JPH0641145A - Cephalosporin derivative - Google Patents

Abstract

PURPOSE:To provide a new cephalosporin derivative useful as an intermediate for an aminothiazol cephalosporin derivative having an excellent antibacterial activity and being a medicine for various bacterial infections. CONSTITUTION:The derivative is a cephalosporin derivative expressed by formula 1 (X is an eliminable group; R<1> is a (lower alkyl substituted) thiazolyl; R<3> is H or a carboxyl protecting group) or its salt, e.g. p- methoxybenzyl-7beta-[(Z)-4-2-(4-methylthiazol-5-yl)ethenyl]-3-cephem-4 -carboxylate. The compound of formula 1 can be obtained by subjecting a compound of formula 2 or its salt to reaction with a compound of formula 3, its reactive derivative or its salt and, if needed, eliminating a carboxyl protecting group. Further, the compound of formula 1 is subjected to reaction with a compound of formula 4 and, if necessary, to eliminate a protecting group, to obtain a cephalosporin antibiotic compound by a short and simple process and in good yield.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel cephalosporin derivative represented by the general formula (1) and a method for producing the same, and a cephalosporin derivative (5) obtained from (1) The present invention relates to a method for producing pharmaceutically acceptable salts and esters thereof, which is useful in the field of medicine.

[0002]

[Chemical 8]

[0003]

2. Description of the Related Art As a method for producing a cephalosporin antibiotic represented by the general formula (5) and a group of analogs thereof (collectively represented by (8)), a reaction route diagram (A) of Atsumi Kunio et al. A manufacturing method is known (Japanese Patent Publication No. 3-6450).
3).

[0004]

[Chemical 9]

(Wherein R ¹ is an amino group or a protected amino group, R ² is a lower alkyl group, a carboxymethyl group or a protected carboxymethyl group, R ³ is a hydrogen atom, a salt-forming cation. Or a carboxyl group-protecting group, and A represents a phenyl group, a furyl group, a thiazolyl group or a lower alkyl thiazolyl group.) This reaction is a compound represented by the general formula (7) or a reactive derivative of the amino group thereof. Alternatively, a salt thereof is reacted with a compound represented by the general formula (6), a reactive derivative of the carboxyl group thereof, or a salt thereof.

[0006]

However, in order to obtain an antibacterial agent useful as a medicine and pharmaceutically acceptable salts and esters thereof from these compounds (8), a carboxyl protecting group and / or an amino group can be prepared by a conventional method. Removal of the protecting group is required. The production method by Atsumi Kunio et al. For acylating compound (7) with a thiazolyl acetic acid derivative to derive compound (8) is as follows. That is, the general formula (6)
When the acylation of (7) is carried out with a reactive derivative at the carboxyl group of the compound represented by R ¹ , R ¹ must be a protected amino group. When the compound (6) is used in the form of free acid or salt, it is desirable to carry out the acylation of (7) in the presence of a condensing agent. In this case, R ³ is a carboxyl group-protecting group. It is necessary to be.

[0007]

According to the present invention, the above problem can be solved by the reaction route diagram B. That is, the production of (1) can be easily carried out by condensation of the 7-aminocephem derivative (2) (wherein R has the same meaning as described above) and the reactive derivative of (3). (1) can be converted to a cephem form (5) by forming a crude aminothiazole ring by reacting with thiourea as a crude product or after being isolated and purified by an ordinary separation means. Especially when the cephem derivative (2a) having no carboxyl group protecting group is used, the deprotection reaction of the carboxyl group is not required after the reaction. In addition, since a 2-aminothiazole ring is formed after acylation with 4-bromobutyric acid derivative at the 7-position, deprotection of the amino group is not required after the reaction, and cephalosporin, which is useful as a drug in a short process in a simple and high yield Can lead to system antibiotics.

[0008]

[Chemical 10]

The compound (1) of the present invention can be produced by the following method. The compound represented by the formula (2) [wherein R has the same meaning as defined above] or its reactive derivative at the amino group or a salt thereof is reactive with the compound represented by the formula (3) or the carboxyl group thereof. It can be produced by reacting a derivative or a salt thereof.

