ³ is the same as the foregoing but not hydrogen) are also generally the original free carboxes. Examples of these kinds of esters, for example, lower alkyl esters, dialkylaminoalkyl esters, benzyl esters, substituted benzyl esters, and alkoxys of carboxylic acids represented by the general formula (III) Alkyl esters;

Moreover, the corresponding mercaptide compound obtained by reacting SH group of the thiol compound of general formula (III) with a base, for example alkali hydroxide or alkaline earth, is also equally used.

The reaction of the compound of the general formula (II) and the thiol compound of the general formula (III) described above is preferably carried out in a solution, and is generally preferably carried out at a pH of 6-9 in an aqueous solvent.

Particularly preferably, the reaction is carried out in an aqueous solution to a hydrous acetone or a hydrous lower alcohol at a temperature of pH 6.5-8.0 at 50 ° C-70 ° C.

Any solvent may be used as long as it dissolves the reagent of another solvent sufficiently at the indicated pH of the reaction solution and does not react directly with the reaction reagent.

In this reaction, the compound of general formula (II) and the compound of general formula (III), which are carboxylic acid compounds, are usually in the form of partial to most salts, and are usually dissolved and reacted in a solvent.

In order to form a part or most of the salt in the form of a salt (for example, an carboxylic acid alkali salt), a compound salt (carboxylate) of the general formulas (II) and (III) may be prepared in advance and dispersed and reacted in a solvent to react. In the state of carboxylic acid, it may be first dissolved or suspended in a solvent, and a warming reaction may be performed in which a suitable organic or inorganic base is added to adjust the pH and to form a salt, thereby adjusting the pH to the required pH range.

Examples of the base used for this purpose are various metal hydroxides, alkali carbonates, alkali bicarbonates, various organic amines, and the like.

After the reaction in this manner, the target product (I) is separated and collected by a conventionally known treatment method.

In this reaction, the thiol compound of the general formula (III) is in the form of the carboxylic acid ester described in the claims, and the active or inactive derivative in this carboxyl group, for example, the carboxylic acid represented by the general formula (III) In the case of mixed acid anhydrides, active amides, acid halides, acid anhydrides, active esters, and the like with various organic or inorganic acids, the hydrolysis is naturally performed in the reaction mixture by reacting in a relatively pH range or by extending the reaction time.

As a result, a compound of alban formula (I) wherein R ³ is hydrogen is obtained.

In this reaction, it is possible to use a derivative of the carboxyl group of the above general formula (III) to increase the reaction rate and improve the reaction yield as the solubility of the reaction reagent in the solvent.

The object (I) obtained here is separated, purified, and obtained as needed, for example in the form of free dicarboxylic acid, a monocarboxylic acid salt, a monoalkali metal salt, an alkaline earth metal salt, and a salt with various other organic amines.

When the desired product (I) is obtained in the form of free dicarbonate or mono carbonate, the salt can be converted by reacting it with a general base under general conditions, if necessary.

In the second method of the present invention, in order to prepare the target compound of the general formula (I), a thiol compound represented by the general formula (III) in the salt of 7-aminocephalosporranic acid or diacid of the general formula (IV) Or a carboxylate or a corresponding mercaptiated compound of this compound is reacted in the same manner as above to obtain a compound represented by the following general formula (V),

(Wherein R ² , R ³ , A are the same as in general formula (I))

Next, to the carboxylic acid compound represented by the general formula (V) obtained here or a carboxylate thereof, or a derivative in which the carboxyl group is closed as an ester, an acid anhydride or a mixed acid anhydride, It is produced by reacting a reactive derivative in the carboxyl group of the carboxylic acid represented by R ¹ -CH ₃ COOH (wherein R ¹ represents a phenyl group or 2-thienyl group or phenoxy group) as an acylating agent.

In the case where the carboxyl group of the compound of formula (V) is closed in the form of a mixed acid anhydride of silyl ester or phosphorous acid (or a chloride or ester of diacid), the primary 7 amino group of the compound of formula (V) In some cases, the corresponding silazane type or phosphite amide type may be closed or activated.

Therefore, even in such a case, the required acylation reaction of the primary amino group at position 7 proceeds smoothly to obtain the target product (I).

