JPH05148272A - Carboxyvinyloxyiminocephalosporins - Google Patents

Abstract

PURPOSE:To obtain the subject compounds capable of providing a new antibiotic substance having excellent antimicrobial activity against both Gram-positive and Gram-negative bacteria. CONSTITUTION:Compounds expressed by formula I [R is (substituted)alkyl, alkenyl, etc.; R<1> and R<3> are H, ester-forming group or salt-forming group; R<2> is (protected)amino; (n) is 0 or 1], e.g. 7beta-[2-(2-amino-4-thiazolyl)-2-(1- sodiooxycarbonylvinyloxyimino)acetamidol-3-(1-ethyl-2pyridinio)thiomet hyl-3- cephem-4-carboxylate. The compounds expressed by formula I are obtained by subjecting, e.g. a compound expressed by formula II as a starting raw material to amidation, sulfoxidation, reduction of the sulfoxide, introduction of pyridiniothio group and deprotection.

Description

Detailed Description of the Invention

[0001]

This invention is of the formula I:

[Chemical 3] (Wherein R is optionally substituted alkyl, alkenyl, cycloalkyl or amino; R ¹ and R ³ are independently hydrogen, an ester-forming group or a salt-forming group; R ² is optionally protected amino) Group; n represents 0 or 1), and carboxyvinyloxyiminocephalosporins.

[0002]

BACKGROUND OF THE INVENTION Cephalosporin derivatives constitute a group of extremely useful antibiotics due to their extensive antibacterial spectrum. Conventionally, a large number of cephalosporins having a carboxyvinyloxyimino group at the 7-position of the cephem nucleus have been synthesized (for example, JP-A-61-25458).
4, JP-A-63-119488, JP-A-6-
4-85, etc.).

However, the development of more effective antibiotics is awaited due to the emergence of new resistant bacteria and the like.

[0003]

Means for Solving the Problems The present inventors have conducted extensive studies for the purpose of developing new and useful cephalosporin antibiotics. They have found that they exhibit an excellent antibacterial action against both, and have completed the present invention. The compounds of the present invention are particularly useful as injectable antibiotics.

The terms are defined below. In the present specification, as alkyl of the alkyl which may have a substituent in the definition of R, a linear or branched saturated hydrocarbon group such as methyl, ethyl, n-propyl, isopropyl,
Examples thereof include butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1,2-dimethylbutyl, hexyl, heptyl and octyl. Examples of cycloalkyl include cyclopropyl, cyclopentyl, cycloheptyl and the like.

As alkenyl, propenyl, allyl,
Examples thereof include butenyl, hexenyl, phenylpropenyl, dimethylhexenyl and the like. Substituents on the alkyl, alkenyl, cycloalkyl or amino groups include hydroxy, amino, alkylamino, alkylthio, alkoxy, acyl, carbamoyl and sulfamoyl. The amino-protecting group in the optionally protected amino group in the definition of R ² is
Preferred is an aromatic or aliphatic acyl group, for example, an aliphatic diacyl group or an aromatic diacyl group.
A diacyl group is an acyl group having up to 14 carbon atoms, for example, a straight chain,
Branched, cyclic, saturated or unsaturated alkanedicarbonyl (succinyl, halogenosuccinyl, dihalogenosuccinyl, azidosuccinyl, methylsuccinyl, dimethylsuccinyl, ethylsuccinyl, propylsuccinyl, ethylidenesuccinyl, propylidenesuccinyl,
Isopropylidene succinyl, methylethylidene succinyl, halogenoglutaryl, dihalogenoglutaryl, methylglutaryl, dimethylglutaryl, ethylglutaryl, propylglutaryl, ethylideneglutaryl, propylideneglutaryl, isopropylideneglutaryl, methylethylidenegluta Ryl, maleoyl, etc., or malic acid, acyl groups of citric acid, etc.), aryldicarbonyl (monoaryl or methylphthalyl, aminophthalyl, nitrophthalyl, hydroxyphthalyl, halogenophthalyl, dihalogenophthalyl, dihalogenoyl, which may have a hetero atom in a monocyclic or bicyclic ring. Phthalyl, pyridinedicarbonyl, etc.) Acyl of monovalent carboxylic acid (linear, branched or cyclic alkanoyl,
Aroyl, aralkanoyl, arylalkenoyl, etc., which may be monocyclic or bicyclic and have heteroatoms, and the like. These groups may have a substituent.

The ester-forming group in the definition of R ¹ and R ³ may have a hydrocarbon group which may be substituted, for example, a lower alkyl group, a lower alkoxyalkyl group or a halogenated alkyl group. Examples thereof include alkyl, aralkyl which may have a substituent on the aromatic ring, and phenacyl which may be substituted on phenyl. Here, the lower alkyl refers to the above straight chain or branched chain saturated hydrocarbon group having 1 to 8 carbon atoms.
The lower alkoxy is an alkoxy having 1 to 8 carbon atoms and includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy, hexyloxy, heptyloxy, octyloxy and the like. The lower alkoxyalkyl is a group formed by substituting the hydrogen atom of the above-defined alkoxy group with the above-defined alkyl, and examples thereof include methoxymethyl and ethoxymethyl.

