JPS628437B2 - - Google Patents

Description

[Detailed description of the invention]

This invention discloses a general formula that has antibacterial activity and is useful as a medicine. (In the formula, R ₁ is a hydrogen atom or an alkanesulfonamide group, R ₂ is an alkylene group, R ₃ , R ₄ and
R ₅ is an aroyl group in which at least one may be substituted with a hydroxy group or a carboxyalkylthioalkanamide, the others are hydrogen atoms or halogen atoms, and R ₆ is an alkanoyloxy group or a tetrazolylthio group which may be substituted with an alkyl group. , X means an oxy group, respectively. In the above general formula () representing the object compound of this invention, examples of the alkanesulfonamide group represented by R ₁ include mesylamino, ethanesulfonamide, propanesulfonamide, butanesulfonamide, pentanesulfonamide, hexanesulfonamide, etc. be done. Furthermore, the alkylene group represented by R ₂ includes linear or branched alkylene groups, such as methylene,
Examples include ethylene, methylmethylene, propylene, trimethylene, tetramethylene, pentamethylene, and hexamethylene. Further, the aroyl group optionally substituted with carboxyalkylthioalkanamide represented by R ₃ , R ₄ and R ₅ includes benzoyl, toluoyl, xyloyl,
carboxymethylthioacetamidobenzoyl,
Examples include carboxyethylthioacetamidobenzoyl, and examples of the halogen atom include an iodine atom, a chlorine atom, a bromine atom, and a fluorine atom. Further, examples of the alkanoyloxy group represented by R ₆ include formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, pentanoyloxy, hexanoyloxy, etc., and examples of the tetrazolylthio group include 1H-tetrazolylthio. For example, the tetrzolyl moiety may be optionally substituted with an alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, or the like. Salts of these target compounds () include salts with inorganic bases such as sodium salts, potassium salts, calcium salts, and magnesium salts, and salts with organic bases such as triethylammonium salts, pyridinium salts, dimethylanilinium salts, and dicyclohexylammonium salts. Examples include salts with basic amino acids such as lysine salts, arginine salts, and histidine salts. These target compounds () have, for example, the general formula (In the formula, R ₁ and R ₆ have the same meanings as above.) (In the formula, R ₂ , R ₃ , R ₄ , R ₅ and X have the same meanings as before.) It can be produced by reacting with carboxylic acids or salts thereof, or reactive derivatives thereof at the carboxy group. 7-(phenylglycinamide)cephalosporanic acids () used as raw materials in this method
In addition to those exemplified as the salts of the target compound (), examples of the salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, acidic acid, trifluoroacetic acid, acetic acid, oxalic acid, Salts with organic acids such as tartaric acid and maleic acid are also exemplified. The other raw material, carboxylic acids (), can be produced, for example, by reacting substituted phenols with halogen-substituted fatty acid esters, and then subjecting the reaction product to a hydrolysis reaction. As salts of carboxylic acids (), salts with inorganic bases such as potassium salts, sodium salts, and calcium salts are often used, and as reactive derivatives at the carboxyl group of carboxylic acids (), acid chlorides, acid bromides, etc. Although acid halides are often used, acid anhydrides, active amides, active esters, etc. can also be used. In addition, when carboxylic acids () are used in the form of free acids or their salts, those commonly used in this type of reaction, such as phosphorus oxychloride, phosphorus trichloride, thionyl chloride, and N,N'-dicyclohexylcarbodiimide, are used. It is desirable to carry out the reaction in the presence of a condensing agent. This reaction is usually carried out in a solvent, and commonly used solvents include water, methylene chloride, chloroform, acetone, ethyl acetate, and dimethylformamide.
Any other solvent that does not adversely affect this reaction can be used. The reaction temperature is not particularly limited, but
It is usually carried out under cooling conditions. Note that this reaction may be carried out in the presence of a base such as sodium hydrogen carbonate, potassium hydrogen carbonate, pyridine, trimethylamine, triethylamine, or the like. Also, among the target compounds (), the general formula (In the formula, R ₁ , R ₂ , R ₄ , R ₅ , R ₆ and X have the same meanings as before, and R' ₃ is substituted with carboxyalkylthioalkanamide and means an aroyl group) The compound may have, for example, the general formula (In the formula, R ₁ , R ₂ , _{R 4} , R ₅ , R ₆ and It can also be produced by reacting mercapto fatty acids or salts thereof with substituted phenylglycinamide) cephalosporanic acids or their salts. As salts of 7-(N-substituted phenylglycinamide) cephalosporanic acids () The salts of the target compound () mentioned above are also exemplified here as they are.Salts of mercapto fatty acids include salts with alkali metals such as sodium and potassium.This reaction is usually carried out by
It is carried out in a solvent, and polar solvents such as water, methanol, and ethanol are often used as the solvent.
