JPS59122496A - Novel delta3-cephem derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R<1>, R<2> are lower alkyl, nitro; A is 1-3C alkylene; R<3> is lower alkyl) and its salt. EXAMPLE:7-{alpha-( 2-Tritylamino-4-thiazolyl )-alpha-[2-( 2-methyl-5-nitro-1-imidazolyl )- ethoxyimi]acetamide}-3-[( 1-methyl-5-tetrazolyl )thiomethyl]-DELTA<3>-cephem-4-carboxylic diphenylmethyl ester. USE:A powerful antibacterial against gram-positive and -negative bacteria, in particular against Pseudomanas areugiosa and anaerobic bacteria. PREPARATION:The reaction between a substituted oxyiminothiazolylacetic acid derivative of formula III (R<4> is amino-protecting group) and a 7-amino-DELTA<3>-cephem derivative of formula IV (R<5> is H, carboxyl-protecting group) is followed by deptrotection. The compound of formula III as a starting substance is novel and obtained from (Z)-alpha-hydroxyimino-alpha-(2-tritylamino-4-thiazolyl)-acetic ethyl ester hydrochloride.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel Δ3-cephem derivatives represented by the following general formula (I), salts thereof, and methods for producing them.

(In the formula, R1 and R2 are the same or different and represent a lower alkyl group or a nitro group, A means a lower alkylene group having 1 to 3 carbon atoms, and R3 means a lower alkyl group. The same applies hereinafter) In the definition of the group in the general formula in this book, the word "lower" means a straight or branched carbon chain having 1 to 5 carbon atoms. Therefore, specific examples of lower alkyl groups include methyl group, ethyl group, propyl group, isopropyl group, butyl group, inbutyl group, tert-butyl group, amyl group, isopentyl group, 1-methylbutyl group, 2-methylbutyl group, Examples include neopentyl group.

Examples of the lower alkylene group having 1 to 3 carbon atoms include a methylene group, an ethylene group, a methylmethylene group, a trimethylene group, and a propylene group.

The present invention also includes pharmacologically acceptable non-toxic salts of the compound represented by general 2), and such salts include alkali metals such as sodium and potassium, alkaline earth salts such as calcium and magnesium, etc. Salts with inorganic bases such as metals.

Ammonium salts, salts with organic bases and basic amino acids such as l-limethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, jetanolamine, arginine, lysine, mineral acid salts with hydrochloric acid, sulfuric acid, phosphoric acid, etc., acetic acid, lactic acid. , salts with organic acids such as tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, and ethanesulfonic acid.

The compound (I) of the present invention has an iminoether type oxime or a 2-substituted thiazole group.

Geometric isomers and tautomers exist in these compounds. The present invention provides these syn, ant
i) It includes all geometric isomers and mutual tautomers of the form.

31 The compound represented by the above general formula (I) and its salt provided by the present invention has α-
Substituted imidazolyl lower alkyloxyimino-α-(2
-amino-4-thiazolyl)acetamide group, and exhibits excellent antibacterial activity against Durham-positive bacteria, Durham-negative bacteria, especially Pseudomonas aeruginosa, and anaerobes. Useful as an antibacterial agent.

The compound of the present invention can be produced by various methods, and typical production methods are exemplified below.

1 (I) 4- (In the reaction formula, R4 means a protecting group for an amine group, and R5 means a protecting group for a hydrogen atom or a carboxy group. The same applies hereinafter) The compound represented by the general formula (n) A substituted oxyiminothiazolyl acetic acid derivative represented by or a reactive derivative thereof and 7-amino- represented by the general formula (TTI)
It can be produced by reacting with a Δ3-cephem derivative and then removing the protecting group.

Here, the protecting group for the amine group means a protecting group commonly used in the field of peptide chemistry, and specifically, for example, formyl group, acetyl group, propionyl group,
tert-butoxycarbonyl group, methoxyacetyl group, methoxypropionyl group, benzyloxycarbonyl group.

Acyl group such as p-nitrobenzyloxycarbonyl group,
Benzyl group, benzhydryl group (diphenylmethyl group)
.

Examples include aralkyl groups such as trityl groups.

Further, specific examples of protective groups for carboxine groups include trimethylsilyl group and benzhydryl group.