Halogen refers to fluorine, chlorine, bromine, iodine and the like. As aralkyl which may have a substituent on the aromatic ring, benzyl, p-methoxybenzyl, p-
Nitrobenzyl etc. can be mentioned. Phenacyl as phenacyl optionally substituted with phenyl, p
-Bromogenacyl, p-nitrophenacyl and the like can be mentioned. A salt-forming group is an organic or inorganic group that forms a pharmaceutically acceptable salt, and is, for example, an alkali metal such as lithium, sodium or potassium;
Alkaline earth metal such as calcium or magnesium; triethylamine, 2-aminobutane, tert-butylamine, diisopropylethylamine, n-butylmethylamine, n-butyldimethylamine, tri-n-butylamine, dicyclohexylamine, N-isopropylcyclohexylamine, Furfurylamine, benzylamine, methylbenzylamine, dibenzylamine, N,
N-dimethylbenzylamine, 2-chlorobenzylamine, 4-methoxybenzylamine, 1-naphthylmethylamine, diphenylbenzylamine, triphenylamine, 1-naphthylamine, 1-aminoanthracene, 2
-Aminoanthracene, dehydroapiethylamine, N
An organic base such as methylmorpholine or pyridine;
Alternatively, a group derived from an amino acid such as lysine, arginine or histidine;

While all compounds of formula I according to the above definitions are useful in achieving the objects of the invention, the following compounds are preferred. They are of the formula I in which R is optionally substituted alkyl, cycloalkyl, alkenyl or amino, more preferably methyl, ethyl, allyl,
Carbamoylmethyl; R ¹ is an alkali metal atom, more preferably sodium; R ² is amino; R ³ is hydrogen; n is 0
Is a compound.

The compounds I of the present invention are prepared by methods commonly used in the chemistry of cephalosporins. However, for more efficient production, the method of the present invention is followed.
That is, for example, formula II:

[Chemical 4] A compound represented by the formula (wherein R ³ is as defined above) is used as a starting material, and amidation, sulfoxidation, sulfoxide reduction, pyridinithioation and deprotection are applied in combination as described in Examples below. According to the method of the present invention consisting of, it is possible to efficiently manufacture.

The final step of the method of the present invention, deprotection, is β
-It can be carried out by a general method used for producing a lactam compound. For example, in anisole and nitromethane, add aluminum chloride under cooling, stir, extract with water under acidic conditions, concentrate the aqueous layer under reduced pressure, and use it as a synthetic resin adsorbent column for styrene / divinyl / benzene copolymer. The final target substance can be obtained by purifying through. The appropriate salt is then formed, if desired, according to conventional methods. Examples of such salts include salts of sodium, potassium, calcium, magnesium, hydrochloric acid, sulfuric acid, methanesulfonic acid, toluenesulfonic acid and the like.

As a result of testing the in vitro antibacterial activity of the compound I of the present invention, it showed an excellent antibacterial activity against various bacteria, both gram-positive and gram-negative bacteria, especially gram-negative bacteria. It has been found that it can be used as a fungicide, an antiseptic, etc. Therefore, the present invention provides an antibacterial composition containing a compound represented by formula 1 as an active ingredient, and a sterilization or bacteriostatic method comprising contacting the compound with bacteria. When the cephalosporin derivative of the present invention is used for therapeutic purposes,
A therapeutically effective amount of a compound of formula I, or salt thereof, is administered to a subject animal, including humans, suffering from a bacterial infection.

Among the compounds (I), light metal salts, particularly compounds in which R ¹ is sodium, potassium and calcium are suitable for intravenous injection, intramuscular injection and infusion, and, if necessary, together with a stabilizer and a dissolution accelerator, It can be supplied as an injection or a vial. The free acid may be neutralized before use and administered as an aqueous solution. Further, the ester is used for oral administration as tablets, capsules, granules, powders, etc., for injection as a medicine, oily injection, etc., and in the form of suppositories, eye drops, ointments, emulsions, sprays, etc. It can also be used externally or for local administration. These formulations are manufactured according to a conventional method using conventional additives.

The route of administration may be oral or parenteral, but parenteral administration is preferred. For parenteral administration, an aqueous solution or suspension suitable for subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, etc. For oral administration, the compounds of the invention in acid or salt form are mixed with conventional pharmaceutical carriers, diluents or excipients and filled into capsules or tablets. Alternatively, it may be in the form of powder, granule or the like.
The dose is about 100 mg per day for parenteral administration.
˜2,000 mg, preferably 500 mg to 1500 mg is suitable. When administered orally, it is usually about 100 per day.
It can be mg-1,000 mg, preferably 150 mg-600 mg.

The present invention will be described in more detail with reference to production examples, examples and experimental examples. However, these examples do not limit the present invention. The abbreviations Boc used in Production Examples and Examples are t-butoxycarbonyl groups, and PMB is p-nitrobenzyl group.

Example 1 Introduction of a pyridiniothio group A. Compound having pyridin-2-ylthio group

[Chemical 5] 1) R = methyl, R ¹ = diphenylmethyl.

