JPH0158192B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention relates to the general formula [In the formula, R represents a hydrogen atom or a lower alkyl group. ] The present invention relates to a cephalosporin derivative represented by Inventor etc. is a general formula [In the formula, R represents a lower alkyl group. ] Cephalosporin derivatives represented by the formula are absorbed at an extremely high rate from the gastrointestinal tract after oral administration, and after absorption, the bivaloyloxymethyl ester portion is hydrolyzed, resulting in a general formula with strong antibacterial activity. [In the formula, R represents a lower alkyl group. We discovered that a new cephalosporin represented by the following formula was produced, and showed that it is an extremely useful compound as an oral cephalosporin agent. (Japanese Patent Application No. 55-136449) Subsequently, the present inventors conducted various studies on the production method of the cephalosporin derivative represented by the formula (), and found that the formula Using a new cephalosporin derivative represented by as raw material, it is nitrosated to form the formula The inventors have discovered that the desired compound () can be produced by alkylating this to produce a compound expressed by the formula (), and finally reacting this with thiourea. completed.

In the general formulas () and (), R represents a linear or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, and isobutyl, but especially Preferred groups are methyl and ethyl groups.

Next, the reaction of the present invention will be explained.

The starting material compound () is 7-amino-3-
Obtained by acylating methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester with 4-chloro-3-oxobutyric acid chloride obtained by reacting diketene with chlorine according to a conventional method. It will be done. The reaction is usually carried out in a solvent, but the solvent used is not particularly limited as long as it does not inhibit the reaction; for example, methylene chloride, chloroform, tetrahydrofuran, dioxane, etc. are used. This acylation reaction is usually suitably carried out in the presence of a base, and examples of the base used include organic bases such as triethylamine, pyridine, dimethylaniline, and diethylaniline. The reaction is completed in minutes to hours at temperatures near or below room temperature. After the reaction is completed, the product () can be separated and purified by a conventional method. For example, it can be isolated by concentration, organic solvent extraction, chromatography, recrystallization, etc.

The reaction of producing compound () by nitrosating compound () is partially known as the nitrosation reaction of a compound having an active methylene group, and is usually performed under acidic conditions to produce compound (). This is carried out by reacting a metal salt or a nitrite under appropriate conditions, but in the case of the compounds of the present invention, the reaction is carried out under conditions where the cephalosporin moiety and the 7-position side chain chlorine atom do not participate in the reaction. There is a need. As such conditions, it is desirable to conduct the reaction under weakly acidic or slightly basic conditions at room temperature or lower.

The reaction is usually carried out in a solvent, but the solvent is not particularly limited as long as it dissolves the starting compound () and does not inhibit the reaction. Examples of such solvents include acid, acetic acid, tetrahydrofuran,
Methanol, ethanol, chloroform, ethyl acetate, benzene, or a mixture of these and water is used, and an appropriate one is selected depending on the type of nitrosating agent.

As the metal nitrite salt used as the nitrosating agent, alkali metal salts of nitrite such as sodium nitrite, potassium nitrite, etc. are usually used, and sodium nitrite is particularly preferred.
As the nitrite ester, esters with lower alcohols such as amyl nitrite and butyl nitrite are commonly used.

When using a nitrite metal salt as a nitrosating agent, the reaction must be carried out under acidic conditions, so if an acidic solvent such as acidic acid or acetic acid is not used, an organic or inorganic acid must be added separately. It is necessary to add Therefore, it is usually preferable to use acidic acid or acetic acid.

The reaction is carried out at or below room temperature and is usually completed within several minutes to several hours.

The post-reaction product () can be isolated and purified by conventional methods. For example, it can be isolated by concentration, organic solvent extraction, chromatography, etc.

The reaction for producing compound () by alkylating compound () is a reaction that partially alkylates an oxime, and is usually carried out by reacting with a suitable alkylating agent in a solvent. .

Any solvent may be used as long as it does not adversely affect this reaction, such as acetone, tetrahydrofuran, dioxane, methanol, ethanol, chloroform, ethyl acetate, ether, N,
N-dimethylformamide or a mixture thereof is used.

Examples of alkylating agents include dimethyl sulfate,
Diethyl sulfate, diazomethane or alkyl halides such as methyl iodide, ethyl iodide, etc. are used. Except when using diazo alkanes such as diazomethane, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, triethylamine, pyridine, etc.
The reaction is carried out in the presence of a base such as dimethylaniline.

The reaction is usually completed in several minutes to several hours at a temperature around room temperature or lower. After the reaction is completed, the product () is separated and purified by a conventional method. For example, it can be isolated by concentration, organic solvent extraction, chromatography, recrystallization, etc.