This acylation reaction may be selected depending on the characteristics of the reaction reagent, using water, a water-soluble solvent, an organic solvent containing no water, and the like as a reaction medium.

Examples of the reaction derivative at the carboxyl group of the carboxylic acid of the acylating agent In other words, R ¹ CH ₂ COOH in the formula (Ⅳ) used in this reaction are listed below as an example.

That is, acid halides of carboxylic acids, acid anhydrides, mixed acid anhydrides with organic and inorganic acids, electron-withdrawing substituents, for example, alcohols or phenols having a nitro group or a halogen in the molecule, are called esters with thiophenols. Esters, active amides, for example, addition compounds of the corresponding carboxylic acids of carbodiimides such as dicyclohexyl carbodiimide, so-called carboxylic acid pseudo halides such as carboxylic acid azide and the like.

As mentioned above, this acylation reaction is normally performed by well-known reaction conditions and acylating agent used when acylating a primary amino group.

For example, in the case of using an acid chloride, acylation is carried out by slowly adding 1-3 moles of acid chlorolide in an appropriate solvent in an appropriate solvent such as water, hydrous acetone, chloroform, dichloromethane and the like at an ice-cold to -10 ° C. It is common to have a reaction.

The object (I) thus produced is processed, known and separated by a known treatment method. If necessary, it may be converted into a salt form by reacting with a common base under ordinary conditions.

When A represents a single bond among the compounds represented by the above general formula (I) or (V) obtained by the above method, these compounds are subjected to deoxidation again to the following general formula (I ') or (V'). It can be derived from the compound represented as.

(Wherein R ¹ and R ² are the same as in general formulas (I) and (V)).

That is, the inventors of the present invention, in which A represents a single bond among the compounds represented by the general formulas (I) and (V), causes decarboxylation under the mildly relaxed conditions of the compound, and the above general formula (I ') and It was found that the compound represented by (V ′) was produced in high yield and the other components were not changed by side reactions during the reaction.

The reaction from the compounds of the general formulas (I) and (V) to the compounds of the general formulas (I ') and (V') proceeds easily in a solvent at pH = 6 or less and room temperature to 100 ° C or less.

The compound of general formula (I ') obtained here is a compound having strong antibacterial action against gram-positive and gram-negative bacteria and having useful value as an antimicrobial agent. In addition, the compound represented by the general formula (V ') is represented by the known acylation method, i.e., by the acylation reaction used to obtain the compound of the general formula (I) from the compound of the general formula (V). As a compound, it has a useful value as an intermediate of manufacture of the compound of general formula (I ').

In addition, the thiol compound represented by the general formula (III) used as a raw material in the present invention can be obtained in high yield by heating and closing the compound represented by the following general formula in the presence of alkali carbonate or caustic alkali. Can be.

(Where R ² , R ³ and A are the same as in the general formula above)

The invention is illustrated by the following examples.

Example 1

To 836 mg of 7- (2-thienyl acetamido) sodium cephalosporanate and 460 mg of 2- (2-mercapto-1,3,4-triazol-5-yl) acetate were added 5 ml of molar and 0.5 A further 12 ml of aqueous solution of N-sodium hydrogen carbonate was added to dissolve the mixture, which was then heated at 62 ° C-65 ° C for 5.5 hours.

After the reaction, 10 ml of ice-water was added, and 8 ml of 1N hydrochloric acid was gradually added under ice-cooling and stirring, and the precipitated white crystals were filtered and washed with water.

A white powder powdered by rinsing with ether immediately after washing with water, 7- (2-thienylacetamido) -3- (5-carboxoxymethyl-1,3,4-triazole in the form of free dicarboxylic acid. 810 mg (82%) of 2-yl) thiomethyl-3-cepem-4-carboxylic acid was obtained.

NMR spectrum (D ₂ O-NaHCO ₃ -DSS) δ (ppm):

3.65 (1 _double line, 2H, -CH ₂ -COONa), 3.82 (1 single line, 2H, -CH ₂ -CONH), 5.0 (double line, 1H, 6th place H, J = 5HZ), 5.50 (double line, 1H , 7th H, J = 5HZ),

200 mg of this product was suspended in 3 ml of water, dissolved in a small amount in 0.1 N aqueous sodium hydroxide solution, and brought to pH 6.

