JPS607636B2 - Method for producing N-acylamino-α-arylacetamide cephalosporins - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a new cephalosporin, and more specifically, it is produced by the following general formula (1) (wherein A represents a pyridine ring,
HO-A1 represents that the pyridine ring is substituted with a hydroxyl group.

The pyridine moiety represented by A may be further substituted with a lower alkyl group. R is a hydroxyl-substituted phenyl group, H
The present invention relates to a method for producing a novel cephalosporin represented by the formula (et represents a 1,3,4-thiadiazole group unsubstituted or substituted with a lower alkyl group having 1 to 4 carbon atoms) and a nontoxic salt thereof.

Furthermore, the structure of general formula (1) will be explained in detail.

In general formula (1), A represents a pyridine ring and “HO-
A- represents that a pyridine ring is substituted with a hydroxyl group, and this pyridine ring may be substituted with a lower alkyl group.

In general formula (1), Het represents 1,314-thiadiazole which is unsubstituted or substituted with a lower alkyl group having 1 to 4 carbon atoms.

Examples of the non-table salts of the general formula (1) include sodium salts, potassium salts, calcium salts, magnesium salts,
Examples include triethylamine salt, jetanolamine salt, morpholine salt, procaine salt, L-arginine salt, and L-lysine salt.

The Q-carbon (phenylglycine moiety) in the 7-position side chain in general formula (1) is an asymmetric carbon atom. There are therefore two optically active isomers. Although the present invention includes these two isomers (D-diastereomer and L-diastereomer) and DL monomer, the preferred compound is D monomer. Currently, cephalosporin compounds such as cephalothin and cefazoline are highly effective and widely used as therapeutic agents for infections caused by gram-positive or gram-negative bacteria.

However, these cephalosporin compounds are ineffective against Pseudomonas aeruginosa infection, which has been increasing in number in recent years and is increasingly becoming an intractable disease. Cephalosporin compounds effective against Pseudomonas aeruginosa infections are not yet commercially available.
The novel compound represented by the general formula (1) obtained by the present invention has strong antibacterial activity against Gram enterobacteria and Gram negative bacteria, and also has strong antibacterial activity against Pseudomonas aeruginosa, Indole enterobacterium Proteus, and Enterobacter bacterium. It also has strong antibacterial activity against bacteria such as Bacillus Eerogenes and Bacterium Serratia, for which conventional cephalosporin compounds have little effect. Furthermore, compounds in which the phenyl ring of general formula (1) is substituted with at least one hydroxyl group significantly increase in vivo behavior, such as increased blood concentration and increased urinary excretion, compared to compounds without substituents. It is an extremely valuable compound as a therapeutic agent for infectious diseases in humans, poultry, and animals, including livestock, with few side effects. An object of the present invention is to provide a method for synthesizing such useful new cephalosporin compounds.

Next, the method for producing this new cephalosporin will be described in detail. That is, the present invention relates to general formula (0) HO-A-COO
A carboxylic acid or a reactive derivative thereof represented by (0) (wherein A is the same as above) and general formula (m) (wherein R and 1 substituted with a lower alkyl group
3,4-thiadiazole group), or a salt thereof, or a derivative thereof; It is a method for producing a compound or its non-digestible salt,
When × is one OCOCH3, further HS-Het
(Het is the same as above) to make × -S-Het
It also includes converting to

More specifically, the inert solvents used in the reaction of general formulas (□) and (m) include polar solvents such as dichloromethane, chloroform, acetone, tetrahydrofuran, dioxane, acetonitrile, methyl isobutyl ketone, ethyl alcohol, and dimethylformamide. A solvent or a non-polar solvent such as benzene, toluene, petroleum ether, n-hexane or a mixture thereof is used.

Depending on the case, a water-containing warm mixed solvent thereof may also be used. The reactive derivative of general formula (b) means a reactive derivative of a carboxyl group.

