JPS5833236B2 - 7-(Alpha-Chikanaminoalkanamide)-3-Chikan-3-Cefem-4-Carbonsanyuudoutaino Seizouhou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a novel 7-(α-substituted aminoalkanamide)-3-substituted-3-cephem-4-carboxylic acid derivative, which is represented by the formula: It is as follows.

(In the formula, M is a carboxy group, R1 is a hydrogen atom, an azide group, an alkanoyloxy group, a pyridyl group, a nitrogen-containing 5-membered heterocyclic thio group which may be substituted with a lower alkyl group (this heterocyclic group is further may contain an oxygen atom or a sulfur atom as an atom, or may be fused with a benzene ring), a lower alkyl-substituted piperazinylthiocarbonylthio group, a benzoylthio group or a thenoylthio group, R2 is an alkanoyl group, R3 is Each represents a hydrogen atom, an alkyl group, an aryl group, or a chenyl group, and the group R
When 1 contains a quaternary nitrogen atom, M means a group represented by the formula -COOe, and the alkanoyl group of R2 is substituted with a phenyl group, phenoxy group, or phenylthio group, and among these substituents, , the phenoxy group further has a halogen, nitro group, alkyl group or alkoxy group as a substituent, and the phenyl group and phenylthio group may be substituted with a halogen or nitro group). This is carried out by reacting compound (I) or a derivative thereof at the carboxy group with an α-substituted amine fatty acid (n) or a reactive derivative thereof at the carboxy group.

Compound (I) is represented by the above-mentioned general formula (I), and more specifically, a hydrogen atom, an azide group, an alkanoyloxy group such as formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, or pyridyl. Nitrogen-containing groups such as imidazolylthio, triazolylthio, tetrazolylthio, oxazolylthio, inxazolylthio, oxadiazolylthio, thiazolylthio, inthiazolylthio, thiadiazolylthio, benzimidazolylthio, benzoxazolylthio, benzothiazolylthio, etc. Heterocyclic thio group, benzoylthio group,
It means a compound having a thenoylthio group or a piperazinylthiocarbonylthio group as R1, and among these groups, the heterocyclic moiety in the nitrogen-containing heterocyclic thio group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary The piperazinyl moiety in the piperazinylthiocarbonylthio group of R1 may be substituted with a lower alkyl group such as butyl, pentyl, or hexyl.

Examples of derivatives at the amino group of these compounds (I) include reaction products of compound (I) and silyl compounds such as bis(trimethylsilyl)acetamide.

In addition, derivatives of the carboxyl group of compound (I) include sodium salts, potassium salts, magnesium salts, calcium salts, triethylamine salts, methyl esters, ethyl esters, flobyl esters, methyl esters, pentyl esters, trimethylsilyl esters, 2
-Mesylethyl ester, 2-iodoethyl ester,
2,2,2-trichloroethyl ester, benzyl ester/l/, 4-meth)oxybenzyl ester, 4-nitrobenzyl ester, phenacyl ester, phenethyl ester, trityl ester, bis(methoxyphenyl)
In addition to esters such as methyl ester, 3,4-dimethoxybenzyl ester, (1-cyclopropyl)ethyl ester, ethynyl ester, 4-hydroxy-3,5-ditertiary butyl benzyl ester, and benzhydryl ester, activated amides , acid anhydrides, acid halides, and the like.

The other raw material, α-substituted amino fatty acids, is represented by the above general formula (n), and more specifically, it has an alkanoyl group such as formyl, acetyl, propionyl, butyryl, imbutyryl, valeryl, etc. as R2. , a hydrogen atom, an alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary-methyl, pethyl, hexyl, an aryl group or chenyl group such as phenyl, naphthyl, tolyl, xylyl, mesityl, cumenyl, etc. It means a compound having as R3.

The alkanoyl group of R2 is substituted with a phenyl group, phenoxy group or phenylthio group, and the phenoxy group which is a substituent on these alkanoyl groups is further substituted with a halogen such as fluoro, chloro, bromo, iodo, etc. Substituted with an alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, or an alkoxy group such as methoxy, ethoxy, propoquine, isopropoxy, butoxy, pentyloxy, hexyloxy Furthermore, the phenyl group and phenylthio group may be substituted with a halogen or a nitro group.

When the substituents are present on two or more phenoxy groups, phenyl groups, and phenylthio groups, those substituents may be the same or different.

Examples of reactive derivatives at the carboxyl group of these α-substituted amino fatty acids include acid...lides, acid anhydrides, active amides, and active esters, but particularly frequently used ones include acid chlorides, acid chlorides, and active esters. Acid azide, dialkyl phosphoric acid mixed anhydride, phenyl phosphoric acid mixed anhydride, diphenyl phosphoric acid mixed anhydride, dibenzyl phosphoric acid mixed anhydride,
...Rogenated phosphoric acid mixed anhydride, dialkyl phosphorous acid mixed anhydride, sulfite mixed anhydride, thiosulfuric acid mixed anhydride, sulfuric acid mixed anhydride, alkyl carbonic acid mixed anhydride, aliphatic carboxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid,
Acid anhydrides such as 2-ethylbutanoic acid, trichloroacetic acid) mixed anhydrides, aromatic carboxylic acid (e.g. benzoic acid) mixed anhydrides, symmetrical acid anhydrides, imidazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole and acid amide, cyanomethyl ester, methoxymethyl ester, vinyl ester, flopargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, methanesulfonylphenyl ester, phenylazophenyl In addition to esters such as ester, phenylthioester, p-nitrophenylthioester, p-cresylthioester, carboxymethylthioester, pyranyl ester, pyridyl ester, hypericyl ester, and 8-quinolylthioester, N.
N-dimethylhydroxylamine, l-hydroxy-2
-(IH)-pyridone, N-hydroxyphthalimide or esters with N-hydroxyphthalimide, etc., and these are the α-substituted amino fatty acids (n
) is selected as appropriate depending on the type.

This reaction is usually carried out in a solvent.

As a solvent, acetone, dioxane, acetonitrile,
Examples include chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, dimethylformamide, pyridine, and other general organic solvents that do not adversely affect the reaction. Among these, hydrophilic solvents are used by mixing with water. You can also.