The filtrate was dried under reduced pressure at room temperature to give about 210 mg of disodium salt.

The ultraviolet absorption spectrum of disodium salt is as follows.

Acetic acid 500 mg of 7- (2-thienylacetamido) -3- (5-carboxymethyl-1,3,4-triazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid Dissolve in a mixed solvent of ethyl, methanol and acetone (about 1: 1: 5), add 2 ml of acetone solution of potassium 2-ethylhexane (1 regulation solution), precipitate, precipitate and wash with acetone. 460 mg of dipotassium salt of was obtained.

(Note) NMR spectra indicated chemical shift δ (ppm) based on the signal of methylproton using DSS, i.e., 3-trimethylsilyl) -propanesulfonic acid sodium as an internal standard.

The antibacterial spectrum of the dipotassium salt of this product is as follows.

However, the lowest growth inhibition concentration of 7- (2-thienyl acetamido) sodium cephalosporanate was indicated for comparison with the numbers sleeping in parentheses.

If the display again compared with the compound in vivo (in Vivo) infection test (maus, in Vivo administration) ED ₅₀ value (値) (㎎ / ㎏) and simultaneously test a contrast agent ED ₅₀ value of in the As follows.

Test bacterium (infection)

A, Salmonella typhi W-901-10

B, Proteus Vulgaris C-73-9 (cephalosporins)

C, Salmonella Enteritidis No.11

D, Staphylococcus aureus Smith S-424

^* Dipotassium salt

In addition, tertiary results were obtained when comparing acute toxicity (in Vivo administration) to mice with the control drug.

Example 2

836 mg of 7- (2-thienyl acetamido) sodium cephalosporanate was dissolved in 5 ml of water,

To this, 520 mg of 3- (2-mercapto-1,3,4-triazol-5-yl) propionic acid was added, followed by dissolving 12 ml of 0.5N-sodium bicarbonate aqueous solution to adjust the pH to 7.0-6.95. This solution was heated to 60 ° C-65 ° C for 6 hours in a nitrogen stream.

After the reaction, 5 ml of ice-water was added, and ice-cooled and stirred, 8.5 ml of 1N hydrochloric acid was added, and the white crystals precipitated as strong acid were filtered and washed with water.

It was immediately washed with ether repeatedly, powdered and filtered with 0.5N-sodium bicarbonate solution at pH 6.0-6.4, and the filtrate was dried by removing water at room temperature under reduced pressure.

Finally, it was vacuum dried overnight with phosphorus pentaoxide as a desiccant. Di of 7- (2-thienyl acetamido) -3- [5- (2-carboxyethyl) -1,3,4-triazol-2-yl] thiomethyl-3-cepem-4-carboxylic acid Obtained as a sodium salt.

The yield is 55 mg (50% yield).

), 3.86(일중선, 2H,

), 5.02(2중선, 1H, 6위H, J=4.5㎐), 5.58(2중선 1H, 7위H, J=4.5㎐),NMR spectrum (D ₂ O-DSS) δ (ppm): Symmetric multiplet of A ₂ B ₂ centered at 2.81 (4H,

), 3.86 (single line, 2H,

), 5.02 (doublet, 1H, 6th place H, J = 4.5 s), 5.58 (doublet 1H, 7th place H, J = 4.5 s),

, 본품의 항균스펙트럼은 다음표와 같다.UV absorption spectrum:

, The antibacterial spectrum of this product is shown in the following table.

Example 3

Take 836 mg of 7- (2-thiethyl acetamido) cephalosporanate and 560 mg of 3- (2-mercapto-1-methyl-1,3,4-triazol-5-yl) propionic acid Reaction was carried out under the same reaction conditions as in Example 2,

7- (2-thienyl acetamido) 3- [5- (2-carboxyethyl) -1-methyl-1,3,4-triazol-2-yl] thiomethyl-3-cepem-4- Disodium salt of carboxylic acid 660 (58%) was obtained.

