JPH0491077A - Pyridone compound - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (X is lower alkyl or phenyl; R1 and R2 are H or OH-protecting group) and its reactive derivative. EXAMPLE:(Z)-4-methanesulfonyloxy-3-oxo-2-(1,5-dibenzyloxy)-4-pyridon-2- ylmethoxyimino)butyric acid. USE:A production intermediate for antibacterial agent. PREPARATION:The compound of formula I can be produced according to the reaction formula by reacting a compound of formula II (R3 is carboxyl- protecting group such as tert. butyl) with a halomethyl compound of formula III (Y is halogen, mesyloxy, etc.) and removing the protecting group from the resultant methoxyimino compound of formula IV.

Description

[Detailed description of the invention] [Industrial application field] The present invention relates to novel pyridone compounds.

More particularly, the present invention relates to novel intermediate compounds used in the preparation of cephalosporin derivatives useful as antimicrobial agents.

[Conventional technology]

Although many synthetic antibacterial agents have been known, recently cephalosporin derivatives having a pyridine-N-oxide structure have been developed.

[Purpose of the invention]

By introducing a novel substituent into the 7-position side chain of the cephem ring, the present inventors have developed a cephalosporin that exhibits remarkable antibacterial activity against Durum-positive and Durum-negative bacteria, particularly against Pseudomonas aeruginosa. Creating compounds (Japanese Unexamined Patent Publication No. 1983)
-152386).

We have now discovered a pyridone compound useful as a new intermediate compound used in the production of these cephalosporin compounds and completed the present invention.

[Means for solving the present invention]

According to the present invention, the general formula (wherein, ) or a reactive derivative thereof is provided.

The lower alkyl group in X is 1, for example, a methyl group,
Examples include ethyl group, propyl group, butyl group, and examples of groups which may be substituted with phenyl group include lower alkyl groups such as methyl group and ethyl group. R1biR
Examples of the hydroxyl protecting group in 2 include tri-lower alkylsilyl groups such as trimethylsilyl groups, acyl groups such as formyl groups, acetyl groups, and propionyl groups, benzyl groups, P-methoxybenzyl groups, P-nitrobenzyl groups, and benzhydryl groups. , aralkyl groups such as trityl groups,
Examples include methoxymethyl group, allyl group, and pyranyl group.

Examples of the reactive derivatives of the pyridone compound of general formula [I] include acid halides (e.g., acid chloride, acid bromide, etc.), active esters (e.g., benzotriazole ester, benzothiazolyl thioester, cyanomethyl ester, nitro phenyl esters, esters with N-hydroxysuccinimide, etc.), mixed acid anhydrides (
Examples include mixed acid anhydrides with ethoxycarboxylic acid, isobutoxycarboxylic acid, trimethylacetic acid, etc.), active amides, and active azides.

The compound of the present invention represented by the general formula CI) can be produced, for example, by the method of the following formula.

0R2C■]
Examples include aryl groups such as methoxybenzyl group and benzhydryl group, and Y represents a halogen atom or a sulfonate group such as mesyloxy group and tosyloxy group;
R, and R2 are the same as above) That is, the hydroxyimino compound [11) and the halomethyl compound (m) are reacted to obtain the methoxyimino compound (IV), and then the carboxyl group of the methoxyimino compound (JV) is reacted. By removing the protecting group R1 by a conventional method, a pyridone compound represented by the general formula (1) can be obtained.

In addition, among the pyridone compounds represented by general formula [1], R
A compound in which U and/or R2 are hydrogen atoms can be produced by removing the corresponding hydroxyl protecting group R1 and/or R2. Specifically, the protecting group R0 and/or R2 of the hydroxyl group in the general formula (IVE) is converted into a protective group R0 and/or R2 of the hydroxyl group in the general formula (IVE) by a conventional method based on the characteristics of the protecting group. Hydrohalic acids such as hydrohydric acid and hydrochloric acid, sulfonic acids such as P-toluenesulfonic acid and methanesulfonic acid, aluminum chloride, aluminum bromide, and trifluoride in the presence or absence of anisole or thioanisole. A method using an acid such as a Lewis acid such as boron chloride or titanium tetrachloride, a method using an alkali such as sodium hydroxide, sodium carbonate, sodium bicarbonate, or aqueous ammonia, or a method using a halogenated silane such as trimethylsilane iodide. The protecting group may be removed by a catalytic reduction method using a catalyst such as palladium or platinum.