The reaction of producing compound () by reacting compound () with thiourea is a reaction of partially synthesizing an aminothiazole derivative using a haloketone and thiourea.

This reaction is also usually carried out in a solvent. The solvent is not particularly limited as long as it does not adversely affect this reaction, but usually includes N,N-dimethylformamide, N,N-dimethylacetamide,
Organic solvents such as methanol, ethanol, tetrahydrofuran or mixtures thereof with water are used.

The reaction is usually completed in 1 to 10 hours at around room temperature. Thiourea is used in an amount of 1 to several equivalents based on compound ().

It is also effective to add an appropriate amount of sodium iodide to accelerate the reaction, or to neutralize the generated hydrogen chloride by adding, for example, a neutral phosphate buffer.

The reaction product () is isolated and purified by conventional methods. For example, it can be isolated by concentration, organic solvent extraction, chromatography, reprecipitation, recrystallization, etc.

Next, the method for producing the compound of the present invention will be specifically explained with reference to Reference Examples and Examples, but the present invention is not limited thereto.

Reference example 1 7-amino-3-methoxymethyl-3-cepheme-4-carboxylic acid pivaloyloxymethyl ester para-toluenesulfonate production method A 7-phenoxyacetamide-3-methoxymethyl-3-cepheme Add and dissolve 38 g of -4-carboxylic acid in 90 ml of N,N-dimethylacetamide, cool to -10°C, and add 18 g of dicyclohexylamine. Then, 30 g of pivalic acid iodomethyl ester was added and the mixture was stirred at 5°C for 1 hour.

After adding 200 ml of ethyl acetate to the reaction solution and removing insoluble matter, the mixture was washed twice with 60 ml of 5% hydrochloric acid, then sequentially with water, 5% sodium bicarbonate, saturated aqueous potassium bicarbonate, and brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography (eluent (n-H _exaoe -E _tpAc (1:1)) to yield 7-phenoxyacetamide-3-methoxymethyl-3-cepheme-4-carboxylic acid pivalo. 40g of yloxymethyl ester was obtained as a pale yellow powder.

NMR spectrum (CDCl ₃ ) δppm 1.25 (9H, s, (CH ₃ ) ₃ C) 3.38 (3H, s, OCH ₃ ) 3.54 (2H, s, 2nd position CH ₂ ) 4.29 (2H, s, 3rd position CH ₂ ) 4.58 (2H, s, PhO CH ₂ -) 5.01 (1H, d, J = 5Hz, 6th position H) 5.6 - 6.1 (3H, m, 7th position and COO CH ₂ O -) 6.7 - 7.6 (6H, m , Phenyl and NH) B 7-Phenoxyacetamide-3-methoxymethyl-3-cephem-4-carboxylic acid Dissolve 31 g of pivaloyloxymethyl ester in 310 ml of dry methylene chloride, add 12.7 ml of pyridine to -50 Cool to ℃. Add 26 g of phosphorus pentachloride, stop cooling and continue stirring for 1 hour to obtain a brown solution.

Cool again to -50°C and slowly add 100ml of methanol dropwise. After the dropwise addition, the mixture was stirred for 30 minutes at around -10°C, then the temperature was brought to around 0°C, and saturated sodium bicarbonate water was added to neutralize the mixture, and the methylene chloride layer was separated. The aqueous layer is extracted once with methylene chloride, the extract is combined with the previously separated liquid, dried over magnesium sulfate, and concentrated under reduced pressure. In order to remove pyridine mixed in the residual liquid, it was azeotropically distilled twice with toluene and twice with ethyl acetate. Dissolve the residue in 200 ml of ethyl acetate and add para-toluenesulfonic acid monohydrate 12
Dissolve g in 100 ml of ethyl acetate, leave in the refrigerator overnight, collect precipitated crystals, wash with ethyl acetate, and dry to obtain colorless cotton-like needle crystals.
24 g of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester paratoluenesulfonate was obtained. Gradually discolors from melting point around 160℃, 177℃
Elemental analysis values separated in the vicinity as C ₁₅ H ₂₇ N ₂ O ₆ S・C ₇ H ₈ O ₃ S Calculated values C, 49.80, H, 5.70, N, 5.28, S,
12.08 Actual measurement value C, 49.76, H, 5.60, N, 5.00, S,
12.06 Reference example 2 7-(4-chloro-3-oxobutyrylamino)-3-methoxymethyl-3-cepheme-4
-Production method of carboxylic acid pivaloyloxymethyl ester 725 mg of diketene was dissolved in 10 ml of dry methylene chloride, cooled to -20°C, and stirred. Chlorine 620 for this
4-chloro-3-oxobutyric acid chloride was prepared by dropping 30 ml of carbon tetrachloride solution containing 4-chloro-3-oxobutyric acid chloride. On the other hand, 7
-Amino-3-methoxymethyl-3-cephem-
Dissolve 2 g of 4-carboxylic acid pivaloyloxymethyl ester p-toluenesulfonate in 20 ml of methylene chloride along with 1.16 ml of diethylaniline.
The mixture was cooled to -10°C, and the above 4-chloro-3-oxobutyric acid chloride solution was added dropwise. After stirring at the same temperature for 30 minutes, the mixture was concentrated under reduced pressure to remove the solvent. This was dissolved again in 50 ml of ethyl acetate, washed sequentially with water, 5% hydrochloric acid, and saline, and then dehydrated and dried over anhydrous magnesium sulfate.
It was concentrated under reduced pressure. This was dissolved in 3 ml of methylene chloride, 30 ml of ether was added, and the mixture was allowed to stand, producing needle-like crystals. This was taken, washed with ether, and dried to obtain 1.47 g of the title compound.