Examples include acid halides, acid anhydrides, acid azolides, active esters, acid azides, and the like. Some of them are dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, dialkyl phosphorous acid, sulfuric acid, methanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, alkyl Mixed or symmetrical acid anhydrides with acids such as carbonic acid, aliphatic carboxylic acids (e.g. pivalic acid, bentanoic acid, isobentanoic acid, 2-ethylbutanoic acid), aromatic carboxylic acids, or imidazoles, substituted imidazoles, dimethyl Acid azolides with pyrazoles, triazoles, tetrazoles, etc., cyanomethyl esters, methoxymethyl esters, vinyl esters, propargyl esters, p-nitrophenyl esters, 2,4-dinitrophenyl esters, trichlorophenyl esters, bentachlorphenyl esters ester, methanesulfonylphenyl ester, phenylazophenyl ester, phenylthiophenyl ester,
p-nitrophenyl thioester, /lactresyl thioester, p-poxymethyl thioester, pyranyl ester, pyridyl ester, piveridyl ester, 8-
Active esters such as quinolyl thioester or esters with N.N'-dimethylhydroxylamine, 1-hydroxy-2(IH)-pyritone, N-hydroxysuccinimide or N-hydroxyphthalimide may be mentioned. When the general formula (0) is used in the form of a free acid (or a salt thereof), for example, N.N'-dicyclohexylcarbodiimide, N-cyclohexy-N-mo'refolinoethylcarbodiimide, N-cyclohexylcarbodiimide, and N-cyclohexylcarbodiimide.

Hexyl N-(4-diethylaminocyclohexyl)
powerlupodiimide, N・N'-diethylcarpodiimide,
N・N′-diisopropylcarbodiimide, N-ethyl-N-(3-dimethylaminopropyl)carbodiimide, N・N′-carbonyldi(2-methylimidazole)
, bentamethyleneketene-N-cyclohexylimine,
Diphenylketene-N-cyclohexylimine, alkoxyacetylene, 1-alkoxy-1-chloroethylene, phosphite trialkyl ester, polyphosphate ethyl ester, polyphosphate isopropylester, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, Oxalyl chloride, triphenylphosphine, 2-ethyl-7-hydro 0
Xybenzisoxazolium salt, 2-ethyl-5-(m
Advantageously, the reaction is carried out in the presence of a binder such as (chloromethylene)dimethylammonium chloride or the like. Thus, amidating agents commonly used in the fields of peptide chemistry or penicillin and cephalosporin chemistry are used in the present invention.

Salts of the compound of general formula (m) include salts of the acid represented by general formula (m) with alkali metals or alkali metals such as sodium, potassium, and calcium, and organic bases such as trimethylamine, triethylamine, quinoline salts, and collidine salts. and organic sulfonic acid salts such as toluenesulfonic acid, naphthalenesulfonic acid, and tetralinsulfonic acid. Derivatives of the compound of general formula (m) include esterified or amidated carpoxyl groups, or Examples include protected carboxyl derivatives, such as carboxyl groups in anhydride form.

Protected carboxyl derivatives contain groups that are easily cleaved to give carboxylic acids after the acylation reaction, such as solvolysis in acidic or weakly alkaline media, such as hydrolysis or alcoholysis, hydrogenolysis, reduction, oxidation, Preferred are groups that yield free carboxylic acid by nucleophilic substitution, photoreaction, or enzymatic reaction. Such protected carboxyl group derivatives include silyl ester,
Organic sudester, toluenesulfonyl ethyl ester, /granitrobenzyl ester, benzyl ester,
Phenacyl ester, 2-furyl methyl ester, diphenyl methyl ester, substituted diphenyl methyl ester/P-methoxybenzyl ester, trityl ester,
Benzoyloxymethyl ester, lower alkanoyloxymethyl ester, dimethylmethylene amino ester, /f-ranitrophenyl ester, methylsulfonylphenyl ester, methylthiophenyl ester, t-butyl ester, 4-picolyl ester, iodoethyl ester, trichloroethyl ester, phthalimidomethyl ester, 3/4 dimethoxy, or 3,5-dimethoxybenzyloxycarbonyl group, 2-nitrobenzyloxycarbonyl group, 2,2-dinitrobenzyloxycarbonyl group, acetyloxy carbonyl group, trichloroacetyloxycarbonyl group, or (R'
(indicates an alkyl or aryl group) and other carboxylic acid protecting groups used in the field of peptide chemistry or the field of penicillin and cephalosporin chemistry.