7β- [2- (2-t-Butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino) acetamido] -3-chloromethyl-3-cephem-4-carboxylic acid 6.23 g (7 mmol) of p-methoxybenzyl ester 1-oxide and 0.96 g (1.1 × 7 mmol) of N-methyl-2-thiopyridone were dissolved in 20 ml of dichloromethane and stirred at room temperature for 6 hours. 20 ml of ether was added to the reaction solution, and the resulting precipitate was washed with ether to give 7β- [2- (2
-t-butoxycarbonylamino-4-thiazolyl) -2-
(1-Diphenylmethoxycarbonylvinyloxyimino) acetamido] -3- (1-methyl-2-pyridinio)
7.09 g of p-methoxybenzyl ester • 1-oxide • chloride of thiomethyl-3-cephem-4-carboxylic acid is obtained. IR ν (CHCl ₃ ) cm ⁻¹ : 3370, 1799, 1718, 1690.

B. Compound having pyridin-4-ylthio group

[Chemical 6]

1) R = methyl, R ¹ = diphenylmethyl, n = 1, X = chloro 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyl) Oxyimino) acetamide] -3-chloromethyl-3-
Cephem-4-carboxylic acid p-methoxybenzyl ester ・ 1-oxide 1.78 g (2 mmol) and 1-methyl-4
-276 mg (2.2 mmol) of thiopyridone are dissolved in 20 ml of dichloromethane and stirred at room temperature for 7 hours. The reaction solution was concentrated to about 1/3 volume, ether was added, and the precipitate was collected by filtration to obtain 7β- [2- (2-t-butoxycarbonylamino
--4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino) acetamido] -3- (1-methyl-4-pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester / 1- 2.01 g of oxide chloride is obtained.

¹ HNMR δ (CDCl ₃ -CD ₃ OD) ppm: 1.55 (s, 9
H), 3.71 (s, 2H), 3.79 (s, 3H), 4.23 (s, 3H), 4.39,
4.45 (ABq, J = 13Hz, 2H), 4.56 (d, J = 5Hz, 1H), 5.22,
5.28 (ABq, J = 12Hz, 2H), 5.64 (d, J = 2Hz, 1H), 5.78 (d,
J = 2Hz, 1H), 6.01 (d, J = 5Hz, 1H), 6.86 (d, J = 8Hz, 2
H), 6.91 (s, 1H), 7.25 ~ 7.45 (m, ArH, 12H), 7.76 (d,
J = 7Hz, 2H), 8.43 (d, J = 7Hz, 2H). IR ν (CHCl ₃ ) cm ⁻¹ : 1800, 1725, 1690, 1635.

2) R = ethyl, R ¹ = diphenylmethyl, n = 1, X = chloro 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyl) Oxyimino) acetamide] -3-chloromethyl-3-
Cephem-4-carboxylic acid p-methoxybenzyl ester 1-oxide (7.12 g, 8.0 mmol) was dissolved in 50 ml of dichloromethane to prepare 1-ethyl-4-thiopyridone.
22 g (8.8 mmol) is added and the mixture is stirred at room temperature for 2.5 hours. The reaction mixture was concentrated to give crude 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino) acetamido] -3- (1-ethyl-4). -Pyridinio) thiomethyl-
This gives 8.20 g of 3-cephem-4-carboxylic acid p-methoxybenzyl ester.1-oxide.chloride.

¹ HNMR δ (CDCl ₃ -CD ₃ OD) ppm: 1.55 (s, 9
H), 1.60 (t, J = 7Hz, 3H), 3.59, 3.73 (ABq, J = 16Hz, 2
H), 3.79 (s, 3H), 4.45 (bs, 2H), 4.49 (q, J = 7Hz, 2H),
4.59 (d, J = 5Hz, 1H), 5.21, 5.29 (ABq, J = 12Hz, 2H),
5.62 (d, J = 2Hz, 1H), 5.78 (d, J = 2Hz, 1H), 6.01 (d, J = 5
Hz, 1H), 6.86 (d, J = 8Hz, 2H), 6.91 (s, 1H), 7.30 ~
7.40 (m, 13H), 7.83 (d, J = 7
Hz, 2H), 8.50 (d, J = 7Hz, 2
H).

3) R = isopropyl, R ¹ = diphenylmethyl, n = 1, X = chloro 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyl) Oxyimino) acetamide] -3-chloromethyl-3-
Cephem-4-carboxylic acid p-methoxybenzyl ester 1-oxide 890 mg (1 mmol) was dissolved in dichloromethane 7 ml, 1-isopropyl-4-thiopyridone 16
Add 9 mg (1.1 mmol) and stir at room temperature for 2 hours. The reaction mixture was concentrated to give crude 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino) acetamido] -3- (1-isopropyl-4). 1.04 g of -pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 1-oxide chloride are obtained.

¹ HNMR δ (CDCl ₃ -CD ₃ OD) ppm: 1.54 (s, 9
H), 1.64 (d, J = 6Hz, 6H), 3.67, 3.73 (ABq, J = 19Hz, 2
H), 3.79 (s, 3H), 4.48 (s, 2H), 4.56 (d, J = 5Hz, 1H),
4.83 (Septet, J = 6Hz, 1H), 5.22, 5.29 (ABq, J = 11.5Hz,
2H), 5.61 (d, J = 2Hz, 1H), 5.77 (d, J = 2Hz, 1H), 6.03
(d, J = 5Hz, 1H), 6.91 (s, 1H), 6.86 (d, J = 8Hz, 2H),
7.3 ~ 7.4 (m), 7.90 (d, J = 7Hz, 2H), 8.55 (d, J = 7Hz, 2
H).