β-methylsulfonylethyl group, phenacyl group.

p-methoxybenzyl group, tert-butyl group, p
Examples include protecting groups that can be easily removed under mild conditions, such as a -nitrobenzyl group.

The reaction is usually carried out in a solvent under cooling or at room temperature. There are no particular restrictions on the solvent as long as it does not participate in the reaction, but 2 commonly used solvents include:

Dioxane, tetrahydrofuran, ether.

Acetone, ethyl methyl ketone, chloroform.

Examples include organic solvents such as dichloromethane, dichloroethane, methanol, ethanol, acetonitrile, ethyl acetate, ethyl formate, dimethylformamide, and dimethyl sulfoxide.

These solvents can also be used as a mixture as appropriate.

The compound (IT) is used in the form of a free carboxylic acid, and is also subjected to a reaction as a reactive derivative of a carboxylic acid.

Suitable examples include mixed acid anhydrides, acid chlorides, active esters, active amides, acid anhydrides, and acid azides. When compound (TI) is used in the form of free carboxylic acid, N,N'-dicyclohexylcarbodiimide, N,
Preferably, a condensing agent such as N'-diethylcarbodiimide is used.

Depending on the type of reactive derivative of carboxylic acid used, it may be preferable to carry out the reaction in the presence of a base in order to allow one reaction to proceed smoothly. Examples of such bases include inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, and potassium carbonate, and organic bases such as trimethylamine, triethylamine, dimethylaniline, and pyridine.

Removal of the protecting group for the carboxy group from the product thus obtained can include, for example, the benzhydryl group.

The p-methoxybenzyl group and the like can be easily formed by contacting with an acid, and the trimethylsilyl group can be easily formed by contacting with water.

Furthermore, when an aralkyl group such as the above-mentioned trityl group or various acyl groups is used as a protecting group, the protective group of the amine group can be easily removed by hydrolysis with an acid. The acids used in this case are formic acid and trifluoroacetic acid.

Hydrochloric acid and the like are preferred.

Note that the removal of the protecting group for the carboxy group and the removal of the protecting group for the amine group can also be carried out simultaneously.

The salt of the compound of the present invention represented by the general formula (I) can be prepared, for example, in advance using a salt of the starting compound in the above-mentioned production method, or by using a method commonly used in the art to prepare the free compound produced by the above-mentioned production method. It can be produced by applying the following salt-forming reaction.

For example, by first adding an n-butanol solution of alkali 2-ethylhexanoate and then adding an organic solvent such as ether or ethyl acetate with different solubility, the alkali metal salt can be prepared by dicyclohexylamine, triethylamine, cyclohexylamine, jetanol, etc. Salts with organic bases and basic amino acids can be produced by adding and reacting organic bases such as amines, arginine, lysine, and basic amino acids in equal or slightly excess amounts, and ammonium salts can be produced by adding aqueous ammonia.

Isolation and purification of the compound 0) of the present invention and its salts are carried out according to conventional methods, including extraction with organic solvents, crystallization, separation and purification by calamacromography and the like.

Antibacterial agents containing the compound shown in general 2) or its salt as a main component can be prepared by any conventional method using any conventional pharmaceutical carrier or excipient. Administration is via tablets, pills,
Oral injections such as capsules and granules, or injections such as intravenous and intramuscular injections.

It may also be in the form of parenteral administration such as suppositories.

The dosage is appropriately determined depending on the individual case, taking into consideration the symptoms, the age and sex of the recipient, and is usually 250 to 3000 mg per day for a caveman.

This is administered in 1 to 4 divided doses a day.

EXAMPLES The present invention will be explained in more detail by way of examples below.

Note that the raw material compound (If) of the present invention is a new substance, and its production method is shown in Reference Example.

Reference Example 1 193 ml of ethylene difuromite, 31.5 g of 1,9-methyl-5-nitroimidazole and 100 ml of glacial acetic acid
The reaction is carried out at 0 to 114°C under reflux for 72 hours. After the reaction, excess ethylene dibromide is distilled off under reduced pressure and concentrated to precipitate crystals. Add 50 ml of water and filtrate raw material 2.
Collect 3.4 g. Dilute the filtrate with 100ml of chloroform.
7. Then extract with 50 ml. Add chloroform layer to water 3
Wash twice with 0ml and 30ml of saturated saline. After drying the organic layer over anhydrous magnesium sulfate, chloroform and ethylene dibromide were distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. n-hexane-
If eluted with ethyl acetate (volume ratio 1:3), 1-(
6.6 g of 2-bromoethyl)-2-methyl-5-nitroimidazole, then 1-(2-bromoethyl)-2-
2.5 g of methyl-4-ditroimidazole are obtained.