When using the α-substituted amino fatty acid (n) in the form of a free acid or its salt in this reaction, for example, N-
N'-Synchronohexylcarbodiimide, N-cyclohexyl-N/-morpholinoethylcarbodiimide, N-
Cyclohexyl-N'=(4diethylaminocyclohexyl)carbodiimide, N-N'-diethylcarbodiimide, N-N'-diisopropylcarbodiimide, N-
Ethyl-N'(3-dimethylaminopropyl)carbodiimide, N-N'-carboxy group (2-methylimidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine,
Alkoxyacetylene, 1-alkoxy-1-chloroethylene, phosphorous trialkyl ester, polyphosphoric acid ethyl ester, polyphosphoric acid inflobil ester, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride,
Condensing agents such as triphenylphosphine, 2-ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5-(m-sulfophenyl)inxazolium hydroxide inner salt, (chloromethylene)dimethylammonium chloride, etc. Advantageously, it is carried out in the presence of

The salts of the α-substituted amine fatty acids (n) include alkali metal salts, alkaline earth metal salts, ammonium salts, and salts with organic bases such as trimethylamine and dicyclohexylamine.

This reaction may also be carried out in the presence of a base such as an alkali metal hydrogen carbonate, trialkylamine, N-N-dialkylbenzylamine, or pyridine, and the base or the liquid condensing agent mentioned above also serves as a solvent. can be used.

Although the reaction temperature is not particularly limited, it is usually carried out under cooling or at room temperature.

The reaction product is isolated and collected by conventional methods.

The desired product, 7-(α-substituted aminoalkanamide)-3-substituted-3-cephem-4-carboxylic acid derivative (■), obtained as described above can be converted into a desired salt by a conventional method.

The objects (III) obtained by the method of this invention are all new compounds and are useful as acid- and penicillinase-stable antibacterial substances.

Next, the method of the present invention will be explained using examples.

1% In addition, E in the ultraviolet absorption spectrum means E crr
L Taste it.

Example I D-N-(2-nitrophenoxy)acetyl-2-phenylglycine 1.7 and triethylamine 5507
/llp was dissolved in 5Qml of tetrahydrone run, and 60% of pivalic acid chloride was added to the solution while stirring at 5-10°C.
Add 07%' and stir for 30 minutes.

To this solution was added 1.4 t of 7-aminocephalosporanic acid and 600 m9 of triethylamine while stirring at -10°C.
Add 50d of chloroform solution containing.

This is stirred at −10° C. or lower for 1 hour and then at 0° C. to room temperature for 4 hours.

The reaction solution is filtered once, and the lachrymal fluid is concentrated under reduced pressure.

The concentrate is dissolved in 50 rfLl of water, adjusted to pH 7.0-7.5 with sodium bicarbonate, and washed with ethyl acetate.

This aqueous solution was made acidic with dilute hydrochloric acid, and 50rnl of ethyl acetate was added.
Extract twice.

The extract is washed with water, dehydrated, and then concentrated under reduced pressure.

When the concentrate is washed with ether, the mp 203-205℃
(decomposition) to obtain 668 ml of powdered D-7-(N-(2-nitrophenoxy)acetyl-2-phenylglycinamide]cephalosporanic acid.

A purified product is obtained by recrystallizing the crystal from acetone.

Elemental analysis: C26H24010N4S Calculated value C53,42, H4,14, H9,59, S5
．． 49 Experimental values C53,36, H4,39, H9,51S5.
33 Ultraviolet absorption spectrum (95% C2H50H) λmax
260.5 mμ, E=205.8 Example 2 6551v of N-DL-(2-nitrophenoxy)acetyl 2-phenylglycine was dissolved in 35mj of tetrahydrofuran.
1 and stirred while cooling with water.

To this was added 618 cm of dicyclohexylcarbodiimide, and the mixture was stirred for 30 minutes.

A chloroform solution containing 550 μ of 7-aminocephalosporanic acid and 606 μ of triethylamine in this solution
Add 5 mA with stirring at 10 to -13°C, stir at the same temperature for 1 hour, at 0°C for 2 hours, and further at room temperature for 3 hours.

The reaction solution is passed through a p-filter, and the p-liquid is concentrated under reduced pressure. The concentrated residue is dissolved in 30 r/L of water, and the pH is adjusted to 7.5-8.0 with an aqueous sodium bicarbonate solution.

After washing twice with ethyl acetate, adjust the pH to 3.5~ with dilute sulfuric acid.
4.0 and extracted with ethyl acetate.

After the extract is washed with water and dehydrated, ethyl acetate is distilled off under reduced pressure.

The residue is washed with ether, dissolved in 95% ethanol and filtered.

Ethanol was distilled off from the P solution under reduced pressure, and the residue was washed with ether, resulting in powdery 7-[DL-N(2-nitrophenoxy)acetyl-2-phenylglycine, mp 117-125°C (decomposition). Amide] cephalosporanic acid 45μ is obtained.

Ultraviolet absorption spectrum (95% C2H50H) λmax
261 mμ, E=157.7 Example 3 630 mg of N-(2-nitrophenyl)acetyl-2-phenylglycine is dissolved in 35 ml of tetrahydrofuran and stirred under water cooling.

Dicyclohexylcarbodiimide 618■ is added to this.

A chloroform solution 3 containing 544 μ of 7-aminocephalosporanic acid and 606 μ of triethylamine in this solution
Add 5rrll with stirring at -10 to -13°C.

This mixture was stirred at the same temperature for 1 hour, at 0° C. for 2 hours, and then at room temperature for 3 hours.

The reaction solution is thoroughly filtered, and the lachrymal fluid is concentrated under reduced pressure.

The concentrate is dissolved in 30 rnl of water and brought to pH 7.5-8.0 with an aqueous solution of sodium bicarbonate.

After washing twice with ethyl acetate, adjust the pH to 3.0~ with dilute sulfuric acid.
3.5 and extracted with ethyl acetate.

After the extract is washed with water and dehydrated, ethyl acetate is distilled off under reduced pressure.

When the residue is washed with ether, m9160-170℃
(decomposition), powdered 7-[N-(2-nitrophenyl)
267.7 m9 of acetyl-2-phenylglycinamide]cephalosporanic acid are obtained.

Ultraviolet absorption spectrum (95% C2H50H) λmax
259 mμ, E=167.8 Example 4 655 μ of N-(3-nitrophenoxy)acetyl-2-phenylglycine was dissolved in 35 rI′Ll of tetrahydrofuran.
and stir while cooling with water.