Suitable examples of the reactive derivative at the amino group of the compound (2) include the compound (2) and a silyl derivative such as bis (trimethylsilyl) acetamide. Suitable salts of the compound (2) include salts with organic acids (eg, acetate, maleate, tartrate, benzenesulfonate, toluenesulfonate, etc.) or salts with inorganic acids (eg, hydrochloride, Acid addition salts such as hydrobromide, sulfate, phosphate, etc .; alkali metal salts or alkaline earth metal salts (eg sodium salts, potassium salts,
Metal salts such as calcium salts, magnesium salts, etc.);
Ammonium salts; organic amine salts (eg, triethylamine salt, dicyclohexylamine salt, etc.) and the like can be mentioned.

Suitable examples of the reactive derivative at the carboxyl group of the compound (3) include acid halides, acid azides, acid anhydrides, active amides, active esters and the like, more specifically, acid chlorides. , Acid bromide; substituted phosphoric acid (eg, dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.), dialkyl phosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid,
Alkyl carbonate (eg methyl carbonate, ethyl carbonate, etc.),
Mixed acid anhydrides with acids such as aliphatic carboxylic acids (eg pivalic acid, valeric acid, isovaleric acid, 2-ethylacetic acid, trichloroacetic acid etc.) or aromatic carboxylic acids (eg benzoic acid etc.); symmetrical acid anhydrides An active amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an active ester (for example, cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH ₃ ) ₂ N ⁺ = CH-] ester, Vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.) or N-hydroxy compound (for example, N, N-dimethylhydroxylamine, 1-hydroxy-2- ( 1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole, etc.) and the like.

The reactive derivative of the compound of the formula (2) is appropriately selected depending on the kind of the compound (3) to be used. The reaction between the compounds (2) and (3) is usually water, acetone, dioxane, acetonitrile, chloroform,
It is carried out in a conventional solvent such as methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine. These solvents may be used as a mixture with water.

In this reaction, when the compound (3) is used in the form of free acid or salt, it is desirable to carry out the reaction in the presence of a condensing agent. Examples of such condensing agent include N, N -Dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide;
N-cyclohexyl-N '-(4-diethylaminocyclohexyl) carbodiimide; N, N'-diethylcarbodiimide; N, N'-diisopropylcarbodiimide;N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide; N, N '-Carbonylbis (2-
Methylimidazole); pentamethylene ketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-
1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride;
Phosphorus trichloride; Thionyl chloride; Oxalyl chloride; Triphenylphosphine; 2-Ethyl-7-hydroxybenzisoxazolium salt; 2-Ethyl-5- (m-sulfophenyl) isoxazolium hydroxide inner salt; 1
-(P-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole; so-called Vilsmeier reagent obtained by the reaction of dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride and the like can be mentioned. This reaction may also be carried out in the presence of an inorganic base or an organic base, and examples of such a base include alkali metal hydrogencarbonates (eg sodium hydrogencarbonate, potassium hydrogencarbonate, etc.), alkali metal carbonates (eg carbonate). Sodium, potassium carbonate, etc.), alkaline earth metal carbonates (eg calcium carbonate, etc.), tri (lower)
Examples thereof include alkylamine (eg, trimethylamine, triethylamine, etc.), pyridine, N- (lower) alkylmorpholine, N, N-di (lower) alkylbenzylamine and the like. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating. Next, the compound (1) thus obtained is reacted with thiourea to form an aminothiazole ring to produce a cephalosporin antibiotic useful as a drug or a cephem derivative having a protected carboxyl group. it can. The reaction of this compound (1) with thiourea is usually carried out by using water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate,
It is carried out in a conventional solvent such as N, N-dimethylformamide or pyridine. These solvents may be used as a mixture with water. The reaction temperature is not particularly limited, and the reaction is usually
It is carried out under cooling or heating.

[0014]

EFFECT OF THE INVENTION The compound represented by the general formula (1) has an excellent antibacterial activity by reacting with thiourea, and is an aminothiazole cephalosporin derivative useful as a therapeutic drug for various bacterial infections. Can be produced in high yield. The present invention will now be described in detail by way of examples.