Melting point 131.5-132.5℃ NMR spectrum (CDCl ₃ ) δppm 1.23 (9H, s) 3.31 (3H, s, OCH ₃ ) 3.54 (2H, s, 2nd position) 3.65 (2H, s, CH ₂ ) 4.26 (2H, s , CH ₂ ) 4.29 (2H, s, CH ₂ ) 4.97 (1H, d, J=5.5Hz, 6th place) 5.65-6.0 (3H, m, 7th place and CH ₂ ) 7.64 (1H, d, J=9Hz ) Example 1 Process for producing 7-(4-chloro-3-oxo-2-hydroxyiminobutylamino)-3-methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester 7-(4-chloro -3-oxobutyrylamino)-3-methoxymethyl-3-cephem-4-
Carboxylic acid pivaloyloxymethyl ester 2.57
Dissolve g in 25 ml of acetic acid and add 409 mg of sodium nitrite.
was gradually added at room temperature and stirred for 30 minutes. Add 200 ml of ethyl acetate to the reaction solution, wash with saturated saline three times, and then
It was dehydrated and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Azeotroped twice with toluene, dried,
2.7 g of the title compound were obtained as a foamy solid.

NMR spectrum (CDCl ₃ ) δppm 1.23 (9H, s) 3.33 (3H, s, OCH ₃ ) 3.59 (2H, s, 2nd position CH ₂ ) 4.33 (2H, s, 3rd position CH ₂ ) 4.75 (2H, s, CH ₂ ) 5.05 (1H, d, J = 5.5Hz, 6th position) 5.6-6.1 (3H, m, 7th position and CH ₂ ) 9.3 (1H, d, J = 9Hz) Example 2 7-(4-chloro -3-oxo-2-(Z)-
Method for producing pivaloyloxymethyl ester 7-(4-chloro-3-oxo-2-hydroxyiminobutyrylamino)-3- 5 g of methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester was added to 40 g of tetrahydrofuran.
ml and add 2 g of sodium carbonate dissolved in 40 ml of water. 5 g of dimethyl sulfate was added to this and stirred for 30 minutes. 150 ml of ethyl acetate was added to the reaction mixture, and the mixture was washed twice each with saturated sodium bicarbonate water and saturated potassium bisulfate water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. This was placed on a 100g silica gel column.
Chromatography was performed using the solvent system chloroform-ethyl acetate (3:1) to obtain a solid containing the title compound. This was dissolved in 30 ml of tether and left on ice to produce needle-shaped crystals, which were collected, washed with ether and dried to obtain 1.9 g of the title compound as needle-shaped crystals.

Melting point 168.5-169.5℃ NMR spectrum (CDC ₃ ) δppm 1.24 (9H, s) 3.33 (3H, s, OCH ₃ ) 3.57 (2H, s, CH ₂ 2nd position) 4.19 (3H, s, OCH ₃ ) 4.30 (2H , s, CH ₃ 3rd place) 4.60 (2H, s, CH ₂ ) 5.03 (1H, d, J=55Hz, 6th place) 5.6-6.1 (3H, m, CH ₂ and 7th place) 7.19 (1H, d, J=9Hz, NH) Reference example 3 7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamide]-3-methoxymethyl-3-cephem-4
-Production method of carboxylic acid pivaloyloxymethyl ester 7-(4-chloro-3-oxo-2-(Z)-
47 mg of pivaloyloxymethyl ester (methoxyiminobutyrylamino)-3-methoxymethyl-3-cepheme-4-carboxylic acid was dissolved in 5 ml of dimethylacetamide, 14 mg of thiourea was added, and the mixture was stirred at room temperature for 4 hours. 50 ml of ethyl acetate was added to the reaction solution, and the mixture was washed three times with 15 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. This was dissolved in 1 ml of chloroform, precipitated by adding 20 ml of isopropyl ether, and dried to obtain 50 mg of the title compound as a colorless powder.