4) R = cyclopropyl, R ¹ = diphenylmethyl, n = 1, X = chloro 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonyl) Vinyloxyimino) acetamido] -3-chloromethyl-3-
Cephem-4-carboxylic acid p-methoxybenzyl ester • 1-oxide 6.23 g (7 mmol) was dissolved in 45 ml of dichloromethane, 1.1-cyclopropyl-4-thiopyridone 1.16 g (7.7 mmol) was added, and the mixture was stirred at room temperature. Stir for 2.5 hours. If the reaction solution is concentrated, 7β- [2- (2-t-
Butoxycarbonylamino-4-thiazolyl) -2- (1-
Diphenylmethoxycarbonylvinyloxyimino) acetamido] -3- (1-cyclopropyl-4-pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 1-oxide chloride 6.75 g is obtained.

¹ HNMR δ (CDCl ₃ -CD ₃ OD) ppm: 1.32 (d, J =
5Hz, 4H), 1.54 (s, 9H), 3.70 (bs, 2H), 3.79 (s, 3H),
4.06 (quintet, J = 5Hz, 1H), 4.45, 4.55 (ABq, J = 14Hz,
2H), 4.61 (d, J = 5Hz, 1H), 5.21, 5.29 (ABq, J = 11Hz, 2
H), 5.60 (d, J = 2Hz, 1H), 5.78 (d, J = 2Hz, 1H), 6.04
(d, J = 5Hz, 1H), 6.87 (d, J = 10Hz, 2H), 6.90 (s, 1H),
7.25 ~ 7.40 (m, 13H), 7.83 (d, J = 7Hz, 8.45 (d, J = 7Hz,
2H).

5) R = cyclopentyl, R ¹ = diphenylmethyl, n = 1, X = chloro 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyl) Oxyimino) acetamide] -3-chloromethyl-3-
Cephem-4-carboxylic acid p-methoxybenzyl ester 1-oxide 4.63 g (5.2 mmol) was dissolved in 35 ml of dichloromethane, and 1.03 g (5.75 mmol) of 1-cyclopentyl-4-thiopyridone was added to room temperature. In 2
Stir for hours. If the reaction solution is concentrated, crude 7β- [2- (2
-t-butoxycarbonylamino-4-thiazolyl) -2-
(1-Diphenylmethoxycarbonylvinyloxyimino) acetamido] -3- (1-cyclopentyl-4-pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester ・ 1-oxide ・ chloride 5.26
get g.

¹ HNMR δ (CDCl ₃ -CD ₃ OD) ppm: 1.55 (s, 9
H), 1.70 ~ 2.10 (m, 6H), 2.3 ~ 2.5 (m, 2H), 3.70 (bs, 2
H), 3.79 (s, 3H), 4.49 (bs, 2H), 4.55 (d, J = 5Hz, 1H),
4.8 ~ 5.0 (m, 1H), 5.21, 5.28 (ABq, J = 11Hz, 2H), 5.6
2 (d, J = 2Hz, 1H), 5.78 (d, J = 2Hz, 1H), 6.04 (d, J = 5Hz,
1H), 6.86 (d, J = 8Hz, 2H), 6.91 (s, 1H), 7.10 ~ 7.39
(m, 13H), 7.90 (d, J = 8Hz, 2H), 8.52 (d, J = 8Hz, 2H).

6) R = allyl, R ¹ = diphenylmethyl, n = 1, X = chloro 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyl) Oxyimino) acetamide] -3-chloromethyl-3-
Cefem-4-carboxylic acid p-methoxybenzyl ester • 1-oxide 890 mg (1 mmol) was dissolved in dichloromethane 7 ml to give 1-allyl-4-thiopyridone 166 mg.
(1.1 mmol) is added and the mixture is stirred at room temperature for 2 hours. The reaction mixture is concentrated to give crude 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino) acetamide]
-3- (1-allyl-4-pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester-1-
1.01 g of oxide chloride is obtained.

¹ HNMR δ (CDCl ₃ -CD ₃ OD) ppm: 1.55 (s, 9
H), 3.56, 3.74 (ABq, J = 20Hz, 2H), 3.79 (s, 3H), 4.43,
4.49 (ABq, J = 14Hz, 2H), 4.56 (d, J = 5Hz, 1H), 5.06
(d, J = 7Hz, 2H), 5.22, 5.29 (ABq, J = 12Hz, 2H), 5.48
(d, J = 15Hz, 1H), 5.55 (d, J = 7Hz, 1H), 5.63 (d, J = 2H
z, 1H), 5.78 (d, J = 2Hz, 1H), 6.02 (d, J = 5Hz, 1H), 5.
95 ~ 6.15 (m, 1H), 6.86 (d, J = 8Hz, 2H), 6.91 (s, 1H),
7.25 ~ 7.45 (m), 7.83 (d, J = 7Hz, 2H), 8.46 (d, J = 7Hz,
2H).

7) R = 2-hydroxyethyl, R ¹ = diphenylmethyl, n = 0, X = chloro 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenyl) Methoxycarbonylvinyloxyimino) acetamide] -3-chloromethyl-3-
Cephem-4-carboxylic acid p-methoxybenzyl ester 6.56 g (7.5 mmol) and 1- (2-hydroxyethyl) -4-thiopyridone 1.34 g (8.62 mmol) were added to dichloromethane (45 ml) and methanol (22 ml). And the mixture is stirred at room temperature for 4 hours. The reaction solution is concentrated under reduced pressure. The residue is dissolved in 40 ml of dichloromethane and added with stirring to a mixture of 300 ml of ether and 100 ml of ethyl acetate. The precipitated precipitate was collected by filtration to obtain crude 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino) acetamide] -3- (1- ( 7.55 g of 2-hydroxyethyl) -4-pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester chloride are obtained. This product can be used for the next reaction without purification.