Any other solvent that does not adversely affect this reaction can be used. Although the reaction temperature is not particularly limited, it is often carried out at room temperature or under heating.
Further, this reaction proceeds advantageously when carried out in the presence of a base such as calcium hydrogen carbonate, pyridine, dimethylamine, triethylamine, or the like. The target compounds produced by these reactions are isolated and purified by conventional methods. If desired, the target compound (2) may be converted into salts such as those exemplified above in accordance with conventional methods. The object compound () and its salts of the present invention are all new compounds, have a broad antibacterial spectrum, exhibit particularly strong antibacterial activity against Pseudomonas aeruginosa, and are useful as antibacterial agents. The antibacterial activity of the target compound () against Pseudomonas aeruginosa was measured by the agar plate dilution method, and the results are shown in the following table. Test compound Compound A (Example 3) Compound B (Example 4) Compound C (Example 5) Result

[Table] The object compound of this invention () and its pharmaceutically acceptable salts are administered in the form of a composition containing an effective and non-toxic amount thereof and suitable for oral or parenteral administration. In this case, oral preparations include fixed preparations such as tablets, capsules, granules, troches, and powders, and liquid preparations such as syrups, and parenteral preparations include injections and suppositories. These compositions are formulated in a conventional manner with inorganic or organic solid or liquid pharmaceutical carriers commonly used in pharmaceutical formulations. Next, the method for producing the object compound () of the present invention will be explained with reference to Production Examples and Examples. Production Example 1 (1) Add 10 g of 2-hydroxy-5-chloro-4'-nitrodiphenyl ketone, 5.85 g of methyl chloroacetate, 7.5 g of potassium carbonate and 200 mg of potassium iodide to 150 ml of dry acetone, and heat under reflux for 3.5 hours. After that, insoluble matters are removed by filtration. Acetone was distilled off from the filtrate under reduced pressure, and the residue was dissolved in ethyl acetate, followed by 5% sodium hydroxide solution.
Add 100ml and shake thoroughly. The ethyl acetate layer is separated, washed with a saturated aqueous solution of sodium chloride, and then dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was washed with petroleum ether to obtain 11.7 g of 2-{4-chloro-2-(4-nitrobenzoyl)phenoxy}acetic acid methyl ester. Infrared absorption spectrum νnudyol _nax : 1755, 1670 cm ^-1 (2) In a solution consisting of 11.5 g of 2-{4-chloro-2-(4-nitrobenzoyl)phenoxy}acetic acid methyl ester obtained above and 60 ml of dioxane.
Add 35 ml of 1N aqueous sodium hydroxide solution and stir at room temperature for 1.5 hours. Dioxane is distilled off from the reaction solution under reduced pressure, the residue is washed with ethyl acetate, and the pH is adjusted to 1 with 10% hydrochloric acid. This is extracted once with 400 ml of ethyl acetate and once with 100 ml. The extract is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. Concentrate this to about 100 ml, filter out the precipitated crystals, and the 2-
10.1 g of {4-chloro-2-(4-nitrobenzoyl)phenoxy}acetic acid is obtained. Infrared absorption spectrum _νnudyolnax : 1750, 1740, 1640 cm ^-1 Nuclear magnetic resonance absorption spectrum (D ₂ O + NaHCO ₃ :
δppm): 4.47 (2H, s), 6.9-7.6 (3H, m), 7.84,
8.16 (2H, AB-q, J = 10Hz, 20Hz) (3) 2.52g of 2-{4-chloro-2-(4-nitrobenzoyl)phenoxy}acetic acid obtained above
10 in a solution consisting of 2.5 ml and 60 ml of dioxane
Add 800 mg of % palladium on carbon, and absorb 554 ml of hydrogen gas at room temperature under normal pressure. After the reaction, insoluble matter is filtered off, and the solvent is distilled off from the filtrate under reduced pressure. Add this to 3.2g of sodium hydrogen carbonate,
Add to a solution consisting of 50 ml of water and 50 ml of acetone. To this, 2.36 g of bromoacetic acid chloride was added dropwise under stirring at 0 to 5°C over 15 minutes. During this time, adjust the liquid pH to 7.0-7.5. This was stirred at the same temperature for 1 hour. Acetone was distilled off from the reaction solution under reduced pressure, the residue was washed with ethyl acetate, and the pH was adjusted to 1 with 10% hydrochloric acid. This is extracted once with 70 ml of ethyl acetate and once with 50 ml. The extract is washed with a saturated aqueous solution of sodium chloride and then dried over magnesium sulfate. Concentrate this under reduced pressure to about 20ml and leave it in the refrigerator overnight.