In the case of these derivatives of general formula (m), salts thereof such as hydrochloride, toluenesulfonate, naphthalenesulfonate, and tetralinsulfonate can also be used. Further, in the case of forming a silyl ester, other sites that can be silylated, such as hydroxyl groups and amino groups, may be silylated.

The reaction temperature of the acid represented by the general formula (0) or its reactive derivative as described above and the 7-amino-acylamidocephalosporin represented by the general formula (m) or its derivative may be any temperature. It can be reacted at 50 o
Do it below o.

Other methods for producing general formula (1) include the following method. That is, an acylaminocarboxylic acid or a reactive derivative thereof represented by the general formula (N) (wherein A and R are the same as above) and a compound represented by the general formula (V) (wherein x is the same as above) or its derivative, × is −
When the OCOC ratio is, the obtained compound has the formula HS-He
This is a method for producing general formula (1) by reacting t (Het is the same as above) with a heterocyclic thiol.

Some compounds of the general formula (blood) are already known.

For example, the patent for 7-[Q-amino-arylacetamido]cephalosboranic acid (indicating a hydroxyl-substituted phenyl group as an aryl group) is published in Japanese Patent Publication No. 46-23.
071, Canadian Patent No. 87 Total 6 Specification, U.S. Patent No. 3,634,416, Japanese Patent Publication No. 1983-
8208 Candies, etc. are listed. In addition, the 3-acetoxy group of cephalosporin can be substituted with various nucleophiles, resulting in 7-
Compounds in which the amino group is acylated with a hydroxyl-substituted phenylglycyl group are described, for example, in Dutch Patent Publication No. 70/05.
Specification No. 51 (Pharmadoc Magazine 8018), US Patent No. 3634416, US Patent No. 36344
Specification No. 18, Japanese Patent Publication No. 47-12579,
Japanese Patent Publication No. 49-31689, Japanese Patent Publication No. 49-54393, Japanese Patent Publication No. 49-49
984. Next, aspects of the present invention will be specifically explained with examples, but the present invention is not limited to the examples only.

Reference example 1 7-[D-Q-(4-hydroxypyridine-3-carbonamide)-Q-p-hydroxyphenylacetamide]
Production method of cephalosporanic acid 71 [D-Q-amino-Q-hydroxyphenylacetamide] 4.21 hours of cephalosporanic acid, 60 minutes of dichloromethane, and 2.02 hours of triethylamine were added under ice-cooling, and 4-hydroxy Pyridine-3-carboxylic acid N-hydroxysuccinimide ester At 2.36 pm, 30% Z of dimethylformamide was added, and the mixture was heated at the same temperature for 30 minutes.

After further reacting at room temperature for 2 hours, 1.66 g of sodium 2-ethylhexanoate was added, and after 1 minute, 200 g of dichloromethane and 100 g of ether were added to crystallize, and the precipitated crystals were collected in a furnace. , and washed with ether. Dissolve this in water, adjust the pH to 2 with Su-HCl while cooling on ice, collect the precipitated crystals in a furnace, wash with water, and dry under reduced pressure over phosphorus pentoxide to obtain the solution for the topic on the evening of 2.1. The compound was obtained. Furthermore, take this free acid in dimethylformamide 13, add 1.1 times the molar amount of sodium 2-ethylhexanoate, add dichloromethane and acetone to crystallize it, and obtain the sodium salt 1 of the title compound. .9 evenings were obtained. Example 1 7-[D-Q-(4-hydroxypyridine-3-hydroxybenamide)-Q-p-hydroxyphenylacetamide]-31(2-methyl-1,3,4-thiadiazole-
5-yl)Thiomethyl-3-cephem-4-carboxylic acid production method 7-(D-Q-amino-Q-p-hydroxyphenylacetamide)-13-(2-methyl-113.4-thiadiazol-5-yl)thiomethyl-3-cephem4 -Carboxylic acid 4.93, triethylamine 2.0
On 2 evenings, 80 ml of dimethylformamide was heated under ice-cooling, 2.36 ml of 4-hydroxypyridine-3-carboxylic acid N-hydroxysuccinimide ester was added, and the mixture was stirred at the same temperature for 30 minutes. .