), 3.87(2중선 2H,

), 4.99(2중선, 1H, 6위H, J=5HZ), 5.53(1H, 7위H, J=5HZ)NMR spectrum (D ₂ O-DSS) δ (ppm): A multiple line having a symmetrical shape of A ₂ B ₂ with 2.82 as the center of symmetry (4H,

), 3.87 (dual 2H,

), 4.99 (doublet, 1H, 6th place, J = 5HZ), 5.53 (1H, 7th place H, J = 5HZ)

UV absorption spectrum:

Antibacterial spectrum is shown in the following table.

Example 4

Water 358 mg of 7- (2-thienylacetamido) cephalosporanate and 256 mg of 3- (2-mercapto-1-phenyl-1,3,4-triazol-5-yl) propionic acid 5 ml and 4.12 ml of 0.5N-sodium bicarbonate aqueous solution were added and dissolved, and the resultant was heated for 4.5 hours in a nitrogen stream in a 63 ° C-65 ° C water bath.

After the reaction, 5 ml of ice water and 3 ml of 1N hydrochloric acid were added while cooling and stirring, and the precipitated white crystals were filtered and washed with water. This was immediately washed thoroughly with ether and powdered.

7- (2-thiethyl acetamido) -3- [5- (2-carboxyethyl) -1-phenyl-1,3,4-thiazol-2-yl] thiomethyl-3-cepem-4- 440 mg of carboxylic acid were obtained. (Yield 87.5%). This was treated in the same manner as in Example 2 to obtain disodium salt.

), 3.84(1중선, 2H,

), 4.92(2중선, 1H, 6위H, J=4.8HZ), 5.58(2중선, 1H, 7위H, J=4.8HZ)NMR of disodium salt (D ₂ O-DSS) δ (ppm): Symmetric broad polyline centered around 2.61 (4H,

), 3.84 (single line, 2H,

), 4.92 (doublet, 1H, 6th H, J = 4.8HZ), 5.58 (doublet, 1H, 7th H, J = 4.8HZ)

UV absorption spectrum

Antibacterial spectrum is shown in the following table.

Example 5

836 mg of 7- (2-thienyl acetamido) sodium cephalosporanate and 520 mg of 2- (2-mercapto-1-methyl-1,3,4-triazol-5-yl) acetate 5 ml and 12 ml of 0.5N-sodium bicarbonate solution were slowly added, dissolved, and treated in a water bath at 60 ° C.-65 ° C., and warmed in a nitrogen stream for 4.5 hours.

The reaction was carried out in the same manner as in Example 2 after the reaction to dissolve the sodium salt of the target product, that is, 7- (2-thienyl acetamido) -3- (5-carboxymethyl-1-methyl-1,3,4-triazole- 714 mg of disodium salt of 2-yl) thiomethyl-3-cepem-4-carboxylic acid was obtained. (Yield 64.5%).

), 3.78(1중선, 2H,

), 3.88(1중선, 2H,

), 5.02(2중선, 1H, 6위H, J=5HZ), 5.55(2중선, 1H, 7위H, J=5HZ),NMR spectrum (D ₂ O-DSS) δ (ppm): 3.59 (single line, 3H,

), 3.78 (single line, 2H,

), 3.88 (single line, 2H,

), 5.02 (doublet, 1H, 6th H, J = 5HZ), 5.55 (doublet, 1H, 7th H, J = 5HZ),

UV absorption spectrum

Antibacterial spectrum is shown in the following table.

Example 6

20 ml of water was added to 418 mg of 7- (2-thienyl acetamido) sodium cephalosporanate and 218 mg of 2-mercapto-1,3,4-triazole-5-carboxylic acid, and 0.5N- An aqueous sodium bicarbonate solution was added to pH 6.8, followed by stirring while heating to 60 ° C.-63 ° C. for 10 hours in a nitrogen stream.

After ice-cooling, 5 ml of ice-water was added, and 1N hydrochloric acid was added dropwise under ice-cooling stirring to pH 1.8, and the precipitated crystals were filtered and washed with water, dissolved in a mixed solvent of ethyl acetate, acetone, and methanol, and 2-methylhexane 2 ml of acetone acetone solution of potassium was gradually added, and the precipitated white precipitate was filtered and washed with ethyl acetate.