To this was added 618 m9 of dicyclohexylcarbodiimide, and the mixture was stirred for 30 minutes while cooling with water.

Add 7-aminocephalosporanic acid 5507n9 to this solution.
and 35 ml of chloroform solution containing 606 ml of triethylamine are added at 10 DEG to -13 DEG C. with stirring.

This mixed solution is stirred at the same temperature for 1 hour, at 0° C. for 2 hours, and further at room temperature for 3 hours.

When the reaction solution was treated in the same manner as in Example 1, mp 115~
122 DEG C. (decomposition) to obtain powdered 7-(N-(3-nitrophenoxy)acetyl-2-phenylchrysinamide)cephalosporanic acid 226.1.

Ultraviolet absorption spectrum (95% C2H60H) λmax
265 m p, E=216.2 Example 5 655 ml of N-(4-nitrophenoxy)acetyl-2-phenylglycine is dissolved in 357 d of tetrahydrone run and stirred under water cooling.

Dicyclohexylcarbodiimide 618 was added to this, and the mixture was stirred for 30 minutes while cooling with water.

A chloroform solution containing 550 μ of 7-aminocephalosporanic acid and 606 μ of triethylamine in this solution
5 ml are added with stirring at -10 to -13°C.

This mixed solution is stirred at the same temperature for 1 hour, at 0° C. for 2 hours, and further at room temperature for 3 hours.

When the reaction solution was treated in the same manner as in Example 1, mp124-12
At 8 DEG C. (decomposition), 137.4 .mu. of powdered 7-[N-(4-nitrophenoxy)acetyl 2-phenylglycinamide]cephalosporanic acid is obtained.

Ultraviolet absorption spectrum (95% C2H50H) λmax
290 mμ, E=201.2 Example 6 640 m9 of N-(4-chlorophenoxy)acetyl-2-phenylglycine is dissolved in 35 ml of tetrahydrofuran and stirred under water cooling.

To this was added 620 cm of synchhexylcarbodiimide, and the mixture was stirred for 30 minutes while cooling with water.

To this solution, 35 mB of a chloroform solution containing 550 g of 7-aminocephalosporanic acid and 6209 g of triethylamine is added at 10 DEG to -13 DEG C. with stirring.

This mixed solution is stirred at the same temperature for 1 hour, at 0° C. for 2 hours, and further at room temperature for 3 hours.

When the reaction solution was treated in the same manner as in Example 1, m'p 125
~130°C (decomposition), powdered 7-(N-(4-chlorophenoxy)acetyl-2-phenylglycinamide)
52.1 m9 of cephalosporanic acid are obtained.

Ultraviolet absorption spectrum (95% C2H50H) λmax
265 mμ, E=158 Example 7 640 ml of N-(2-chlorophenoxy)acetyl-2-phenylglycine was dissolved in 35 rnl of tetrahydrone and stirred under water cooling.

To this was added 620 rv of dicyclohexylcarbodiimide, and the mixture was stirred for 30 minutes while cooling with water.

Add 7-aminocephalosporanic acid 5501n9 to this solution.
and 35 ml of a chloroform solution containing 620 μ of triethylamine! Add while stirring at 10 to -13°C.

This mixed solution is stirred at the same temperature for 1 hour, at 0° C. for 2 hours, and further at room temperature for 3 hours.

When the reaction solution was treated in the same manner as in Example 1, mp128-13
5 DEG C. (decomposition), powdery +17) 7-(N-(2-chlorophenoxy)acetyl 2-phenylglycinamide) cephalosporanic acid 100.61n9 is obtained.

Ultraviolet absorption spectrum (95% C2H50H) λmax
266 mμ, E=143.7 Example 8 D-N-(2,6-dichlorophenoxy)acetyl-2
-Phenylglycine 3.71 yohtriethylamine 1
．． Dissolve 22 in 70wLl of tetrahydrofuran,
Pivalic acid chloride 1.
Drop 21.

This was stirred for 30 minutes at -10°C or lower, and then -
Below 5°C, 7-aminocephalosporanic acid 3.7z and triethylamine 2.5'? Add dropwise 70 ml of a chloroform solution containing .

This is stirred at -10°C or lower for 1 hour, at 0-5°C for 1 hour, and further at room temperature for 3 hours.

The precipitate in the reaction solution is removed, and the solution F is concentrated under reduced pressure.

50 ml of water is added to the concentrate, and sodium hydrogen carbonate is added thereto to adjust the pH to 7.5-8.0.

The mixture is then acidified with dilute hydrochloric acid and extracted with ethyl acetate.

The extract is washed with a saturated aqueous solution of sodium chloride, and then concentrated under reduced pressure.

Washing the concentrate with ether yields powdered D-7-(N
-(2,6 cyclophenoxy)acetyl-2-phenylglycinamide]cephalosporanic acid 4.15P is obtained.

When Honjima is recrystallized from aqueous acetone, mp167-16
At 8°C (decomposition), a powdered purified product is obtained.

Ultraviolet absorption spectrum (95% C2H60H) λmax
261.5 mμ, E=112 Example 9 DI, -N-(2,6-dichlorophenoxy)acetyl-2-phenylglycine 710 μl and triethylamine 210 μl were dissolved in 15 ml of tetrahydrofuran, and this was stirred in an ice-water bath. pivalic acid chloride 24
0r11? Add.

To this solution was added dropwise 15 rnl of a chloroform solution containing 550 μ of 7-aminocephalosporanic acid and 210 μ of triethylamine at -17 to -20°C, and
Stir for 30 minutes at °C, 1 hour in an ice-water bath, and 3 hours at room temperature.

The reaction solution was concentrated under reduced pressure, and the concentrate was dissolved in 30 ml of water.

Add a saturated aqueous solution of sodium hydrogen carbonate to this aqueous solution and p
After adjusting to H7.5 to 8.0, wash with ethyl acetate.

After making this acidic with hydrochloric acid, it is extracted with ethyl acetate.

The extract is washed with water, dehydrated, and then concentrated under reduced pressure.

When the concentrate is washed with ether, the mp 140-144°C (
decomposition) to obtain 135.6 µ of powdered 7-(DL-N-(2,6-dichlorophenoxy)acetyl-2-phenylglycinamide)cephalosporanic acid.