After further reacting at room temperature for 2 hours, sodium 2-
1.66 ml of ethyl hexanoate was added, and after 10 minutes, 200 ml of acetone and 200 ml of ether were added to precipitate crystals. The crystals were collected in a furnace and washed with ether. Furthermore, this cake was dissolved in water and cooled on ice for one day at CI to pH 2.
The precipitated crystals were collected in a furnace, washed with water, and then dried under reduced pressure over phosphorus pentoxide to obtain the title compound of 2.6. Furthermore, a sodium salt was obtained in the same manner as in Reference Example 1. The melting point of the sodium salt was 225-235oo (decomposed). Example 2 7-(D-Q-amino-Q1p-hydroxyphenylacetamide)-3-(2-methyl-1.3.4-thiadiazol-5-yl)thiomethyl-3-cephem-4-
Carboxylic acid 4.93 days, triethylamine 2.02 days,
80 g of dimethyl sulfoxide was added at room temperature, 2.36 g of 4-hydroxypyridine-3-carboxylic acid-N-hydroxysuccinimide ester was added, and the mixture was allowed to stand for 30 minutes.

1.66 sodium 2-ethylhexanoate in the reaction solution
After 10 minutes, 2.0% acetone was added to precipitate crystals. The crystals were collected in a furnace, washed with acetone and ether, and then dried under reduced pressure over phosphorus pentoxide to obtain a sodium salt of the same compound as in Example 1 on May 2, 2015. Example 3 7-[D-Q-(4-hydroxypyridine-3-carboxyamido)-Q-(p-hydroxyphenyl)acetamide]-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl )-Production method of 3-cephem-4-carboxylic acid 7-[D-Q-(4-hydroxypyridine-3-carboxyamide)-Q-(p-hydroxyphenyl)acetamide] Cephalosporanic acid sodium salt 0.564, 2-methyl -5-Mercapto 103・
4-thiadiazole 0.18 m, baking soda 0.10 m, pH
A solution of 20 ml of 6.0 phosphate buffer was allowed to react at 60-65° C. for 7 hours.

Some insoluble matter was removed in the furnace, and the furnace liquid was ice-cooled and adjusted to pH 2.0 using SHU-HCI. The precipitated crystals were collected in a furnace, washed with water and ether, and then dried under reduced pressure over IJ pentoxide to obtain the title compound with a weight of 0.50 mm. Example 4 The following compound was synthesized in the same manner as in Example 1.

7-[D-Q-(4-hydroxy-6-methylpyridine-3-carboxyamide)-Q-(p-hydroxyphenyl)acetamide]-131(2-methyl-1,3,4
-thiadiazol-5-ylthiomethyl)-3-cephemu 4-carboxylic acid sodium salt mP230-23bi○
(Degradation) Next, the antibacterial test results of the example compounds will be shown.

Next is Kuseikawa'.

to refuse. (Note) Staphylococcus aureus FS2
89 is a penicillin-resistant strain CEG: Cephaloglycin C
ET: Cephalothin CEZ: Cefazoline

Claims (1)

[Claims] 1 General formula HO-A-COOH (In the formula, A represents a pyridine ring, and HO-A- represents that this pyridine ring is substituted with a hydroxyl group. Represented by A The pyridine ring may be further substituted by a lower alkyl group. , Het is
It represents a 1,3,4-thiadiazole group which is unsubstituted or substituted with a lower alkyl group having 1 to 4 carbon atoms. ), or a salt thereof, or a derivative thereof. There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (wherein A, R, and Het are the same as above). A method for producing N-acylamino-α-arylacetamidocephalosporins as shown. 2 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, A represents a pyridine ring, and HO-A- represents that this pyridine ring is substituted with a hydroxyl group. Pyridine represented by A The ring may be further substituted with a lower alkyl group.R represents a hydroxyl-substituted phenyl group. represents a 1,3,4-thiadiazole group unsubstituted or substituted with a lower alkyl group having 1 to 4 carbon atoms.
There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, A, R, and Het are the same as above.) A method for producing N-acylamino-α-arylacetamidocephalosporins.