-1.28 g of {4-chloro-2-(4-bromoacetamidobenzoyl)phenoxy}acetic acid is obtained. Infrared absorption spectrum _νnujiolnax : 3390, 1765, 1745, 1670,
1630, 1590cm ^-1 (4) 2-{4-chloro-2-(4-bromoacetamidobenzoyl)phenoxy}acetic acid obtained above
After adding 1.2 g to 12 ml of thionyl chloride and heating under reflux for 1 hour, thionyl chloride was distilled off from the reaction solution, and the residue containing acid chloride was dissolved in 5 ml of acetone. After dropping the acetone solution of the acid chloride prepared above into a solution consisting of 1.25 g of 7-(D-2-phenylglycinamide) cephalosporanic acid, 840 mg of sodium bicarbonate, 70 ml of water and 70 ml of acetone under ice cooling, 30 at the same temperature
Stir for a minute. During this time, adjust the pH to 7.5 with a 5% aqueous sodium hydrogen carbonate solution. Pour the reaction solution into 150 ml of water, layer with 150 ml of ethyl acetate, and adjust the pH to 2 with 10% hydrochloric acid. Separate the aqueous layer, extract with 70 ml of ethyl acetate, and combine the extract with the ethyl acetate layer. After washing this with a saturated aqueous sodium chloride solution and drying over magnesium sulfate, the solvent is distilled off under reduced pressure. The residue was crystallized with diethyl ether and the precipitate was collected by filtration.
1.82 g of 7-[D-N-[2-{4-chloro-2-(4-bromoacetamidobenzoyl)phenoxy}acetyl]-2-phenylglycinamide]cephalosporanic acid are obtained. Infrared absorption spectrum _νnujiolnax : 3290, 1780, 1740, 1710,
1680, 1650 cm ^-1 Production Example 2 5.0 g of 2-{4-chloro-2-(4-nitrobenzoyl)phenoxy}acetic acid obtained in (1) and (2) of Production Example 1, 1.5 g of 10% palladium carbon, and A solution consisting of 100 ml of dioxane is allowed to absorb the calculated amount of hydrogen gas at room temperature and under normal pressure. Insoluble matter was removed from the reaction solution by filtration, and the filtrate was mixed with 3.4 g of sodium hydrogen carbonate and water.
Add to the solution consisting of 100 ml. A solution consisting of 2.54 g of chloroacetic acid chloride and 2 ml of dry acetone is added dropwise to this solution with stirring at 0-5°C.
During this time, adjust the liquid pH to 7.0-7.5. After dripping,
Stir at the same temperature for 1 hour. Dioxane is distilled off from the reaction solution under reduced pressure, and the remaining solution is washed with ethyl acetate. Adjust this to PH1 with 10% hydrochloric acid, and use ethyl acetate.
Extract once with 150ml and once with 50ml. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was washed with diethyl ether to give 2-{4-
4.4 g of chloro-2-(4-chloroacetamidobenzoyl)phenoxy}acetic acid is obtained. Infrared absorption spectrum _νnujiolnax : 3300, 1770, 1645, 1680,
1620, 1600cm ^-1 2-{4-chloro-2-(4-chloroacetamidobenzoyl)phenoxy}acetic acid obtained above 960
After adding 10 mg of thionyl chloride to 10 ml of thionyl chloride and heating under reflux for 1 hour, the residue containing acid chloride was added to 5 ml of dry acetone.
dissolve in The acetone solution of the acid chloride prepared above was added to a solution consisting of 1 g of 7-(D-2-phenylglycinamide)cephalosporanic acid, 630 mg of sodium bicarbonate, 50 ml of water, and 50 ml of acetone for 15 minutes at 0 to 5°C. After adding dropwise, stir at the same temperature for 20 minutes. During this time, adjust the liquid pH to 7.0-7.5. Insoluble matter is filtered off from the reaction solution and washed with water. Combine the filtrate and washing liquid, add 100 ml of water, layer with 150 ml of ethyl acetate, adjust the pH to 2 with 10% hydrochloric acid, and separate the ethyl acetate layer. The aqueous layer is further extracted with 50 ml of ethyl acetate, combined with the previously separated ethyl acetate layer, and washed with a saturated aqueous sodium chloride solution. From this, the solvent was distilled off under reduced pressure and the residue was powdered with diethyl ether.