Ultraviolet absorption spectrum (95% C2H60H) λmax
263.5 m p, E=122.5 Example 1O N-(2-nitrophenoxy)acetylvaline 600 m
9 and 620 μl of synchhexylcarbodiimide are dissolved in 35 rrLl of anhydrous chloroform.

This and 550ml of 7-aminocephalosporanic acid? and 35rrL of anhydrous chloroform solution containing 620μ of triethylamine were added at -10 to -13℃, and at the same temperature
Stir for 1 hour in an ice-water bath and for an additional 3 hours at room temperature.

When the reaction solution was treated in the same manner as in Example 1, mp 146-1
51'C (decomposition), powdered 7-(N-(2-nitronenoxy)acetylvalineamide)cephalosporanic acid 42Iv is obtained.

Ultraviolet absorption spectrum (95%C2H50H) λmax
261 mμ, E=200.9 Example 11 N-(2-nitrophenoxy)acetylalanine 810
(1) and triethylamine 330■ are dissolved in 25 ml of anhydrous tetrahydrofuran, and pivalic acid chloride 365rn9 is added dropwise thereto with stirring at 5 to 10°C.The mixed acid anhydride solution obtained is stirred at 10°C or lower for 30 minutes. To this was added dropwise 25 ml of an anhydrous chloroform solution containing 820 ml of 7-aminocephalosporanic acid and 330 ml of triethylamine at -5°C or lower.

This mixture is stirred for 1 hour at 10° C. or lower and for 4 hours at 0° C. to room temperature.

When the reaction solution was treated in the same manner as in Example 1, mp156-17
4°C (decomposition), powdered 7-(N-(2-nitrophenoxy)acetylalaninamide]cephalosporanic acid 5
Obtain 27.3 ■.

Ultraviolet absorption spectrum (95% C2H60H) λmax
261.5 mμ, E=196.2 Example 12 N-(2-nitrophenoxy)acetylglycine 762
II19 and triethylamine 350rrlI? was dissolved in 25 rrL of anhydrous tetrahydrone, and 360 mg of pivalic acid chloride was added dropwise thereto with stirring at 5 to 10°C. The mixed acid anhydride solution obtained was stirred at 10°C or lower for 30 minutes, and then 7 amino acid 25 ml of an anhydrous chloroform solution containing 816 ml of cephalosporanic acid and 350 ml of triethylamine was added dropwise at below -10°C for 1 hour and stirred at 0°C to room temperature for 4 hours.

When the reaction solution was treated in the same manner as in Example 1, mp 112-1
At 17°C (decomposition), powdered 7-CN-(2-nitrophenoxy)acetylglycinamide]cephalosporanic acid 907■ is obtained.

Ultraviolet absorption spectrum (95% C2H50H) λmax
259mtt, E=200.6 Example 13 D-N-(4-chlorophenylthio)acetyl 2-phenylchrysine 503.7■, triethylamine 151m
180 m9 of pivalic acid chloride are added dropwise to a solution consisting of 9 and 10 rrLl of dry tetrahydrofuran.

To this was added 408 In9 of 7-aminocephalosporanic acid, 303 m9 triethylamine and 10 in dry chloroform.
A solution consisting of m1 was added dropwise at a temperature below 5°C, and the mixture was stirred at a temperature below -10°C for 40 minutes and at room temperature for 4° and 5 hours.

The reaction solution is concentrated under reduced pressure, water is added to the residue, and the mixture is made acidic with dilute hydrochloric acid.

This is extracted with ethyl acetate, and the extract is washed with water and dried.

This was concentrated under reduced pressure and the residue was triturated with ether.
When the precipitates were counted, 7-(D-N-(4-chlorophenylthio)acetyl-2-phenylglycinamide)cephalosporanic acid 3 with a mp of 142 to 146°C (decomposed)
Obtain 22.5 ■.

Ultraviolet absorption spectrum (95% C2H50H) λmax
258.5 m p, E=257.8 Example 14 D-N-(2-nitrophenylthio)acetyl 2-phenylglycine 2.59, triethylamine 0.85? 1.26 P of pivalic acid chloride is added dropwise to a solution consisting of 40 rrLl of dry tetrahydrofuran while stirring at 5 to 10°C, and the mixture is stirred at -10°C or below for 30 minutes.

A solution consisting of 2.31 ml of 7-aminocephalosporanic acid, 1.82 ml of triethylamine and 40 ml of dry chloroform was added dropwise to the mixture at -15°C or lower, and the mixture was stirred at -10 to -15°C for 1 hour and at room temperature for 5 hours.

Add ethyl acetate to the reaction solution, and make acidic with 10% hydrochloric acid.

The ethyl acetate layer is separated, washed with water, dried, and concentrated under reduced pressure.

When the residue is powdered with ether and the precipitate is extracted with P, mp is obtained.
7-CI)-N-(2nitrophenylthio)acetyl-2-phenylglycinamide]cephalosporanic acid i, ssy at 125-127°C (decomposition) is obtained.

Ultraviolet absorption spectrum (95% C2H50H) λmax
246mlt, E=308.5Example 15 D-N-(2-methoxyphenoxy)acetyl 2-phenylglycine 790η and triethylamine 304■
to 15 rrL of anhydrous tetrahydrofuran solution containing 5
Pivalic acid chloride 362■ while stirring at ~10℃
was added dropwise and stirred for 30 minutes at -10°C or lower, and then 15 ml of an anhydrous chloroform solution containing 8207% of 7-aminocephalosporanic acid and triethylamine 7551119 was added dropwise at =5°C or lower.

This mixture was stirred at -10 to 15°C for 1.5 hours, and then
Stir for a further 5 hours at room temperature.

The reaction solution was concentrated under reduced pressure, the concentrate was dissolved in water, and the pH was adjusted to 7.0 to 8.0 with an aqueous sodium hydrogen carbonate solution.
Wash with ethyl acetate.

The aqueous layer is separated, adjusted to pH 4.0 with 10% hydrochloric acid, and then extracted with ethyl acetate.

The extract is washed with water, dried over sodium sulfate, and then concentrated under reduced pressure.

When the concentrate is washed with ether, the mp 130-131°C
(Decomposition) to obtain 220 μg of 7-[DN(2-methoxyphenoxy)acetyl-2-phenylglycinamide]cephalosporanic acid in powder form.