Dipotassium salt of 7- (2-thienyl acetamido) -3- (5-carboxy-1,3,4-triazol-2-yl) thiomethyl-3-cepem-4-carboxylic acid was obtained. .

The yield was 440 mg (85.75%).

), 자외선흡수스펙트럼

NMR spectrum (D ₂ O-DSS) δ (ppm): 5.01 (doublet, 1H, 6th H, J = 4.8HZ), 5.55 (doublet, 1H, 7th H, J = 4.8HZ), 3.84 ( Singlet, 2H,

), UV absorption spectrum

Antibacterial spectrum is shown in the following table.

Example 7

418 mg of 7- (2-thienyl acetamido) cephalosporanate and 312 mg of 2-mercapto-1-methyl-1,3,4-triazole-5-carboxylic acid were the same as in Example 2. Treatment to obtain 7- (2-thienyl acetamido) -3- (5-carboxy-1-methyl-1,3,4-triazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid 520 mg of disodium salt of was obtained.

NMR spectrum (D ₂ O-DSS) δ (ppm): 3.66 (doublet, 3H,> N-CH ₃ ), 5.02 (doublet, 1H, 6th H, J = 4.8HZ), 5.58 (doublet, 1H, 7th H, J = 4.8HZ)

UV absorption spectrum

Antibacterial spectrum is shown in the following table.

Example 8

418 mg of 7- (2-thienyl acetamido) sodium cephalosporanate and 265 mg of 2-mercapto-1-phenyl-1,3,4-triazole-5-carboxylic acid as in Example 2 Treatment to obtain 7- (2-thienyl acetamido) -3- (5-carboxy-1-phenyl-1,3,4-triazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid The disodium salt of was obtained.

)NMR spectrum (D ₂ O-DSS) δ (ppm): 4.76 (doublet, 1H, 6th H, J = 4.6HZ), 5.54 (doublet, 1H, 7th H, J = 4.6HZ), 3.80 ( 1H 2H,

)

UV absorption spectrum

Antibacterial spectrum is shown in the following table.

Example 9-13

7- (2-thienyl acetamido) sodium cephalosporanate, which is one example of the compound of formula (II), and various thiol compounds of the formula (III) shown in the following table, respectively, in the same manner as in Example 2 The resulting compound was subjected to post-treatment to obtain various target compounds (I) shown in the following table.

Example 14-17

A solution of 4 g of triethylamine in 10 ml of anhydrous chloroform was added dropwise while 5.44 g of 7-aminocephalosporranic acid was suspended in 50 ml of anhydrous chloroform, followed by cooling (0 ° C) and stirring.

The solution which melt | dissolved 3.75 g of phenoxy acetyl chloride in 20 ml of anhydrous chloroform was dripped here, cooling this to -5 degreeC and fully stirring.

After stirring at -5 ° C for 1 hour and again at 20 ° C for 2 hours, the mixture was poured into 100ml of ice water and stirred sufficiently.The pH of the sap layer was adjusted to 7.5 to remove chloroform at 40 ° C or below under reduced pressure, and 100ml of ethyl acetate was added thereto. Stir and adjust the pH of the fluid layer to 1.8.

The ethyl acetate layer was separated and washed with water, 0.5N-aqueous sodium hydrogen carbonate solution was added thereto, stirred sufficiently, and the pH of the aqueous layer was adjusted to 6.2.

The aqueous layer was separated and lyophilized.

5.0 g of sodium salt of 7- (phenoxyacetamido) cephalosporonic acid were obtained.

); 3.17 및 3.58(AB 4중선, 2H, 2위

, JAB=17HZ); 4.60(1중선, 2H,

); 5.075(2중선, 1H, 6위 -H, J=4.8HZ); 5.73(2중선, 1H, 7위 -H, J=4.8HZ); 6.87-7.45(다중선, 5H, 벤젠환프로톤).NMR spectrum (D ₂ O-DSS) δ (ppm): 2.10 (single line, 3H,

); 3.17 and 3.58 (AB quadruple, 2H, 2nd

, JAB = 17HZ); 4.60 (single line, 2H,

); 5.075 (doublet, 1H, 6th-H, J = 4.8HZ); 5.73 (doublet, 1H, 7th-H, J = 4.8HZ); 6.87-7.45 (multiline, 5H, benzene ring protons).