1.34 g of -[D-N-[2-{4-chloro-2-(4-chloroacetamidobenzoyl)phenoxy}acetyl]-2-phenylglycinamide]cephalosporanic acid are obtained. Infrared absorption spectrum _νnujiolnax : 3400, 3380, 1790, 1740,
1710, 1675, 1655cm ^-1 Example 1 2-(2-hydroxyphenoxy)acetic acid 1.68g
After stirring a solution of and 10 ml of thionyl chloride at 60°C for 1.5 hours, excess thionyl chloride was distilled off under reduced pressure. Dry the residue containing the acid chloride with 10 ml of acetone
dissolve in 7-(D-2-phenylglycinamide)-3-(1-methyl-1H-tetrazole-
The acetone solution of the acid chloride obtained above was added dropwise to a solution consisting of 2.5 g of 5-yl)thiomethyl-3-cephem-4-carboxylic acid, 1.26 g of sodium hydrogen carbonate, 70 ml of acetone, and 70 ml of water while stirring under ice cooling. do. During this time, the pH of the reaction solution was adjusted to 7.5 with a 5% aqueous sodium hydrogen carbonate solution. After stirring this at the same temperature for 1 hour, the solvent was distilled off under reduced pressure. Add ethyl acetate to the residue, then 10%
After adjusting the pH to 2 with hydrochloric acid, shake thoroughly. The ethyl acetate layer is separated, washed successively with water and a saturated aqueous solution of sodium chloride, and then dried over magnesium sulfate. The solvent is distilled off, 15 ml of acetone and a small amount of diethyl ether are added to the residue, and the mixture is stirred for 30 minutes. When the precipitated powder is collected by filtration, 7-[D-N
-{2-(2-hydroxyphenoxy)acetyl}
2.3 g of -2-phenylglycinamide]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid are obtained.
When this is purified by column chromatography (filling agent: activated carbon), 1.65 g of purified product with a mp of 130 to 135°C (decomposition) is obtained. Infrared absorption spectrum _νnujiolnax : 1780cm ^-1 Nuclear magnetic resonance absorption spectrum (DMSO-d ₆ δppm) 3.63 (2H, broad s), 3.93 (3H, s), 4.25
(2H, broad s), 4.6 (2H, s), 5.0 (1H,
d, J=5Hz), 5.6~5.85 (2H, m), 6.75~
6.9 (4H, m), 7.3-7.5 (5H, m) Example 2 A solution consisting of 1.44 g of 2-(2-benzoyl-4-chlorophenoxy)acetic acid and 7 ml of thionyl chloride was heated under reflux for 1.5 hours, and then the excess The thionyl chloride of is distilled off under reduced pressure and the residue containing the acid chloride is dissolved in 20 ml of dry acetone. 7-{D
-2-(3-mesylaminophenyl)glycinamide}-3-(1-methyl-1H-tetrazole-
5-yl)thiomethyl-3-cephem-4-carboxylic acid 1.88g, sodium bicarbonate 840mg, water 120g
ml and 120 ml of acetone, add the acetone solution of the acid chloride obtained above at 2-3℃ for 15 minutes.
It takes several minutes to drip. During this time, adjust the pH to 7.0 to 7.5 with 5% sodium hydrogen carbonate solution. After stirring this at the same temperature for 1 hour, the pH was adjusted to 6 to 7, and acetone was distilled off under reduced pressure. The remaining liquid was washed with diethyl ether, layered with ethyl acetate, and then adjusted to pH 3 with 10% hydrochloric acid. After thoroughly shaking this, the ethyl acetate layer is separated. The ethyl acetate layer is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure. Diethyl ether was added to the residue, stirred for 1 hour, and the precipitated powder was collected by filtration.