Ultraviolet absorption spectrum (95%C,,H50H) λma
x267mμ, E=150.5 Example 16 D-N-(3-methoxyphenoxy)acetyl-2-phenylglycine 950m9 and triethylamine 36
Add 45 ml of pivalic acid chloride to 15 TLl of anhydrous tetrahydrofuran solution containing 4 m9 of pivalic acid chloride while stirring at 5-10°C.
After adding 2■ dropwise and stirring for 30 minutes at -10℃ or less,
A chloroform solution containing 980 m9 of 7-aminocephalosporanic acid and 760 m9 triethylamine was added to this.
mJ is added dropwise at a temperature below -5°C.

This mixed solution is stirred at -10 to -15°C for 1.5 hours, and further stirred at 0°C to room temperature for 4 hours.

When the reaction solution was treated in the same manner as in Example 15, mp125~
127°C (decomposition), powdered 7CD-N-(3-methoxyphenoxy)acetyl 2-phenylglycinamide]
Cephalosporanic acid 3451n9 is obtained.

Ultraviolet absorption spectrum (95% C2H50H) λmax
268 mμ, E=150 Example 17 D-N-(2,6-simethoxyphenoxy)acetyl-
15ml of anhydrous tetrahydrofuran solution containing 870ml of 2-phenylglycine and 304ml of triethylamine
Add pivalic acid chloride 3 while stirring at 5-10°C.
After stirring for 30 minutes at -10°C or lower, 15ral of an anhydrous chloroform solution containing 820m9 of 7-aminocephalosporanic acid and 635Tn9 of triethylamine was added dropwise at -15°C or lower.

This mixture is stirred at -10-15°C for 1 hour, and further stirred at 0°C-room temperature for 5 hours.

The reaction solution is concentrated under reduced pressure, and the concentrate is dissolved in water, adjusted to pH 7.0-8.0 with an aqueous sodium bicarbonate solution, and washed with ethyl acetate.

The aqueous layer is separated, adjusted to pH 2.0 with dilute hydrochloric acid, and extracted with ethyl acetate.

The extract is washed with water, dried over sodium sulfate, and then concentrated under reduced pressure.

When the concentrate is washed with ether, the mp 97-105°C (
decomposition) to obtain powdered 7-CD-N-(2,6-simethoxyphenoxy)acetyl-2-phenylglycinamide]cephalosporanic acid 4507/llp.

Ultraviolet absorption spectrum (95% C2H50H) λmax
256 mμ, E=146.5 λmax 270 mμ, E=129 Example 18 N-(2-nitrophenoxy)acetyl-2(2-chenyl)glycine 1540rn9 and triethylamine 605η in 20ml of anhydrous tetrahydrofuran solution at -5 to -10°C Pivalic acid chloride 7 while stirring
After stirring for 30 minutes at -10°C or lower, 2 ml of an anhydrous chloroform solution containing 7-aminocephalosporanic acid 1650cm and triethylamine 12707114j was added dropwise at -5°C or lower.

This mixed solution was stirred at 10 to -15°C for 1.5 hours, then 0°C to
Stir for a further 4 hours at room temperature.

The reaction solution is concentrated under reduced pressure, and the concentrate is dissolved in water.

Add sodium hydrogen carbonate aqueous solution to this aqueous solution to adjust the pH.
7.0-8.0 and wash with ethyl acetate.

The aqueous layer is separated, adjusted to pH 2.0 with dilute hydrochloric acid, and extracted with ethyl acetate.

The extract is washed with water, dried over sodium sulfate, and then concentrated under reduced pressure.

Washing the concentrate with ether gives powdered 7-(N-(
1090 ml of 2-nitrophenoxy)acetyl-2-(2-chenyl)glycinamide]cephalosporanic acid is obtained.

If you recrystallize this product 500 from acetone, the mp187~
189°C (decomposition) to obtain crystalline purified product 1001n9.

Ultraviolet absorption spectrum (20% tetrahydrofuran) λmax 235mμ, E=301 λmax 270mp, E=195 Example 19 D-N-(2-nitro-4-chlorophenoxy)acetyl-2-phenylglycine 1830■ and triethylamine 6051rlI? 725 μm of pivalic acid chloride was added dropwise to 30 μm of anhydrous tetrahydrofuran solution containing 7-aminocephalosporanic acid while stirring at 5°C to 0°C.
A solution of 301 flL of anhydrous chloroform containing 1n9 and 1260 mm of triethylamine is added dropwise at below -5°C.

This mixture was stirred at -10 to -15°C for 1.5 hours, then 0°C.
~Stir for an additional 4 hours at room temperature.

When the reaction solution was treated in the same manner as in Example 15, powdered 7-(
D-N-(2nitro-4-chlorophenoxy)acetyl-2-phenylglycinamide]cephalosporanic acid 1
Get 160 ■.

When 500cm of this product is recrystallized from aqueous acetone, mp1
A purified product is obtained at 65-168°C (decomposition).

Ultraviolet absorption spectrum (20% tetrahydrofuran) λmax 279.5 mμ, E=339 Example 2゜D -N-(2-tertiary butylphenoxy)acetyl-
Anhydrous tetrahydrofuran solution 1 containing 1040 m9 of 2-phenylglycine and 361779 triethylamine
4341v of pivalic acid chloride was added dropwise to 5 ml of the solution while stirring at 5 to 10°C, and after stirring at -10°C or lower for 30 minutes, 7-aminocephalosporanic acid 98Q was added to the solution.
Immediate and triethylamine 755rnI? 15 ml of an anhydrous chloroform solution containing the mixture was added dropwise at -5°C or below.

This mixture was stirred at -10 to -15°C for 1.5 hours, and then
~Stir for an additional 4 hours at room temperature.

The reaction solution is concentrated under reduced pressure, and the concentrate is dissolved in water.

Add sodium hydrogen carbonate aqueous solution to this and adjust the pH to 7.0.
~8.0 and wash with ethyl acetate.

The aqueous layer is separated, adjusted to pH 4.0 with hydrochloric acid, and extracted with ethyl acetate.

After washing the extract with water and drying over sodium sulfate, ethyl acetate was distilled off under reduced pressure.

After washing the residue with a mixture of ether and petroleum ether,
810 ml of powdered D-7-1:'N-(2-tert-butylphenoxy)acetyl-2-phenylchrysinamide]cephalosporanic acid is obtained.