Physical properties Melting point 75-76°C Infrared absorption spectrum νenI-'; ] +5
2, 1450-1460°14] 5.1360,42
55.1180.1140 nuclear magnetic resonance spectrum (C
in DCl3) δ (ppm); 2.56 (3H,s,
CH3-) 3.72 (2H, t, -cH, -) 4.68 (2H, t, -cI (2-) m!//e: 235 (M++2), 233
(M”), + 89 (M+-NO2) 154 (M
+-Br), +07 (BrCH2CH2'') Melting point 98-99°C Infrared absorption spectrum ν am; 3080.
1530.1490°1410.1390.1325.
1290.1265.1225.1+75°1120.
990 Nuclear magnetic resonance spectrum (in CDCl3) δ (ppm)
: 2.46 (3H,S, CH3-)3.66 (2
H, t, -CH2-)4.38(2H, t, -CH
2-) 7□, 80 (IH・°・Early H) Mass spectrum □ ~ , m/e; 235 (M"-1-2), 233 (M
”), 134 (M”-99) 107 (BrCH2CH
2”) (Z)-α-hydroxyimino-α-(2-tritylamino-4-thiazolyl)ethyl acetate hydrochloride 4.93
g was dissolved in 35 ml of dimethyl sulfoxide, 2 g of powdered anhydrous potassium carbonate was added, and the mixture was reacted for 30 minutes at room temperature.

To this was added 2.4 g of 1-(2-bromoethyl)-2-methyl-5-nitroimidazole, and the mixture was allowed to react at room temperature for 3 days.

Disperse the reaction solution in 200 ml of ice water and add 100 ml of ethyl acetate.
m1. Then extract with 50 ml. Collect the organic layer.

Wash twice with 50 ml of water and then with 50 ml of saturated saline at °C. After drying the ethyl acetate layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting caramel was subjected to silica gel column chromatography, eluted with ethyl acetate-benzene (volume ratio 3:1), and fractions containing the target product were collected. The caramel obtained by distilling off the solvent was crystallized from methanol.

A target product of 430 cm was obtained. Melting point 134.5-135.5
°CKBr - Infrared absorption spectrum ν cm, 1730.1
520.1460°1355, +295.1180.
1030.695 nuclear magnetic resonance spectrum (CDCl3
Medium) δ (ppm); 1.25 (3H, t, CH3-)
2.44 (3H, s, CH3-) 4.25 (2H, q, -CH2-,) 4.58 (
4H,s, CH2CH2)72~7.4(15H,
3φ) Mass spectrum m'e; 61 (1 (M'), 533 (PI'-7
7), 0 (M'-C, H, N303) (z) α-(2
Add 880 μm of ethyl -methyl-5-nitro-1-imidazolylethoxyimino)-α-(2-tritylamino-4-thiazolyl)acetate to 9 ml of methanol lI,
And water 5. A solution in which 456 mg of potassium carbonate was dissolved in 3 ml was added to obtain a suspension. Tetra Hytron Run 2
Add 0ITll to make a homogeneous solution at 50-55℃ for about 4 hours.
React for 0 hours.

After completion of the reaction, methanol and tetrahydrofuran were distilled off under reduced pressure. Oml of water was added to the residue, acidified with 3 ml of 2N hydrochloric acid, and extracted twice with 50 ml of ethyl acetate. The organic layer was collected and washed first with 10 ml of water twice and then with 10 ml of saturated saline.

After drying over anhydrous magnesium sulfate, the caramel obtained by distilling off ethyl acetate under reduced pressure was subjected to silica gel column chromatography and eluted with chloroform-isopropanol-formic acid (volume ratio 9:r O: 2) to obtain the desired product. Collect the fractions containing Jl and evaporate the solvent under reduced pressure.
(Z)-α-(2-methyl-5-nitro-1-imidazolylethoquinimino) α-(2-tritylamino-
1g of 25Orl (1thiazolyl)acetic acid was obtained.