NMR spectrum (CDCl ₃ ) δppm 1.22 (9H, s) 3.30 (3H, s, OCH ₃ ) 3.53 (2H, s, 2nd position CH ₂ ) 4.00 (3H, s, OCH ₃ ) 4.30 (2H, s, 3rd position CH ₂ ) 5.05 (1H, d, J = 5.0Hz, 6th place) 5.7-6.3 (5H, m, 7th place NH ₂ and CH ₂ ) 6.63 (3H, s) 8.27 (1H, d, J = 9Hz, NH ) Example 3 7-(4-chloro-3-oxo-2-(Z)-
Ethoxyiminobutyrylamino)-3-methoxymethyl-3-cephem-4-carboxylic acid Method for producing pivaloyloxymethyl ester 7-(4-chloro-3-oxo-2-hydroxyiminobutyrylamino)-3- Example 3: 505 mg of methoxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester was dissolved in 5 ml of tetrahydrofuran, 106 mg of sodium carbonate was dissolved in 5 ml of water, and treated with 308 mg of diethyl sulfate for 1 hour. After post-treatment and chromatographic purification in the same manner as above, 96 mg of a solid containing the title compound was obtained. When this was dissolved in ether and left on ice, the title compound was precipitated as needle-shaped crystals, which were collected, washed with ether, and dried to obtain 57 mg.

Melting point 171-172℃ NMR spectrum (CDCl ₃ ) δppm 1.23 (9H, s) 1.39 (3H, t, J=7Hz) 3.35 (3H, s, OCH ₃ ) 3.57 (2H, s, CH ₂ 2nd position) 4.32 ( 2H, s, CH ₂ 3rd place) 4.43 (2H, c, J = 7Hz) 4.60 (2H, s, CH ₂ ) 5.04 (1H, d, J = 5.5Hz, 6th place) 5.6-6.1 (3H, m, CH ₂ and 7th position) 7.17 (1H, d, J = 9Hz, NH) Reference example 4 7-[2-(2-aminothiazol-4-yl)-2-(Z)-ethoxyiminoacetamide]- 3-methoxymethyl-3-cephem-4
-Production method of carboxylic acid pivaloyloxymethyl ester 7-(4-chloro-3-oxo-2-(Z)-
ethoxyiminobutyrylamino)-3-methoxymethyl-3-cephem-4-carboxylic acid 57 mg of pivaloyloxymethyl ester was dissolved in 6 ml of dimethylacetamide, 17 mg of thiourea was added, and the same procedure as in Example 4 was carried out. Work-up gave 63 mg of the title compound as a colorless powder.

NMR spectrum (CDCl ₃ ) δppm 1.22 (9H, s, C(CH ₃ ) ₃ ) 1.31 (3H, t, OCH ₂ CH ₃ ) 3.30 (3H, s, OCH ₃ ) 3.53 (2H, s, 2nd position CH ₂ ) 4.28 (2H, q, O CH ₂ CH ₃ ) 4.30 (2H, s, 3rd place CH ₂ ) 5.01 (1H, d, J=5Hz, 6th place H) 5.7~6.2 (5H, m, 7th place H, _NH2 and
COOCH ₂ O-) 6.76 (1H, s, thiazole 5th H) 7.70 (1H, d, J=9Hz, CONH) Reference example 5 7-[2-(2-aminothiazol-4-yl)-2-( Z)-Methoxyiminoacetamide]-3-methoxymethyl-3-cephem-4
-Production method of carboxylic acid pivaloyloxymethyl ester 7-(4-chloro-3-oxo-2-(Z)-
Dissolve 100 mg of pivaloyloxymethyl ester (methoxyiminobutyrylamino)-3-methoxymethyl-3-cephem-4-carboxylic acid in 1 ml of N,N-dimethylacetamide, add 86 mg of sodium iodide, and stir at room temperature for 15 minutes. After that, thiourea 15
1 ml of a neutral phosphate buffer (KH ₂ PO ₄ -Na ₂ HPO ₄ ) of pH 6.86 was added, and the mixture was stirred for 3 hours. 20 ml of ethyl acetate was added to the reaction solution, which was washed successively with 5% sodium thiosulfate, water, and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
This was dissolved in 1 ml of chloroform, precipitated by adding 20 ml of isopropyl ether, taken and dried to obtain 100 mg of the title compound as a colorless amorphous powder. The physical constants of this compound were consistent with those obtained in Example 4.

Claims (1)

[Claims] 1. General formula A cephalosporin derivative represented by the following formula: where R represents a hydrogen atom or a lower alkyl group.