180 m9 of dicyclohexylamine was added to an acetone solution containing 600 m9 of this product, and when the precipitate was counted, the result was a mp of 177-178°C (decomposition), and a powdery D-7-(
300 ml of dicyclohexylamine salt of N,-(2-tert-butylphenoxy-2-phenylglycinamide)cephalosporanic acid is obtained.

Elemental analysis: C30Hss Na Os S ”C12H
23N” 2H20 calculated value C62.06, H7.4
4, N6.89, S3.94 Experimental value C62,24, H7,12, N6.74.33
．． 98 Ultraviolet absorption spectrum (95% C2H50H) λmax
268 mμ, E=113 Example 21 N-(3-1lifluoromethylphenoxy)acetyl-
2-(2-chenyl)glycine 3.6Sl' and 7~
3.2r of aminocephalosporanic acid was added to 30rrLl of anhydrous tetrahydrofuran, and after cooling to 5°C, 1.41ml of pivalic acid chloride was added dropwise while stirring.
Stir for an additional 30 minutes.

After cooling this to -5°C, 3.0% of 7-aminocephalosporanic acid was added to it. (l and triethylamine 2.21
was dissolved in 30 r/ll of anhydrous chloroform.
Cool to below ℃ and drop.

This mixture is stirred for 15 hours below 5°C and then for 3.5 hours at room temperature.

Insoluble materials are removed from the reaction solution, and Solution F is concentrated under reduced pressure.

Water and ethyl acetate are added to the residue, diluted hydrochloric acid is added to make it acidic, and the mixture is extracted with ethyl acetate.

The extract is washed with water, dried, and concentrated under reduced pressure.

The number of crystals precipitated in the concentrated solution is mp 148~
Crystals of 7-[N(3-1-lifluoromethylphenoxy)acetyl 2-(2-chenyl)glycinamide]cephalosporanic acid having 151'C (decomposition) are obtained.

Ultraviolet absorption spectrum (95%C2H50H) λmax
220rILμ, E=256.7λmax240mμ
, E=213 λinf 268 mμ, E=142.6 Example 22 N-(2-nitro-4-chlorophenoxy)acetyl-
The reaction was carried out analogously to Example 21 using 3.0 P of 2-(2-chenyl)glycine and 2.71 P of 7-aminocephalosporanic acid and worked up similarly, resulting in mp 1
577 ml of crystals of 7-[N-(2-nitro-4-chlorophenoxy)acetyl-2-(2-chenyl)glycinamide]cephalosporanic acid are obtained at 50-155°C.

Ultraviolet absorption spectrum (20% tetrahydrofuran) λinj 240mμ, E=311.4λinf
263 mμ, E=188 Example 23 N-(2,6-dichlorophenoxy)acetyl 2-(2
-chenyl)glycine 3.6r and 7-aminocephalosporanic acid 3.21 and with similar work-up, the mp 150-15
1.3 Fl of crystals of 7-[N(2,6-dichlorophenoxy)acetyl-2(2-chenyl)chrysinamide]cephalosporanic acid at 5°C (decomposition) are obtained.

Ultraviolet absorption spectrum (pH 6,4 phosphate buffer) λi
nf 220 m μ, E=296.2λinf
236 m μ, E=224λinf 265 m
μ, E=134 Example 24 D-N-(2,6-xylyloxy)acetyl 2-phenylchrysine 1. FW',) 0.71 pivalic acid chloride was added dropwise to a solution consisting of 0.71 ethylamine and 30 ml of dry tetrahydrofuran at -5°C, and the mixture was stirred at the same temperature for 30 minutes.

30 ml of a dry chloroform solution containing 1.5 l of 7-aminocephalosporanic acid and triethylamine i,oy
are added all at once to the solution prepared above at a temperature below -10°C, and the mixture is stirred at the same temperature for 1 hour and then at room temperature for 3 hours.

After filtering the reaction solution and concentrating the solution under reduced pressure, water is added to the residue.

This is made acidic with dilute hydrochloric acid, extracted with ethyl acetate, and the extract is washed with water and dried.

This was concentrated under reduced pressure and the residue was triturated with ether.
When precipitates are counted, mp 120-130℃ (decomposition)
7. [:D-N(2,6-xylyloxy)acetyl-2-phenylglycinamide]cephalosporanic acid 1
011t is obtained.

Ultraviolet absorption spectrum (20% tetrahydrofuran) λmax 260m, cz, E=157.1 Example 25 N-phenylacetyl-2-phenylglycine 550■
was dissolved in 15 r/l of tetrahydrofuran and stirred while cooling with water.

To this, dicyclohexylcarbodiimide 610rIT9
and stir for 30 minutes while cooling with water.

A chloroform solution containing 542 kg of 7-aminocephalosporanic acid and 606 kg of triethylamine in this solution.
5rfLl was added with stirring at -10 to -13°C,
The mixture was stirred at the same temperature for 1 hour, at 0°C for 2 hours, and then at room temperature for 3 hours.

The reaction solution is thoroughly filtered, and the lachrymal fluid is concentrated under reduced pressure.

Dissolve the concentrate in 30rrLl of water and add hydrogen carbonate) IJ
Adjust the pH to 7.5 to 8.0 with an aqueous solution of aluminum.

After washing twice with ethyl acetate, adjust the pH to 3.0~ with dilute sulfuric acid.
3.5 and extracted with ethyl acetate.

After the extract is washed with water and dehydrated, ethyl acetate is distilled off under reduced pressure.

When the residue is washed with ether, the mp120-128℃
(decomposition), powdered tour (N-phenylacetyl-2-
Phenylglycinamide) cephalosporanic acid 55.7
Get 9.

Ultraviolet absorption spectrum (95% C2H50H) λmax
253 mμ, E=175 Example 26 DL-N-(3-phenylpropionyl)-2(2-chenyl)glycine 3.01 and triethylamine 1.
21 was dissolved in 30 ml of dry tetrahydrofuran, 1.41 ml of pivalic acid chloride was added to this solution, and the mixture was stirred for 30 minutes.

This is followed by 3.7-aminocephalosporanic acid. Of, triethylamine 2.21 L and dry chloroform 3011 L
A solution consisting of 1 is added dropwise at -5°C or below.

The mixture is stirred for 1.5 hours below -5°C and then for 3.5 hours at room temperature.

The reaction solution is concentrated under reduced pressure, and water and ethyl acetate are added to the residue.