NMR δ (CDCl ₃ ) ppm: 1.55 (s, 9H), 3.40,
3.49 (ABq, J = 13Hz, 2H), 3.95 (t, J = 5Hz, 2H), 4.17,
4.48 (ABq, J = 13Hz, 2H), 4.58 (t, J = 5Hz, 2H), 4.89 (d,
J = 4.8Hz, 1H), 5.19, 5.26 (ABq, J = 14.8Hz, 2H), 5.63
(d, J = 2.2Hz, 1H), 5.77 (d, J = 4.8Hz, 1H), 5.82 (d, J =
2.2Hz, 1H), 6.85 (A of ABq, J = 9.0Hz, 2H), 6.93 (s, 1
H), 7.24-7.40 (m, 14H), 7.71 (d, J = 7.0Hz, 2H), 8.56
(d, J = 7.0Hz, 2H) IR ν (CHCl ₃ ) cm ^-1 : 3396, 1784, 1720, 1628, 1245,
1153.

8) R = 2-hydroxypropyl, R ¹ = diphenylmethyl, n = 0, X = chloro 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenyl) Methoxycarbonylvinyloxyimino) acetamide] -3-chloromethyl-3-
Cephem-4-carboxylic acid p-methoxybenzyl ester 5.88 g (6.73 mmol) and 1- (1-hydroxy-
1.31 g (7.74 mmol) of 2-propyl) -4-thiopyridone are dissolved in a mixture of 20 ml of methanol and 40 ml of dichloromethane and stirred at room temperature for 4 hours. The reaction solution is concentrated under reduced pressure. The residue is dissolved in 40 ml of dichloromethane and added with stirring to a mixture of 300 ml of ether and 100 ml of ethyl acetate. If the precipitate that precipitates is collected by filtration, the crude 7β- [2- (2-t-
Butoxycarbonylamino-4-thiazolyl) -2- (1-
Diphenylmethoxycarbonylvinyloxyimino) acetamide] -3- (1- (1-hydroxy-2-propyl)
This gives 6.79 g of -4-pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester chloride.

¹ HNMR δ (CDCl ₃ ) ppm: 1.55 (s, 9H), 1.5
8 (d, J = 8.0Hz, 3H), 3.38-4.238 (m, 6H), 4.45, 4.49 (d
d, J = 8.0Hz, J = 12Hz, 1H), 4.89 (d, J = 4.8Hz, 1H), 5.1
9, 5.25 (ABq, J = 8.0Hz, 2H), 5.62 (d, J = 2.0Hz, 1H),
5.79 (d, J = 4.8Hz, 1H), 5.82 (d, J = 2.0Hz, 1H), 6.83 (A
of ABq, J = 8.0Hz, 2H), 6.92 (s, 1H), 7.72 (d, J = 7.2H
z, 2H), 8.61 (d, J = 7.2Hz, 2H) J = 7.0Hz, 2H). IR ν (CHCl ₃ ) cm ⁻¹ : 3398, 1784, 1720, 1623, 1153.

9) R = carbamoylmethyl, R ¹ = diphenylmethyl, n = 1, X = chloro 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonyl) Vinyloxyimino) acetamide]-
3-Chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 1-oxide 6.23 g (7 mmol) and 1-carbamoylmethyl-4-thiopyridone 1.30
g (1.1 eq) is dissolved in 25 ml of dimethylformamide and stirred at room temperature for 4 hours and 15 minutes. The reaction solution is ether 5.
Pour into 00 ml and filter off the resulting precipitate. Dissolve this in dichloromethane, dry and evaporate the solvent to give 7β.
-[2- (2-t-Butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino) acetamido] -3- (1-carbamoylmethyl-4-pyridinio) thiomethyl-3-cephem This gives 7.39 g of 4-carboxylic acid p-methoxybenzyl ester / 1-oxide chloride. IR ν (CHCl ₃ ) cm ⁻¹ : 1794, 1718, 1690.

10) R = 2-methylthioethyl, R ¹ = diphenylmethyl, n = 0, X = chloro 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenyl) Methoxycarbonylvinyloxyimino) acetamide] -3-chloromethyl-3-
Cephem-4-carboxylic acid p-methoxybenzyl ester 1.52 g (1.74 mmol) and 1- (2-methylthioethyl) -4-thiopyridone 0.37 g (2 mmol) were mixed with 10 ml of dichloromethane and 6 ml of methanol. Comic,
Stir at room temperature for 4 hours. A mixture of 100 ml of ether and 30 ml of ethyl acetate was added to the reaction solution, and the resulting precipitate was collected by filtration to obtain 7β- [2- (2-t-butoxycarbonylamino-4-
Thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino) acetamido] -3- (1- (2-methylthioethyl) -4-pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 1.8 g of chloride are obtained.