The 7- (phenoxyacetamide) cephalosporanate sodium salt obtained here was reacted with various thiol compounds represented by the general formula (III) in the same manner as in Example 2, and the post-treatment was performed. Various target compounds (I) were obtained.

Example 18-21

2.72 g of 7-aminocephalosporranic acid was suspended in 30 ml of anhydrous chloroform, and 2.20 g of triethylamine was added thereto while cooling and stirring at 0 ° C.

The solution which cooled this to -5 degreeC and fully stirred, and melt | dissolved 1.85 g of phenyl acetate chlorides in 10 ml of anhydrous chloroform was dripped here.

After stirring at -5 ° C for 1 hour and at room temperature for 2 hours, the mixture was placed in 50 ml of ice water and stirred sufficiently to adjust the pH of the sap layer to 7.5. The chloroform was removed under 40 deg. C under reduced pressure, and 50 ml of ethyl acetate was added thereto and stirred. While adjusting the pH of the fluid layer to 1.8.

The ethyl acetate layer was separated and washed with water, and 0.5N-sodium hydrogencarbonate solution was added thereto, followed by stirring sufficiently to adjust the pH of the aqueous layer to 1.8.

The aqueous layer was aliquoted and lyophilized.

3.76 g of sodium salt of 7- (phenylacetamido) cephalosporan acid were obtained.

); 3.31 및 3.68(AB4중선, 2H, 2위

, J_AB=18HZ); 3.71(1중선, 2H,

); 5.10(2중선, 1H, 6위-H, J=4.7HZ); 5.65(2중선, 1H, 7위-H, J=4.7HZ); 7.42(1중선, 5H, 벤젠환프로톤); 4.95 및 4.71(2중선, 2H, 3위-CH₂-, J=13HZ) 여기에서 얻어진 7-(페닐아세트 아미도) 세팔로스포란산 나트륨염과 일반식(Ⅲ)으로 표시하는 각종의 티올화합물을 각각 실시예 2와 동일하게 반응시켜 후처리를 한 결과 다음표에 표시한 각종의 목적 화합물(Ⅰ)을 얻었다.NMR spectrum (D ₂ O-DSS) δ (ppm); 2.10 (single line, 3H,

); 3.31 and 3.68 (AB quartet, 2H, 2nd

, J _AB = 18 HZ); 3.71 (single line, 2H,

); 5.10 (doublet, 1H, sixth-H, J = 4.7HZ); 5.65 (doublet, 1H, seventh-H, J = 4.7HZ); 7.42 (single line, 5H, benzene ring proton); 4.95 and 4.71 (doublet, 2H, 3-position-CH _2- , J = 13HZ) 7- (phenylacetamido) cephalosporic acid sodium salt obtained here and various thiols represented by the general formula (III) After the compound was reacted in the same manner as in Example 2, the resultant was subjected to post-treatment to obtain various target compounds (I) shown in the following table.

Example 22

Disodium of 7- (2-thienyl acetamido) -3- (2-carboxy-1-methyl-1,3,4-triazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid 4 ml of an aqueous solution containing 539 mg of salt was added dropwise with 2 ml of 1N hydrochloric acid while cooling with ice, and the precipitated white precipitate was filtered and washed with a small amount of cold water. This was immediately dissolved in 4 ml of acetone, a small amount of activated carbon was added, stirred briefly, and filtered.

The filtrate was removed at 30 ° C. or lower under reduced pressure, and the residue was dissolved by adding ethanol to the residue. The solution was adjusted to pH = 6 by adding 0.5N-sodium bicarbonate solution, and concentrated at 30 ° C. or lower to obtain 7- (2-thienylacetamido). A sodium salt of) -3- (1-methyl-1,3,4-triazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid precipitated.

After cooling sufficiently, it was filtered and washed with ethanol.

The yield was 403 mg (85%). 20 mg of the target product was recovered from the solution (total yield 89.5%).