Add dilute hydrochloric acid to make it acidic, and separate the ethyl acetate layer.

This is washed with water, dried, and then concentrated under reduced pressure.

The number of precipitates in the concentrated liquid is mp166-168℃
(Decomposition) of 7-(DL-N-(3-phenylpropionyl)-2-(2-chenyl)glycinamido)cephalosporanic acid 1.51 is obtained.

Ultraviolet absorption spectrum (95% C2H50H) λmax
240 mμ, E=260 λinf 270 m μ, E=132 Example 27 The following compound is obtained in the same manner as above.

(1) 7-CD-N-(2-nitrophenoxy)acetyl-2-phenylglycinamine-3-methyl-
3-cephem-4-carboxylic acid mp178-180℃ (decomposition) Elemental analysis: C24H22N408S Calculated value C54,75, H4,21, Nl O,64,
86,09 Experimental value C54,39, H4,19, N10.37, S
5.93 (2) 7-CD -N-(2-nitrophenoxy)
Acetyl-2-phenylglycinamide]-3(2-thenylcarbonylthiomethyl)-3cephem-4-carboxylic acid mp105-113℃ (decomposition) Ultraviolet absorption spectrum (20% tetrahydrofuran) λmax 264mp, E=210.1λinf
300 mμ, E=150.1(3) 7-CD
-N-(2-nitronenoxy)acetyl-2-phenylglycinamide) -3benzoylthiomethyl-3-
Sodium salt of cephem-4-carboxylic acid mp180℃ (decomposition) Elemental analysis: Ca1H2609N4 S2 calculated value C5
6,201H3,93, N8.46 Experimental value C56,4
5, H4.01, N8.12 ultraviolet absorption spectrum (2
0% tetrahydrofuran) λmax 272.5 mp, E=282(4)
7-CD-N-(2-nitrophenoxy)acetyl-2
-phenylglycinamide) -3-(5-methyl-1
・3,4-oxadiazol-2-yl 9thiomethyl-3
-Cephem-4 carboxylic acid mpH5-120℃ (decomposition) Ultraviolet absorption spectrum (pH6,4 phosphate buffer) λm
ax257mμ, E=227 (5) 7-(D-N-(2-nitrophenoxy)acetyl-2-phenylglycinamide]-3-(1-methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem Synchhexylamine salt of -4-carboxylic acid mp178-179℃ (decomposition) Ultraviolet absorption spectrum (95% C2H50H) λmaX
2601 rLμ, E=149 (6) 7-CD-N-(2-nitrophenoxy)acetyl-2-phenylglycinamide] -3-(5-
Dicyclohexylamine salt of methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carphonic acid mp192-193°C (decomposition) Ultraviolet absorption spectrum (95% C2H50H) λmax
260mμ, E=140.5(7) 7-CD
-N-(2-nitrophenoxy)acetyl-2-phenylglycinamide)-3(5-methyl-4H-1.2.
4-triazol-3-yl)thiomethyl-3-cephem-4carboxylic acid mp154℃ (decomposition) Ultraviolet absorption spectrum (pH 6, 4 phosphate buffer) λm
ax 268.5 mμ, E=203(8)7-CD
-N-(2-nitrophenoxy)acetyl-2-phenylglycinamide]-3(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acidmp135℃(decomposition) Ultraviolet absorption spectrum (pH 6,4 phosphate buffer) λm
ax 269.5mμ, E=216(9) 1-(
4-Carboxy-7-(D-N-(2nitrophenoxy)acetyl-2-phenylglycinamide)-3-cephem-3-ylmethyl]pyridinium hydroxide inner salt mp 200°C (decomposition) Ultraviolet absorption spectrum (20% tetrahydrofuran ) λmax 260.5mμ, E=160(10)
7-CD-N-(2,6-dichlorophenoxy)acetyl-2-phenylchrysinamide]3-benzoylthiomethyl-3-cephem 4-carboxylic acid mp 173°C (decomposition) Ultraviolet absorption spectrum (30% tetrahydrofuran) λmax 240 mμ , E=190 λmaX 276 mμ, E=210 αυ 7-CD-N-(2,6-dichlorophenoxy)
Acetyl-2-phenylglycinamide]3-(1-methyl-IH-tetrazol-5yl)thiomethyl-3-
Cephem-4-carboxylic acid mp 135-140℃ (decomposition) Ultraviolet absorption spectrum (pH 6, 4 phosphate buffer) λm
ax265mμ, E=128 (12) 7-CD-N-(2,6-dichlorophenoxy)acetyl-2-phenylglycinamide]3-(
5-methyl-1,3,4-thiadiazol-2-yl)
Thiomethyl-3-cephem 4-carboxylic acid ultraviolet absorption spectrum (pH 6,4 phosphate buffer) λm
ax271mμ, E=159 (13) 7-[:'D-N-(2-nitrophenoxy)acetyl-2-(2-chenyl)glycinamide]
3-C4-1f-1-piperazinyl)thiocarbonylthiomethyl-3-cephem-4-carboxylic acid mp 157-168°C (decomposition) Ultraviolet absorption spectrum (20% tetrahydrofuran) λmax 269 mμ, E = 260.8 (14) 7- CD-N-(2-nitrophenoxy)acetyl-2-(2-chenyl)glycinamide]
3-azidomethyl-3-cephem-4-carboxylic acid mp 100-108°C (decomposition) Ultraviolet absorption spectrum (20% tetrahydrofuran) λinf 263 mp, E = 197.15 (15
) 7-(DL-N-(2-nitrophenoxy)acetyl-2-(2-chenyl)glycinamide]-3-
Dicyclohexylamine salt of (1-methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-4carboxylic acid mp 175-176°C (decomposition) Ultraviolet absorption spectrum (95% C2H50H) λmaX
2357rLμ, E=290 λmax270mμ, E=145 (16) 7-(DL-N-(2-nitrophenoxy)acetyl-2-(2-chenyl)glycinamide]
-3-(5-methyl-1,3,4-thiadiazole-2
-yl)thiomethyl-3-cephem-4-carboxylic acid mp131-135℃ (decomposition) Elemental analysis: C25N22 N6 o8s4 calculated value C4
5,31, H3,35, N12.68, S19.35 Experimental value C45,61, H3,42, N12.63, S
19.63 Ultraviolet absorption spectrum (20% tetrahydrofuran) λmax 269 mμ, E = 247.3 (1n 7-CD-N-(2-nitrophenoxy)acetyl-2-(2-chenyl)glycinamide] 3-(
2-Benzimidazolyl)thiomethyl 3-cephem-4
-Carboxylic acid mp155-160℃ (decomposition) Ultraviolet absorption spectrum (20% tetrahydrofuran) λmax 274mμ, E=224.6 zmaX 2'827rLμ, E=222λmax29
1 m μ, E = 201-2 λinf 268 m μ, E = 220.4 (1,8
) 7-1: D-N-(2-nitro-4-chlorophenoxy)acetyl-2-phenylglycinamide]-3
-(1-Methyl-IH-tetrazo-/L/-5-yl)thiomethyl-3-cephem-4-carboxylic acid m9163-170℃ (decomposition) Ultraviolet absorption spectrum (pH 6,4 phosphate buffer) λm
ax2677Jz, E=177.4 (19) 7-CD -N-(2-tertiary butylphenoxy)acetyl-2-phenylglycinamide]3-
Methyl-3-cephem-4-carboxylic acid ultraviolet absorption spectrum (pH 6,4') phosphoric acid buffer) λmax 264m
μ, E=141 (20) 7-CD-N-(2,6-xylyloxy)acetyl-2-phenylglycinamide to 3-methyl-3-cephem-4-carboxylic acid UV absorption spectrum (pH 6,4 phosphate buffer liquid) λm
A ) Example 28 D-N-(2-nitro-410lophenylacetyl)-
A solution consisting of 2.01 pivalic acid chloride and 50/7 il of tetrahydrone chloride was added dropwise to a solution consisting of 2-phenylglycine 6, Oz, 1.74 f of dry triethylamine, and 50 ml of tetrahydrofuran over a period of 7 minutes at -5°C. After finishing, stir at the same temperature for 30 minutes.