¹ HNMR δ (CDCl ₃ ) ppm: 1.55 (s, 9H), 2.1
6 (s, 3H), 3.06 (t, J = 5.8Hz, 2H), 3.34, 3.55 (ABq, J = 1
5.5Hz, 2H), 3.79 (s, 3H), 4.22, 4.46 (ABq, J = 15.0Hz,
2H), 4.74 (t, J = 5.8Hz, 2H), 4.89 (d, J = 4.8Hz, 1H),
5.20, 5.24 (ABq, J = 18.0Hz, 2H), 5.63 (d, J = 2.0Hz), 5.7
7 (d, J = 4.8Hz, 1H), 5.83 (d, J = 2.0Hz, 1H), 6.85 (Aof
ABq, J = 8.8Hz, 2H), 6.93 (s, 1H), 7.30-7.82 (m, 15H),
7.76 (d, J = 7.0Hz, 2H), 8.65 (d, J = 7.0Hz, 2H) IR ν (CHCl ₃ ) cm ^-1 : 3398, 1785, 1720, 1242, 1153.

11) R = 2-sulfamoylethyl, R ¹
= Diphenylmethyl, n = 1, X = chloro 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino) acetamide] -3-chloromethyl- 3-
Cephem-4-carboxylic acid p-methoxybenzyl ester 1-oxide 6.23 g (7 mmol) and 1- (2-sulfamoylethyl) -4-thiopyridone 1.68 g (1 equivalent) were dissolved in 30 ml of dimethylformamide. , At room temperature 3
Stir for 50 minutes. The reaction solution was poured into 500 ml of ether, and the deposited precipitate was collected by filtration and dried to obtain crude 7β- [2-
(2-t-butoxycarbonylamino-4-thiazolyl)-
2- (1-Diphenylmethoxycarbonylvinyloxyimino) acetamido] -3- (1- (2-sulfamoylethyl) -4-pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester-1 -Oxide
7.78 g of chloride are obtained. The physical constants of this compound were not measured, and after reduction of sulfoxide, sulfide (IRν (CHCl ₃ )
cm ⁻¹ : 1784, 1717, 1628).

12) R = Boc amino, R ¹ = diphenylmethyl, n = 1, X = chloro 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonyl) Vinyloxyimino) acetamido] -3-chloromethyl-3-
Cephem-4-carboxylic acid p-methoxybenzyl ester 1-oxide 890 mg (1 mmol), 1-t-butoxycarbonylamino-4-thiopyridone 250 mg (1.1
The mmol is stirred in 7 ml of dichloromethane at room temperature for 2 hours. The reaction solution was concentrated to give crude 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino) acetamido] -3- (1-t-butoxy). Carbonylamino-4-pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 1-oxide chloride 1.11
get g.

¹ HNMR δ (CDCl ₃ ) ppm: 1.55 (s, 18H), 3.
43, 3.69 (ABq, J = 20Hz, 2H), 3.80 (s, 3H), 4.38, 4.49
(ABq, J = 12Hz, 2H), 4.54 (d, J = 5Hz, 1H), 5.23, 5.31 (A
Bq, J = 10.5Hz, 2H), 5.64 (d, J = 2Hz, 1H), 5.79 (d, J = 2H
z, 1H), 6.03 (d, J = 5Hz, 1H), 6.87 (d, J = 8Hz, 2H), 6.
92 (s, 1H), 7.25 ~ 7.40 (m), 7.73 (d, J = 7Hz, 2H), 8.37
(d, J = 7Hz, 2H).

Example 2 Sulfoxide Reduction A. Compound having pyridin-2-ylthio group

[Chemical 7]

1) R = methyl, R ¹ = diphenylmethyl, X = iod. 7β- [2- (2-t-Butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino) acetamide] -3- (1-methyl-prepared in Example 1 (A) 2-pyridinio) thiomethyl-3-
Cefem-4-carboxylic acid p-methoxybenzyl ester • 1-oxide • chloride 7.09 g (7 mmol) was dissolved in 70 ml of acetone, cooled to -20 ° C, and stirred while stirring 11.62 g (10 × 7 mmol)
And 2.99 ml (6 equivalents) of acetyl chloride were added, and -20 to
Stir at -10 ° C for 1 hour. The reaction solution is poured into a solution of 6.56 g (9 equivalents) of sodium hydrogen sulfite in 210 ml of ice water.
The precipitate is collected by filtration, washed with water, dissolved in dichloromethane, dried, and concentrated. Ether was added to the residue and the precipitate was collected by filtration to give 7β- [2- (2-t-butoxycarbonylamino-4-
Thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino) acetamido] -3- (1-methyl-
7.50 g of 2-pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester iodide are obtained. Yellow solid. IR ν (CHCl ₃ ) cm ^-1 : 3400, 1787, 1717, 1687sh.

B. Compound Having Pyridin-4-ylthio Group The sulfoxide of the compound prepared in the same manner as in Example 1 (B) is reduced.