When using the above method, the reaction is generally from -20 to 60'
This is carried out within the range of 15 minutes to 12 hours by adding an appropriate solvent as necessary.

Compound (1) of the present invention is useful as an intermediate compound in the production of cephalosporin derivatives having a pyridine-N-oxide structure.

For example, a cephalosporin compound useful as an antibacterial agent having a pyridine-N-oxide structure can be produced by the following production process.

2 (I) [■] [■] (wherein, R4 represents a carboxyl group protecting group, X, R
In other words, the compound of the present invention CI) and the 7-aminocephalosporin compound [■] are combined to form a cephalosporin substituted at the 7-position using a condensation reaction used in the field of β-lactam agents. A sporin compound (VI) is obtained, then a cephalosporin compound (VI) substituted at the 7-position is reacted with thiourea to obtain a cephalosporin compound [■] having an aminothiazole ring, and then the cephalosporin compound [■] ] by subjecting it to a deprotecting group reaction commonly used in the field of β-lactam agents to obtain pyridine-N-
EXAMPLES A cephalosporin compound [■] having an oxide structure can be produced.The present invention will be explained in more detail with reference to Examples and Reference Examples.

Example 1. 25.5 g of 5-dibenzyloxy-2-chloromethyl-4-pyridone was dissolved in 250 mQ of dry acetone,
Furthermore, 10.7 g of sodium iodide was added and stirred for 1 hour. Filter the precipitate and cool the filtrate to -30"C.

Then triethylamine 13゜Om Q, then 4-
Methanesulfonyloxy-3-oxo-2-hydroxyiminobutyric acid t-butyl ester 26.2g - 20℃
Add below. After stirring at 20'C for 2 hours, 1.3Q of water,
Add 0.50 ethyl acetate and separate the layers. The aqueous layer is further extracted twice with 250 mQ of acetic acid ester, combined with the previous ethyl acetate layer, and washed twice with a mixture of 500 mQ of water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain an oily 4-methanesulfonyloxy-3-oxo-2-(1,5-dibenzyloxy-4-
Pyridon-2-ylmethoxyiminobutyrate t-butyl ester is obtained.

300 mL of cooled trifluoroacetic acid is added to the obtained oil and reacted at room temperature for 90 minutes. Concentrate the reaction solution under reduced pressure,
After adding ethyl ether to this and collecting the resulting precipitate by filtration,
The precipitate was suspended in water IQ, 500 ml of chloroform,
Adjust the pH to 7.3 with saturated sodium bicarbonate solution. After filtering the insoluble matter, the aqueous layer is adjusted to pH 2.7 with IN-hydrochloric acid, and the precipitate formed is collected by filtration, washed with water, and then dried to obtain the desired (Z)-4-
Methanesulfonyloxy-3-oxo-2-(1,5-
27.1 g of dibenzyloxy-4-pyridon-2-ylmethoxyimino)butyric acid are obtained.

1H-NMR (DMSO-d, δ): 3, 23 (3
H,s), 5.02 (2H,s).

6, 27 (LH, s), 8.13 (LH, s)
Reference Example (1) (Z)-4-methanesulfonyloxy-3-oxo-2-(1,,5-dibenzyloxy-4-pyridon-2-ylmethoxyimino)butyric acid 10 obtained in Example
．． Dissolve 5 g in 200 mQ of dimethylacetamide, add 3.0 g of 1-hydroxybenzotriazole,
Cool to -5°C. Add to this 3. dicyclohexylcarbodiimide. Add C)g and stir at 0°C for 2 hours. Add 7.8 g of 7-amino-3-(1,2,3,-thiadiazol)-5-ylmethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester, and react at 5° C. for 20 hours. Insoluble materials are collected by filtration, 800 mQ of ethyl acetate is added to the filtrate, and the mixture is washed with 5% sodium bicarbonate solution, water, and saturated brine in this order.

After drying over anhydrous magnesium sulfate, it is concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform:methanol=40:1) to give (6R,7R)-7-[(Z
)-4-methanesulfonyloxy-3-oxo-2-(
1,5dibenzyloxy-4-pyridon-2-ylmethoxyimino)acetamidoco3-(1,2゜3-thiadiazol-5-ylthiomethyl)3-cephem-4-
Carboxylic acid P-methoxybenzyl ester 11.4g
get.