[D-N-{2-(2-benzoyl-4-chlorophenoxy)acetyl}-2-(3-mesylaminophenyl)glycinamide]-3-(1-methyl-
1H-tetrazol-5-yl)thiomethyl-3
-1.75 g of cefem-4-carboxylic acid are obtained. Infrared absorption spectrum _νnudjolnax : 1780cm ^-1 nuclear magnetic resonance absorption spectrum (DMSO-d ₆ +D ₂ O:
δppm): 3.0 (3H, s), 3.65 (2H, broad s), 4.0
(3H, s), 4.36 (2H, broad s), 4.63 (2H,
s), 5.02 (1H, d, J=4Hz), 5.57 (1H,
s) 5.74 (1H, d, J=4Hz), 7.08~7.9
(12H, m) Example 3 After stirring a solution consisting of 4.74 g of 2-(2-hydroxy-3,5-dichlorophenoxy)acetic acid and 30 ml of thionyl chloride at 50 to 60°C for 2.5 hours, excess thionyl chloride was removed. is distilled off under reduced pressure and the residue containing the acid chloride is dissolved in 20 ml of dry acetone. 7-
(D-2-phenylglycinamide)-3-(1-
The acetone solution of the acid chloride obtained above was added to a solution consisting of 5.07 g of methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, 2.52 g of sodium bicarbonate, 150 ml of acetone, and 100 ml of water on ice. Cool and add dropwise while stirring. During this time, the pH of the reaction solution was adjusted to 7 to 7.5 by adding 5% aqueous sodium hydrogen carbonate solution. After stirring this at the same temperature for 1 hour, acetone was distilled off under reduced pressure. Add ethyl acetate to the residual solution, shake thoroughly, and separate the aqueous layer. Ethyl acetate is layered on this, the pH is adjusted to 3 with 10% hydrochloric acid, the mixture is shaken, and the ethyl acetate layer is separated. The ethyl acetate layer is washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. Concentrate this under reduced pressure,
The residue was powdered with diethyl ether, collected by filtration, and washed with diethyl ether to give 7-[D-
N-{2-(2-hydroxy-3,5-dichlorophenoxy)acetyl}-2-phenylglycinamide]-3-(1-methyl-1H-tetrazole-
3.8 g of 5-yl)thiomethyl-3-cephem-4-carboxylic acid are obtained. This was dissolved in ethyl acetate and subjected to silica gel column chromatography, and the resulting powder was dissolved in distilled acetone and purified by activated carbon column chromatography. Get the product. Infrared absorption spectrum _νnudyolnax : 1778cm ^-1 nuclear magnetic resonance absorption spectrum (acetone-d ₆ +
D ₂ O: δppm) 3.58, 3.83 (2H, AB-q), 4.02 (3H, s),
4.37 (2H, broas s), 4.83 (2H, s), 5.06
(1H, d, J=6Hz), 5.82 (1H, d, J=6
Hz), 5.93 (1H, s), 7.03~7.08 (2H, m),
7.32-7.67 (5H, m) Example 4 2-(2-benzoyl-4-chlorophenoxy)acetic acid 2.15g, thionyl chloride 10ml, benzene 10
After stirring a mixture of 1 drop of N,N-dimethylformamide and 1 drop of N,N-dimethylformamide at 70 DEG C. for 2 hours, the solvent is distilled off under reduced pressure and the residue containing the acid chloride is dissolved in 20 ml of acetone. 7-(D-2-phenylglycinamide)cephalosporanic acid 2.0g, sodium bicarbonate 1.33g, acetone 30ml and water 60ml
The acetone solution of the acid chloride obtained above was added dropwise to the solution over 30 minutes while stirring on ice.
After stirring this at room temperature for 2 hours, ethyl acetate is added to the reaction solution. After adjusting the pH to 2 with 10% hydrochloric acid under ice-cooling, insoluble matter was filtered off. The filtrate is extracted twice with ethyl acetate and the extract is washed with saturated aqueous sodium chloride solution and water. This was dried over magnesium sulfate, the solution was distilled off under reduced pressure, and the residue was powdered with diethyl ether to give 7-[D-N-{2-(2-benzoyl-4) with a mp of 117°C (decomposition).