[Chemical 8]

1) R = methyl, R ¹ = diphenylmethyl, X = chloro / iodo 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino) ) Acetamide] -3- (1-methyl-4-
Pyridinio) thiomethyl-3-cephem-4-carboxylic acid p
-Methoxybenzyl ester / 1-oxide / chloride 2.
01 g (1.98 mmol) was dissolved in 20 ml of acetone, 3.29 g (19.8 mmol) of potassium iodide and 0.84 ml (11.8 mmol) of acetyl chloride were added at -20 ° C, and -20 to -10 ° C. Stir for 1.5 hours. To the reaction solution was added a solution of 5.0 g of potassium hydrogen sulfite in 50 ml of water,
Extract with dichloromethane. The aqueous solution was washed with water, dried, and concentrated to give crude 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino) acetamide] -3- (1
-Methyl-4-pyridinio) thiomethyl-3-cephem-4-
2.08 g of a mixture of carboxylic acid p-methoxybenzyl ester chloride and iodide is obtained.

¹ HNMR δ (CDCl ₃ —CO ₃ OD) ppm: 1.55 (s, 9
H), 3.40, 3.56 (ABq, J = 18Hz, 2H), 3.79 (s, 3H), 4.27
(s, 3H), 4.25, 4.44 (ABq, J = 12Hz, 2H), 4.90 (d, J = 5H
z, 1H), 5.20, 5.23 (ABq, J = 11Hz, 2H), 5.63 (d, J = 2H
z, 1H), 5.75 (d, J = 5Hz, 1H), 5.82 (d, J = 2Hz, 1H), 6.8
4 (d, J = 8Hz, 2H), 6.93 (s, 1H), 7.25 ~ 7.45 (m, Ar-H, 1
2H), 7.74 (d, J = 7Hz, 2H), 8.51 (d, J = 7Hz, 2H). IR ν (CHCl ₃ ) cm ⁻¹ : 1783, 1719, 1630.

2) R = ethyl, R ¹ = diphenylmethyl, X = chloro / iode Crude 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonyl) Vinyloxyimino) acetamide] -3- (1-ethyl-4
-Pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester ・ 1-oxide ・ chloride 8.4 g was dissolved in acetone 80 ml, and chlorinated with potassium iodide 13.3 g (80 mmol) at -30 ° C. Acetyl 1
3.4 ml (48 mmol) was added and the mixture was stirred at -18 to -30 ° C for 2 hours. The reaction solution was poured into 3% sodium hydrogensulfite water under ice cooling, stirred for 20 to 30 minutes, and the resulting precipitate was collected by filtration to give 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl). -2- (1-Diphenylmethoxycarbonylvinyloxyimino) acetamide] -3-
(1-Ethyl-4-pyridinio) thiomethyl-3-cephem-
8.10 g of a mixture of 4-carboxylic acid p-methoxybenzyl ester chloride and iodide is obtained.

¹ HNMR δ (CDCl ₃ -CD ₃ OD) ppm: 1.55 (s, 9
H), 1.62 (t, J = 8Hz, 3H), 3.40, 3.59 (ABq, J = 17Hz, 2
H), 3.79 (s, 3H), 4.29, 4.46 (ABq, J = 13Hz, 2H), 4.58
(q, J = 8Hz, 2H), 4.90 (d, J = 5Hz, 1H), 5.19, 5.23 (ABq,
J = 10Hz, 2H), 5.63 (d, J = 2Hz, 1H), 5.75 (d, J = 5Hz, 1
H), 5.82 (d, J = 2Hz, 1H), 6.85 (d, J = 10Hz, 2H), 6.94
(s, 1H), 7.32 ~ 7.40 (m, 13H), 7.81 (d, J = 7Hz, 2H),
8.60 (d, J = 7Hz, 2H).

3) R = isopropyl, R ¹ = diphenylmethyl, X = chloro / iodo 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyl) Oxyimino) acetamido] -3- (1-isopropyl-4-pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 1-oxide chloride 1.03 g (1 mmol) and iodinated Potassium 1.66
g (10 mmol) was dissolved in 10 ml of acetone and -30
0.43 ml (6 mmol) of acetyl chloride was added at ℃,-
Stir for 2 hours at 20 to -30 ° C. The reaction solution was poured into 3% sodium hydrogen sulfite water under ice cooling, stirred for 20 to 30 minutes, and the formed precipitate was collected by filtration to obtain crude 7β- [2- (2
-t-butoxycarbonylamino-4-thiazolyl) -2-
(1-Diphenylmethoxycarbonylvinyloxyimino) acetamido] -3- (1-isopropyl-4-pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester / mixture of chloride and iodide 1.
07 g are obtained.

¹ HNMR δ (CDCl ₃ -CD ₃ OD) ppm: 1.55 (s, 9
H), 1.68 (d, J = 6Hz, 6H), 3.41, 3.62 (ABq, J = 20Hz, 2
H), 3.79 (s, 3H), 4.32, 4.51 (ABq, J = 12Hz, 2H), 4.90
(d, J = 5Hz, 1H), 4.96 (Septet, 1H), 5.21, 5.24 (ABq,
J = 13Hz, 2H), 5.63 (d, J = 2Hz, 1H), 5.76 (d, J = 5Hz, 1
H), 5.83 (d, J = 2Hz, 1H), 6.85 (d, J = 9Hz, 2H), 6.93
(s, 1H), 7.3 ~ 7.4 (m), 7.86 (d, J = 7Hz, 2H), 8.65 (d, J
= 7Hz, 2H).