[0015]

【Example】

Example 1 7β-[(Z) -2- (2-amino-4-thiazolyl)
2-Methoxyiminoacetamide] -3-[(Z)-
2- (4-methylthiazol-5-yl) ethenyl]-
3-Cephem-4-carboxylic acid (2a) 7β-amino-3-[(Z) -2- (4-methylthiazol-5-yl) ethenyl] -3-cephem-4-carboxylic acid 537 mg (1.66 mmol) ) And baking soda 454m
g (5.1 mmol) was dissolved in 18 ml of water and 12 ml of tetrahydrofuran, and (Z) -4-bromo-2 was added at 5 ° C.
-Methoxyimino-3-oxobutyric acid chloride 565 mg
A solution of (2.33 mmol) in 3 ml of tetrahydrofuran is added dropwise and stirred for 5 minutes. After confirming the disappearance of the raw materials by liquid column chromatography, 253 mg of thiourea (3.
3 mmol of an aqueous solution of 2 mmol) is added and reacted at 25 ° C. for 1.5 hours. The reaction solution is concentrated under reduced pressure, washed with ethyl acetate, and adjusted to pH 3.5 with 1M hydrochloric acid. The deposited precipitate was filtered and dried under reduced pressure to obtain 738 mg of the target product as a white powder.
(84%) is obtained.

NMR (DMSO-d ₆ ) δ ppm: 2.
31 (3H, s), 3.18 (2H, q), 3.83
(3H, s), 5.11 (1H, d), 5.65 (1
H, dd), 6.37 (1H, d), 6.71, (1
H, s), 6.76 (1H, d), 8.89 (1H,
s). Example 2 p-methoxybenzyl 7β-[(Z) -4-bromo-
3-oxo-2-methoxyiminobutyrylamide] -3
-[(Z) -2- (4-methylthiazol-5-yl)
Ethenyl] -3-cephem-4-carboxylate (1
b) p-methoxybenzyl 7β-amino-3-[(Z)-
2- (4-methylthiazol-5-yl) ethenyl]-
3-Cephem-4-carboxylate 443 mg (1 m
mol) and (Z) -4-bromo-3-oxo-2-methoxyiminobutyric acid (224 mg, 1 mmol) were dissolved in methylene chloride (8.8 ml), cooled to -20 ° C, and pyridine (0.1 mol) was added.
32 ml (4 mmol) is added. At the same temperature, 0.1 ml (1.1 mmol) of phosphorus oxychloride is added and reacted for 10 minutes. After the reaction, ethyl acetate and saturated brine are added and the layers are extracted and separated. The organic layer is washed with saturated brine and dried over magnesium sulfate. The solvent is removed and the product is purified by silica gel column chromatography (ethyl acetate: chloroform = 1: 1) to obtain 400 mg (62%) of the desired product.

NMR (DMSO-d ₆ ) δ ppm: 2.
42 (3H, s), 3.28 (1H, d), 3.50
(1H, d), 3.80 (1H, s), 4.13-4.
17 (2H, m), 4.18 (3H, s), 5.1
7-5.14 (3H, m), 5.92 (1H, dd),
6.31 (1H, d), 6.58 (1H, d), 6.
83 (2H, d ), 7.22 (2H, d), 8.61
(1H, s). Example 3 p-methoxybenzyl 7β-[(Z) -2- (2-a
Mino-4-thiazolyl) -2-methoxyiminoacetoa
[Mido] -3-[(Z) -2- (4-methylthiazole-
5--yl) ethenyl] -3-cephem-4-carboxy
Rate (2b) p-methoxybenzyl 7β-[(Z) -4-bromo-
3-oxo-2-methoxyiminobutyrylamide] -3
-[(Z) -2- (4-methylthiazol-5-yl)
Ethenyl] -3-cephem-4-carboxylate 34
5 mg (0.53 mmol) of tetrahydrofuran 6.
Dissolve in 9 ml and 0.7 ml of water and cool with ice. 1 ml of an aqueous solution of 76 mg (1 mmol) of thiourea was dropped into the solution, and the mixture was reacted at the same temperature for 1 hour. After the reaction, the solvent is removed, the mixture is extracted with chloroform and dried over magnesium sulfate.
After removing the solvent, the product was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain 295 m of the desired product.
g (89%) was obtained.