Infrared absorption spectrum ν, ,, C; 3:3B0
．． +730.1525°14N), +360.12
60. + 180.695 nuclear magnetic resonance spectrum (
(in CDCl2) δ (ppm): 2. =14 (3H
,s, CHJ-)4.58(4H,m, -CH,
, -CH2-) 6.58 (IH,S, W7p) 71-7.4 (15H,:(φ) 7417 (IH,s, 'j, 7'A) 15
Example 1 233■ of the raw material compound obtained in Reference Example 1 (3) was suspended in 10+++ dichloromethane, 65 μt of pyridine was added under ice cooling, 9 then 87 mg of phosphorus pentachloride was added, and 4 to 5
The reaction was carried out at ℃ for 30 minutes to obtain an acid chloride solution.

On the other hand, 200 mg of 7-amino-3-(1-methyl-5-tetrazolyl)thiomethyl-f-cephem-4-carboxylic acid diphenylmethyl ester and 10 m of dichloromethane.
1, cooled to -30°C, added 323 μl of pyridine, and added the above acid chloride solution at below -30°C. -3
After reacting for 1 hour at 0 to -35°C.

Add 0 ml of 6N hydrochloric acid and 1 ml of dichloromethane and extract. The dichloromethane layer is washed twice with 5 ml of water and 5 ml of saturated brine, dried over anhydrous magnesium sulfate, and then dichloromethane is distilled off under reduced pressure to obtain caramel. The caramel was subjected to silica gel column chromatography, eluted with benzene-ethyl acetate (volume ratio 2:1), fractions containing the target product were collected, the solvent was distilled off under reduced pressure, and the resulting caramel was transferred to ether-n-. Powdered with xane (volume ratio 1:1).

7-[α-(2-tritylamino-4-thiazolyl)-
α-(2-(2-Methyl-5-nitro-1-imidazolyl)ethoxyimino]acetamide)-3-((1-7'
methyl-5-tetrazolyl)thiomethyl]-Δ3-cephem-4-carboxylic acid diphenylmethyl ester 130m
get g.

Infrared absorption spectrum v,,,, cm, 3350.2910.17
75.1710.1680°1520, +460.1
415.1355.125 sail 1180, 1050.99
0 Nuclear magnetic resonance spectrum (in d6-DMSO) δ (ppm
); 2.33 (3H,s, CH3-)366~
3.70 (2H, m, C2()3.86 (3H,
s, >N-CH,)410~4.6 (6H,-CH
2CH2-, c3-Cfi2-)5.12 (IH, d
, C6-H) 5.7.4 (IH, q, C7-H) 6.71 (I
H, s, Irya) φ 6.85 (IH, s, -C 壓φ) 7.1~7.6 (25H, 5φ) 7.98 (IH, s, 17'fl and) 8.78
(IH, s, -N-) 9.57 (IH, d, -CON...-) A mixture of 4 ml of trifluoroacetic acid and 0.5 ml of anisole was heated at 20°C.
After cooling, add 125 mg of the above compound. 19～
After reacting at 21°C for 1 hour, 22 ml of water was added dropwise at a temperature below 20°C, and the reaction was further carried out at 19-21°C for 1 hour. After the reaction is complete, trifluoroacetic acid and water are distilled off under reduced pressure. To the resulting residue, 1 ml of ethanol is added to homogenize, and then water and ethanol are distilled off. The residue was triturated with 20 ml of ether to give 7-[α-(2-amino-4-thiazolyl)-α-
[2-(2-methyl-5-nitro-1-imidazolyl)
ethoxyimino]acetamide)-3-((1-methyl-
5-tetrazolyl)thiomethyl]-Δ3-cephem-4
- 83 mg of carboxylic acid was obtained.