"H-NMR (DMSO-d6.δ): 3.16 (3
H,s), 3.82 (3H,s).

6.54 (LH, s), 8.40 (LH, 5) (2
) (7) (6R,7R)-7-[(Z)-4-methanesulfonyloxy-3-oxo-2-(1,5-dibenzyloxy-4-pyridon-2-ylmethoxyimino)
acetamide]-3(1,2,3-thiadiazole-5-
ylthiomethyl)-3-cephem-4-carboxylic acid p-
Dissolve 1.36 g of methoxybenzyl ester in 5.3 mQ of dimethylacetamide, and add 8 mQ of a methanol solution containing 129 mg of thiourea. After stirring at room temperature for 30 minutes, leave to stand for 20 hours. Add 70m of ethyl ether to the reaction solution.
A gummy precipitate forms when fl is added. The supernatant liquid is removed, and 40 mQ of ethyl ether is further added to form a powder.

This was collected by filtration, washed with ethyl ether, and dried (6R
,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2(1,5-dibenzyloxy-4-pyridon-2-ylmethoxyimino)acetamidoco3-
(l, 2,3-thiadiazol-5-ylthiomethyl)
1.2 g of -3-cephem-4-carboxylic acid p-methoxybenzyl ester are obtained.

"H-NMR (DMSO-d Glδ): 3, '72
(3H,s), 6.72 (LH,s).

7, 23 (5H, s), 7.27 (5H, s)
8.32 (IH, 5) (3) Add 1.4 g of aluminum chloride to 3.0 mQ of ice-cooled nitromethane. This solution contains the above obtained (6
R,7R)-7-[(z)2-(2-aminothiazol-4-yl)2-(1,5-dibenzyloxy-4-pyridon-2-ylmethoxyimino)acetamide]3-
(1,2,3-thiadiazol-5-ylthiomethyl)
A solution of 1.2 g of -3-cephem-4-carboxylic acid P-methoxybenzyl ester in methylene chloride and then anisole O,'7mQ are added dropwise. Stir for 10 minutes under water cooling and then for 2 hours at room temperature. After the reaction, the reaction solution was ice-cooled with 4.8 mQ of n-butanol, 1.2 mQ of methanol, and 2 mQ of 1N hydrochloric acid.
．． Add dropwise to 4mQ of mixed solution. Add 2. saturated saline to this solution.
4. Add mfl little by little, leave to stand still, and then separate the liquids. water layer n
- Extract with 4.8 mQ of butanol and wash the organic layer three times with 4.2 mfl of saturated brine of IN hydrochloric acid. Add 4 liters of water to the organic layer
．． Add 8 mQ and adjust the pH to 3.1 with 5% aqueous sodium bicarbonate.

The formed precipitate is collected by filtration, washed with water and then ethyl acetate, and then dissolved in 5% aqueous sodium bicarbonate. This is Diaion HP-20
The product was subjected to column chromatography, eluted with 20% methanol aqueous solution, frozen v7, and dried to obtain 0.6 g of the disodium salt of the title compound.

1H-NMR (DMS○-dGlδ): 3, 23 (2
H, ABq), 4.30 (2H, ABq).

4,,95 (LH, d, J=5Hz), 5.05
(2H, ABq).

5, 48 (LH, d, J: 5Hz), 6.39
(LH,s).

6,79 (LH,s), 7.36 (LH,s)
.

8, 93 (LH, s) Patent applicant Kaken Pharmaceutical Co., Ltd. Procedural amendment (voluntary) 1. Case description 1990 Patent Application No. 205255 Postal code +1
3 4. Subject of amendment (1) Change "2 hours of 2 hours in Column 5 of Detailed Description of the Invention J, Contents of Amendment (]) Line IO on page 7 of the specification" to "24 hours (2 hours)" in the specification.
) On page 15, line 3 of the specification, "n-butanol in the aqueous layer" is corrected to "n-butanol in the aqueous layer."

Claims (1)

[Claims] (1) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I] (In the formula, X is a lower alkyl group or a phenyl group that may have a substituent, and R_1 and R_2 are each independently A pyridone compound or a reactive derivative thereof, which means a protecting group for a hydrogen atom or a hydroxyl group.