NMR spectrum (D ₂ O-DSS) δ (ppm); 3.70 (single line, 3H,> N-CH ₃ ); 3.88 (single line, 2H, -CH ₂ -CONH); 5.02 (doublet, 1H, 6H, J = 5.0HZ); 5.56 (doublet, 1H, 7th H, J = 5.0HZ); 8.50 (single line 1H, triazole ring proton).

Antibacterial spectrum;

Esheriah. Corey (Escherichia cdi) 6.25γ / ml

Proteus. Bulgarian (Protens Vnlgaris) 50γ / ml

Salmonella 1.56γ / ml

Staphyro Checkers. Auuris (Staphylococcns anrens) 0.78γ / ml

Pseudomonas. Psendomonas Aernginosa C-73-28 1.56γ / ml

Klovebsier, Kiebsiella pnaenmonia C-73-20 0.98γ / ml

Example 23

To 525 mg of disodium salt of 7- (2-thienyl acetamido) -3- (2-carboxy-1,3,4-triazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid Sodium salt of 7- (2-thienyl acetamido) -3- (1,3,4-triazol-5-yl) thiomethyl 3-cefe-4-carboxylic acid by treatment in the same manner as in Example 22 412 Mg (yield 90%) was obtained.

); 4.04(폭넓은 1중선, 2H,

); 4.96(2중선, 1H, 6위H, J=4.8HZ); 5.525(2중선, 1H, 7위H, J=4.8HZ); 8.22(1중선, 1H, 트리아졸환프로톤).NMR spectrum (D ₂ O-DSS) δ (ppm); 3.81 (single line, 2H,

); 4.04 (wide single line, 2H,

); 4.96 (doublet, 1H, 6th H, J = 4.8HZ); 5.525 (doublet, 1H, 7th H, J = 4.8HZ); 8.22 (single line, 1H, triazole ring proton).

Antibacterial spectrum;

Esheriah. Etcherichia Coli 12.5γ / ml

Proteus. Bulgarian (Protens Vnlgaris) 25γ / ml

Salmonella 6.25γ / ml

Staphylococcus. Auphysium (Staphylococcus anreus) 0.20γ / ml

Example 24

Disodium of 7- (2-thienyl acetamido) -3- (2-carboxy-1-phenyl-1,3,4-triazol-5-yl) thiomethyl-3-cepem-4-carboxylic acid 7- (2-thienyl acetamido) -3- (1-phenyl-1,3,4-triazol-5-yl) thiomethyl-3-cepem 505 mg (yield 94%) of sodium salt of 4-carboxylic acid were obtained.

); 3.76(1중선, 2H,

); 4.96(2중선, 1H, 6위H, J=5.0HZ); 5.63(2중의 2중선, 1H, 7위H); 8.85(1중선, 1H, 트리아졸환프로톤); 9.13(2중선, 1H,

, J=8HZ)NMR spectrum (DMSO-d ₆ -TMS) δ (ppm); 3.56 (Wide singlet, 2H, 2nd

); 3.76 (single line, 2H,

); 4.96 (doublet, 1H, 6th H, J = 5.0HZ); 5.63 (doublet of doublets, 1H, 7th position H); 8.85 (single line, 1H, triazole ring proton); 9.13 (doublet, 1H,

, J = 8HZ)

Antibacterial spectrum;

Esheriah. Escherichia Coli 25γ / ml

Proteus. Bulgarian (Protens Vulgaris) 100γ / ml

Salmonella 12.5γ / ml

Staphylococcus. Augius (Staphylococcus anreus) 0.2γ / ml

Claims (1)

Characterized by reacting a cephalosporin antibiotic represented by the following general formula (II) or a salt thereof with a heterocyclic thiol compound represented by the following general formula (III), a carboxylate thereof, or a corresponding mercaptide compound: A method for producing a cephalosporin antibiotic derivative or a salt thereof represented by the following general formula (I).

Food, R ¹ is a phenyl group or 2-thienyl group or a phenoxy group, R ² is hydrogen, lower alkyl group, phenyl group, substituted lower alkyl group or substituted phenyl group, R ³ is hydrogen, a lower alkyl group or a substituted lower alkyl group, A represents a single bond or a linear or branched alkylene or alkenylene group.