Infrared absorption spectrum νInax”, 3340-3380.1770
．． 1670.1520°1355, 1250.1180
．． 1050 nuclear magnetic resonance spectrum (in d6-DMSO)
δ (ppm); 2.39 (3Hls, CHa
) 3.5 to 3.7 (2H, m, C2(H) ■ 3.92 (3H, s, N-CH5) 42 to 4.6
(6H, -CH2CH2-, C, -CH2-)19- 5.09 (IH, d, C6-H) 5.74 (IH, q, C, -H) 6.72 (I
H, II, XTH) 8.01 (IH, s, V!) ' 8.78 (l H, s, -Njj-) 9.6
0 (IH, d, -CON几-) Reference example 2゜(Z)-α-hydroxyimino-α-(2-tritylamino-4-thiazolyl)ethyl acetate hydrochloride 22.43
g was dissolved in 150 mt of dimethyl sulfoxide.

Add 9.1 g of powdered potassium carbonate and allow to react at room temperature for 30 minutes. -1-(2) obtained in Reference Example 1 (2)
-bromoethyl)-2-methyl-4-nitro-20-imidazole (11.65 g) was added, and the mixture was allowed to react at room temperature for 3 days. The reaction solution was dispersed in 400 ml of ice-water and extracted twice with 200 ml of ethyl acetate. Collect the organic layer and add 1 part water.
Wash twice with 00 ml of water and then twice with 50 ml of saturated saline.

After drying the ethyl acetate layer with anhydrous magnesium sulfate.

The caramel obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography, and ethyl acetate-benzene (
Fractions containing the target product were collected and the solvent was distilled off under reduced pressure to obtain 265 g of caramel.

Infrared absorption spectrum, ::;cm-'; 1730.1530.1500
~1490°1290, 1180.1030.695 Nuclear magnetic resonance spectrum (CDCl, medium) δ (ppm);
1. ．． 28 (3H,t, CHs)2.02
(3H, s, CHl-) 4.21 (2H, t, -CH2-) 4.28 (2
H, q, -CH2-)4゜51 (2H, t, -C
H2-) 6.50 (IH, s, input b) 7.2~7.4 (15H, 3φ) 7.74 (IH, S, early, H) □ NO.

(Z)-α-(2-methyl-5-nitro-3-imidazolylethoxyimino)-α-(2-)ditylamino-4
~thiazolyl) 262 g of ethyl acetate to 145 g of methanol
ml, add a solution of 1.36 g of potassium carbonate in 15.8 ml of water, and heat to 9.5 ml at 54-55°C.
Let time react. After the reaction, methanol was distilled off under reduced pressure, and the resulting residue was acidified by adding 30 ml of water and 15 ml of 2N hydrochloric acid, and extracted twice with 50 ml of ethyl acetate. The organic layer was collected, first with 50 ml of water twice, then with 50 ml of saturated saline.
After washing with m1 and drying anhydrous magnesium sulfate, ethyl acetate was distilled off under reduced pressure, and the resulting residue was crystallized with ethyl acetate-ether (volume ratio 1:1) to give (Z)-α-(2-
Methyl-5-nitro-3-imidazolylethoxyimino)-α-(2-) IJ thylamino-4-thiazolyl)
188 g of acetic acid was obtained.

Melting point 149-155°C (decomposition) Infrared absorption spectrum ν 0m3380-3350.1725.1525.
1500°1410, 1290.1, 160.103
0.695 nuclear magnetic resonance spectrum (in d6-DMSO)
δ (ppm); 2.40 (3H,s, CH3
-)4.28(2H,t, -CH2-)4.52(
2H,t, -CH2-)6.61 (IH,s,
X7H) 71-7.4 (15H, 3φ) Example 2 1 g of the compound 4661T obtained in Reference Example 2 (2) was suspended in 20 ml of dichloromethane, 130 μl of pyridine was added under water cooling, and then 175 ff1 g of phosphorus pentachloride was added. was added and reacted at 4 to 5°C for 30 minutes to obtain an acid chloride solution. Separately, 400 mg of 7-amino-3-(1-methyl-5-tetrazolyl)thiomethyl-Δ3-cephemu-4-carboxylic acid diphenylmethyl ester was dissolved in 20 ml of dichloromethane and cooled to -30°C. This and pyridine 6
Add 45μt, and add the acid chloride solution from below at -30°C. After reacting for 1 hour at -30~-40°C.