1.7 g of -chlorophenoxy)acetyl}-2-phenylglycinamide]cephalosporanic acid are obtained. Infrared absorption spectrum _νnujiolnax : 3400, 3250, 1785, 1730,
1710, 1695, 1640 cm ^-1 nuclear magnetic resonance absorption spectrum (DMSO−d ₆ : δ
ppm) 2.10 (3H, s), 3.61 (2H, broad s), 5.01
(2H, q, J = 14Hz), 5.18 (1H, d, J = 5
Hz), 4.81 (2H, s), 5.7-6.3 (2H, m), 7.3
~8.2 (8H, m), 8.34 (1H, d, J=8Hz),
9.28 (1H, d, J = 8Hz) Example 5 7-[D-N-[2-{4-chloro-2-(4-bromoacetamidobenzoyl) obtained in Production Example 1]
A solution consisting of 1.63 g of phenoxy}acetyl]-2-phenylglycinamide]cephalosporanic acid, 280 mg of mercaptoacetic acid, 670 mg of sodium bicarbonate, 40 ml of water and 15 ml of acetone is stirred at room temperature for 5 hours. Pour the reaction solution into 50 ml of ice water, layer with 7.0 ml of ethyl acetate, and adjust the pH to 2 with 10% hydrochloric acid. After thoroughly shaking this, the ethyl acetate layer is separated. The aqueous layer is extracted with 50 ml of ethyl acetate, combined with the previously separated ethyl acetate layer, washed with a saturated aqueous solution of sodium chloride, and then dried over magnesium sulfate. From this, ethyl acetate was distilled off under reduced pressure,
After powdering the residue with diethyl ether, the precipitate was collected by filtration to give 7-[D-N-[2-{2-(4-carboxymethylthioacetamidobenzoyl)-
1.58 g of 4-chlorophenoxy}acetyl]-2-phenylglycinamide]cephalosporanic acid are obtained. This is purified by silica gel column chromatography [elution solvent: ethyl acetate (7) + acetic acid (1)] to obtain a purified product with a mp of 136-147°C (decomposed). Infrared absorption spectrum _νnudyolnax : 1760-1770cm ^-1 nuclear magnetic resonance absorption spectrum (acetone-d ₆ +
D ₂ O: δppm) 2.05 (3H, s), 3.26 to 3.75 (6H, m), 4.68
(2H, s), 4.81, 5.62 (2H, AB−q, J=16
Hz), 5.06 (1H, d, J=5Hz), 5.62 (1H,
s), 5.8 (1H, d, J=5Hz), 7.2~7.9
(9H, m) Example 6 7-[DN-[2-{4-chloro-2-(4-chloroacetamidobenzoyl) obtained in Production Example 2
A solution consisting of 1.15 g of phenoxy}acetyl]-2-phenylglycinamide]cephalosporanic acid, 0.21 g of mercaptoacetic acid, 510 mg of sodium bicarbonate, 15 ml of acetone and 30 ml of water is stirred at room temperature for 3.5 hours. Acetone is distilled off from the reaction solution under reduced pressure, and the remaining solution is adjusted to pH 1 with 10% hydrochloric acid, and then extracted once with 100 ml of ethyl acetate and once with 50 ml. The extracts are combined, washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was powdered with diethyl ether, and the precipitate was collected by filtration to give 7-[D-N-[2
1.0 g of -{4-chloro-2-(4-carboxymethylthioacetamidobenzoyl)phenoxy}acetyl]-2-phenylglycinamide]cephalosporanic acid is obtained.

Claims (1)

[Claims] 1. General formula (In the formula, R ₁ is a hydrogen atom or an alkanesulfonamide group, R ₂ is an alkylene group, R ₃ , R ₄ and
R ₅ is an aroyl group in which at least one may be substituted with a hydroxy group or a carboxyalkylthioalkanamide, the others are hydrogen atoms or halogen atoms, and R ₆ is an alkanoyloxy group or a tetrazolylthio group which may be substituted with an alkyl group. , X means an oxy group) and salts thereof. 2 General formula (In the formula, R ₁ is a hydrogen atom or an alkanesulfonamide group, R ₂ is an alkylene group, R ₃ , R ₄ and
R ₅ is an aroyl group in which at least one may be substituted with a hydroxy group or a carboxyalkylthioalkanamide, the others are hydrogen atoms or halogen atoms, and R ₆ is an alkanoyloxy group or a tetrazolylthio group which may be substituted with an alkyl group. , X means an oxy group, respectively) In the method for producing a 7-(N-substituted phenylglycinamido)cephalosporanic acid derivative and its salts, the general formula (In the formula, R ₁ and R ₆ have the same meanings as above) (wherein R ₂ , R ₃ , R ₄ , R ₅ and - A method for producing a (N-substituted phenylglycinamide) cephalosporanic acid derivative and its salts.