This solution was dissolved in a solution consisting of 6.2 r of 7amino-3-(1-methyl-IH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, 2.81' of triethylamine, 15 r/l of acetone, and 15 r/l of water. =
Add all at once at 25°C.

The cooling bath is removed and the mixture is stirred at room temperature for 1.5 hours.

Tetrahydrofuran and acetone were distilled off from the reaction solution under reduced pressure, and water and ethyl acetate were added to the residue.
Add dilute hydrochloric acid to adjust pH to 2.

After removing insoluble matter, the ethyl acetate layer is separated, washed with water, and then dried over magnesium sulfate.

Ethyl acetate is distilled off from this solution under reduced pressure, and the precipitated solid 3.2z is dissolved in acetone.

After removing insoluble matter from this solution and treating the P solution with activated carbon, acetone is distilled off under reduced pressure.

Ether was added to the residue and stirred overnight, and the precipitate was collected at mp173°C (decomposed) and powdered 7-[D
-N-(2-nitro-4-chlorophenylacetyl)-
2-phenylglycinamide]-3-(1-methyl-L
1.49P of H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid is obtained.

Nuclear magnetic resonance absorption spectrum δ (DMSO-da): 3.67 (2)L
broad s), 99m 3.95 (3H, S), 4.08 (2H, d), 4.3
3 (2H,s), 5.05 (IH,d), 5.
67 (2H, m), 7.02-8.13 (8H.

m) Example 29 D-N-(2-nitro-4-chlorophenylacetyl)
-2-phenylglycine 2.0P, triethylamine 0
．． A solution consisting of 0.69P of pivalic acid chloride and 4r/'Ll of tetrahydrofuran was added to a solution consisting of 58f and 20ml of tetrahydrofuran at 0 to -5℃ for 5 minutes.
After adding for a few minutes, the mixture was stirred at the same temperature for 30 minutes.

Add 7-amino-3-(5-methyl-1,3,4) to this solution.
-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid 1.98P, triethylamine 0.
A solution consisting of 82 g, 10 ml of acetate and 10 ml of water is added all at once at -10°C.

After stirring this mixture vigorously for 30 minutes at -5 to 9°C,
Return to room temperature and stir for an additional hour.

The precipitate in the reaction solution is removed, and acetone and tetrahydrofuran are distilled off from Solution F under reduced pressure.

Add an aqueous solution of sodium bicarbonate to the residue while cooling with water, and remove the precipitate.

Water is added to this solution to dissolve it, ethyl acetate is layered on this solution, and the pH is adjusted to 2 with dilute hydrochloric acid.

After removing the precipitate, the ethyl acetate layer is separated, and the ethyl acetate is distilled off from this solution under reduced pressure.

Washing of the residue with ether gave 7CD-N-(2-nitro-4-chlorophenylacetyl)-2-phenylglycinamide]-3-(5-
0.21 of methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid is obtained.

Nuclear magnetic resonance absorption spectrum δ (DMSOd6): 2.67 (3H, s
), 99m

Claims (1)

[Scope of Claims] 1 General formula [wherein M is a carboxy group, R1 is a hydrogen atom, an azido group, an alkanoyloxy group, a pyridyl group, or a nitrogen-containing 5-membered heterocyclic thio group optionally substituted with lower alkyl (This heterocyclic group may further contain an oxygen atom or a sulfur atom as a hetero atom, and may be fused with a benzene ring), a lower alkyl-substituted piperazinylthiocarbonylthio group, a benzoylthio group, or a thenoylthio group. and when the group R1 contains a quaternary nitrogen atom, M means a group represented by the formula -COO○] or its derivatives in the amino group and/or carboxy group. Formula (wherein R2 means an alkanoyl group, R3 means a hydrogen atom, an alkyl group, an aryl group or a chenyl group, respectively, and the alkanoyl group of R2 is substituted with phenyl, phenoxy or phenylthio, and these substituents Among them, the phenoxy group further has a halogen, nitro group, alkyl group, or alkoxy group as an unsubstituted group, and the phenyl group and phenylthio group may be substituted with a halogen or nitro group). -A 7-(α-substituted aminoalkanamide) of the general formula (wherein R1, R2, R3 and M have the same meanings as before) is produced by the action of substituted amino fatty acids or reactive derivatives thereof at the carboxy group. 3-Substituted-3-cephem-4-carboxylic acids are 7-(α-
(substituted aminoalkanamide) 3-substituted-3-cephem-
Method for producing 4-carboxylic acid derivative.