Add 10 mj of 6N hydrochloric acid and 10 ml of dichloromethane for extraction. The dichloromethane layer was washed twice with 10 ml of water and 10 ml of saturated brine, dried over anhydrous magnesium sulfate, and then dichloromethane was distilled off under reduced pressure to obtain caramel. The caramel was subjected to silica gel column chromatography, eluted with benzene-ethyl acetate (volume ratio 1:2), fractions containing the target product were collected, and the solvent was distilled off under reduced pressure. (volume ratio 1:1) to powder 7-[α-[2-(2-methyl-5-nitro-3-imidazolyl)ethoxyimino-α-[2-tritylamino-4-thiazolyl]acetamide] -3-((1-methyl-5-tetragylyl)thiomethyl)-Δ3-cephemu 4-carboxylic acid diphenylmethyl ester 4]Qmg is obtained.

Infrared absorption spectrum 1/KBrcm-'; 3330-3370.17
75.1715°1670, 1520.1490.13
70°1290, 1155.1050.750°95 Nuclear magnetic resonance spectrum (in CDC13) δ (ppm)
; 2.38 (3H1s, CH3) 3.70 (
2H,s, C2< )3.82 (3H,s, N
-CH5)4.1~4.4 (4H,m, CH",
C3CH,,'-)4.48 (2H,d, -CH2
-) 5.02 (IH, d, C, -H) 5.91 (IH, q, C, -H) 6.60 (l H, s, -Nj@-) 6.69
(l Hls , , i, To )6.90 (IH,
s, -CHφ2) 6.98 (IH, s, -CONH-) 7.1~7
．． 5 (25H, 5φ) □ Add 410 r of the compound obtained in (1) to a mixture of 10 mZ of trifluoroacetic acid and 1 ml of anisole at 20°C or below.
Add llg. After reacting at 19 to 21°C for 1 hour, trifluoroacetic acid was distilled off under reduced pressure, and 20 mZ of ether-n-hexane (volume ratio 1:1) was added to the oily residue obtained.
Add to powder. After removing r, add 10% trifluoroacetic acid again.
Dissolve in mZ at below 20°C, and add 7 ml of water dropwise at below 20°C. After completion of the dropwise addition, the mixture is allowed to react at 19 to 21°C for 1 hour.

After completion of the reaction, 20 ml of ethanol was added to the residue obtained by distilling off trifluoroacetic acid under reduced pressure to make a homogeneous solution, and then a portion of the ethanol was distilled off. 30% of the residue in ether
ml of 7-[α-(2-amino-4-thiazolyl)-α-(2-(2-methyl-5-nitro3
-imidazolyl]ethoxyimino]acetamide)-3-
((]-]nanal-5-tetrazolylthiomethyl]-Δ
245 mg of 3-cephem-4-carboxylic acid are obtained.

Infrared absorption spectrum νmax"", 1770.1670-1660.
1530.1390°1290, 1190.1170.
1630.825 nuclear magnetic resonance spectrum (d6-DMS
(in O) δ (ppm); 2.30 (3H,8,CH
3-) 3.64 (2H, Q, C2< ) 3.92 (3H, s, >N-CH5) Old ~ 4.5
(6H, m, -CH2CH2coC3-CH,, -)5
．． 08 (IH, d, C, H) 5.71 (IH, q, C7H) 6.75 (IH, s, 5 divination) 27- 8.23 (] H+ s, fiTx) 9.62 (
IH, d, -CON Tsuji-) Patent applicant Yamanouchi Pharmaceutical Co., Ltd. 28-

Claims (1)

[Claims] 1 (wherein Hl and R2 are the same or different and represent a lower alkyl group or a nitro group, A represents a lower alkylene group having 1 to 3 carbon atoms, and R3 represents a lower alkyl group) .) A novel Δ3-cephem derivative or a salt thereof I (wherein R1 and R2 are the same or different and represent a lower alkyl group or a nitro group, and A represents a lower alkylene group having 1 to 3 carbon atoms. R4 means a protecting group for an amino group. The same applies hereinafter) A substituted oxyiminothiazolyl acetic acid derivative or a reactive derivative thereof represented by the general formula (wherein, R3 is a lower alkyl group and R5 is a hydrogen atom or a carboxy A novel Δ3-cephem derivative represented by the general formula, which is obtained by reacting with a 7-amino-Δ3-cephem derivative represented by the formula (meaning a protecting group for a group; the same shall apply hereinafter) and then removing the protective group. manufacturing method.