NMR (DMSO-d ₆ ) δ ppm: 2.
40 (3H, s), 3.27 (1H, d), 3.48
(1H, d), 3.80 (3H, s), 4.02 (3
H, s), 5.09 (1H, d), 5.15 (1H,
d), 5.18 (1H, d), 5.58 (2H, br
s), 6.08 (1H, dd), 6.32 (1H,
d), 6.57 (1H, d), 6.79 (1H, s),
6.83 (2H, d), 7.23 (2H, d), 8.0
3 (1H, d), 8.54 (1H, s). Example 4 7β-[(Z) -2- (2-amino-4-thiazolyl)
-2-Methoxyiminoacetamide] -3-[(Z)-
2- (4-methylthiazol-5-yl) ethenyl]-
3-Cephem-4-carboxylic acid trifluoroacetate p-methoxybenzyl 7β-[(Z) -2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamide] -3-[(Z)- 2- (4-methylthiazole)
278 mg (0.44 mmol) of 5-yl) ethenyl] -3-cephem-4-carboxylate are dissolved in 0.56 ml of anisole. 2.8 ml of trifluoroacetic acid was added under ice cooling, and the reaction was carried out at the same temperature for 45 minutes. After the reaction, 12 ml of isopropyl ether is added dropwise to cause precipitation. The mixture is stirred for 1 hour as it is, filtered, washed well with 12 ml of isopropyl ether, dried and dried to obtain 252 mg (91%) of the desired product.
%) Was obtained.

NMR (DMSO-d ₆ ) δ ppm: 2.
39 (3H, s), 3.37 (1H, d), 3.54
(1H, d), 3.89 (3H, s), 5.27 (1
H, d), 5.86 (1H, dd), 6.38 (1H,
d), 6.74 (1H, d), 6.82 (1H, d),
8.97 (1H, s), 9.77 (1H, d).

Front page continuation (72) Inventor Katsuharu Iinuma 788 Kajiyama, Odawara-shi, Kanagawa Meiji Seika Co., Ltd., Research Institute of Pharmaceutical Sciences (72) Inventor, Atsushi Sato 788 Meiji Seika Co., Ltd., Meiji Seika Co., Ltd.

Claims (3)

[Claims] 1. A compound represented by the general formula (1): (In the formula, X is a leaving group, R ¹ is a lower alkyl group, R ² is a thiazolyl group optionally substituted by a lower alkyl group, R ^2
3 represents a hydrogen atom or a carboxyl protecting group. ) The cephalosporin derivative or its salt represented by these. 2. A general formula (2): (In the formula, R ² represents a thiazolyl group which may be substituted with a lower alkyl group, R ³ represents a hydrogen atom or a carboxyl protecting group.) Or a salt thereof and a compound represented by the general formula (3): ] (In the formula, R ¹ represents a lower alkyl group, and X represents a leaving group.)
The compound represented by the formula (1) or a reactive derivative thereof or a salt thereof is reacted, and the carboxyl protecting group is eliminated as the case requires. (In the formula, R ¹ , R ² , R ³ and X have the same meanings as described above.) A process for producing a cephalosporin derivative or a salt thereof. 3. A compound represented by the general formula (1): (In the formula, X is a leaving group, R ¹ is a lower alkyl group, R ² is a thiazolyl group optionally substituted by a lower alkyl group, R ^2
3 represents a hydrogen atom or a carboxyl protecting group. ), A cephalosporin derivative represented by the formula (4): By reacting with a compound represented by the formula (1) and further removing an amino-protecting group and / or a carboxyl-protecting group, if necessary. (In the formula, R ¹ , R ² and R ³ have the same meanings as described above.) A method for producing a cephalosporin derivative or a salt thereof, comprising obtaining a compound represented by the above.