4) R = cyclopropyl, R ¹ = diphenylmethyl, X = chloro / iodo 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonyl) Vinyloxyimino) acetamido] -3- (1-cyclopropyl-4-pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 1-oxide chloride 7.45 g (7 mmol) of acetone After dissolving in 75 ml, 11.6 g (70 mmol) of potassium iodide and 13.0 ml (42 mmol) of acetyl chloride were added, and -20 to 20
Stir at −30 ° C. for 2 hours. The reaction solution was poured into 3% sodium hydrogen sulfite water under ice cooling and stirred for 20 to 30 minutes.
The resulting precipitate was collected by filtration to give crude 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino) acetamide] -3- (1-cyclo 7.98 g of a mixture of propyl-4-pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester chloride and iodide are obtained.

¹ HNMR δ (CDCl ₃ -CD ₃ OD) ppm: 1.38 (d, J =
5Hz, 4H), 1.55 (s, 9H), 3.41, 3.62 (ABq, J = 19Hz, 2
H), 3.79 (s, 3H), 4.20 (quint, J = 5Hz, 1H), 4.35, 4.4
7 (ABq, J = 13Hz, 2H), 4.90 (d, J = 5Hz, 1H), 5.19, 5.25
(ABq, J = 13Hz, 2H), 5.63 (d, J = 2Hz, 1H), 5.75 (d, J = 5
Hz, 1H), 5.82 (d, J = 2Hz, 1H), 6.84 (d, J = 10Hz, 2H),
6.94 (s, 1H), 7.30 ~ 7.39 (m, 13H), 7.80 (d, J = 7Hz, 2
H), 8.54 (d, J = 7Hz, 2H).

5) R = cyclopentyl, R ¹ = diphenylmethyl, X = chloro / iod. 7β- [2- (2-t-Butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino) acetamido] -3- (1-cyclopentyl-4-pyridinio) thiomethyl-3-cephem 5.76 g (5.2 mmol) of 4-carboxylic acid p-methoxybenzyl ester 1-oxide chloride was dissolved in 50 ml of acetone, and 8.63 g (52 mmol) of potassium iodide and 2.22 ml (31 ml) of acetyl chloride were dissolved. Mmol), and added -18
Stir at ~ -30 ° C for 2 hours. The reaction solution was poured into 3% sodium hydrogen sulfite water under ice cooling and stirred for 20 to 30 minutes, and then the resulting precipitate was collected by filtration to obtain crude 7β- [2- (2-t-
Butoxycarbonylamino-4-thiazolyl) -2- (1-
Diphenylmethoxycarbonylvinyloxyimino) acetamido] -3- (1-cyclopentyl-4-pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester / mixture of chloride and iodide 5.4
Get 0 g.

¹ HNMR δ (CDCl ₃ -CD ₃ OD) ppm: 1.55 (s, 9
H), 1.8 ~ 2.1 (m, 6H), 2.4 ~ 2.6 (m, 2H), 3.41, 3.63 (AB
q, J = 18Hz, 2H), 3.79 (s, 3H), 4.32, 4.50 (ABq, J = 13H
z, 2H), 4.90 (d, J = 5Hz, 1H), 4.95 ~ 5.10 (m, 1H), 5.2
1, 5.24 (ABq, J = 12Hz, 2H), 5.63 (d, J = 2Hz, 1H), 5.75
(d, J = 5Hz, 1H), 5.83 (d, J = 2Hz, 1H), 6.85 (d, J = 8 Hz,
2H), 6.93 (s, 1H), 7.25 ~ 7.40 (m, 13H), 7.84 (d, J = 8
Hz, 2H), 8.61 (d, J = 8Hz, 2H).

6) R = allyl, R ¹ = diphenylmethyl, X = chloro / iodo 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyl) Oxyimino) acetamide] -3- (1-allyl-4-
Pyridinio) thiomethyl-3-cephem-4-carboxylic acid p
-Methoxy benzyl ester / 1-oxide / chloride 1.
01 g (1 mmol) and potassium iodide 1.66 g (1
(0 mmol) was suspended in 10 ml of acetone, cooled to -30 ° C, 0.43 ml (6 mmol) of acetyl chloride was added,
Stir at −20 to −30 ° C. for 2 hours. The reaction solution was poured into 3% sodium hydrogen sulfite water under ice cooling and stirred for 20 to 30 minutes, and then the resulting precipitate was collected by filtration to obtain crude 7β- [2-
(2-t-butoxycarbonylamino-4-thiazolyl)-
2- (1-Diphenylmethoxycarbonylvinyloxyimino) acetamido] -3- (1-allyl-4-pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester / mixture of chloride and iodide 1 .0
4 g are obtained.

¹ HNMR δ (CDCl ₃ -CD ₃ OD) ppm: 1.55 (s, 9
H), 3.41, 3.59 (ABq, J = 18Hz, 2H), 3.79 (s, 3H), 4.34,
4.46 (ABq, J = 12Hz, 2H), 4.91 (d, J = 5Hz, 1H), 5.17
(d, J = 7Hz, 2H), 5.19, 5.25 (ABq, J = 12Hz, 2H), 5.50
~ 5.63 (m, 2H), 5.63 (d, J = 2Hz, 1H), 5.78 (d, J = 5Hz, 1
H), 5.83 (d, J = 2Hz, 1H), 5.98 ~ 6.18 (m, 1H), 6.85 (d, J
= 9Hz, 2H), 6.93 (s, 1H), 7.30 ~ 7.38 (m), 7.81 (d, J = 7
Hz, 2H), 8.56 (d, J = 7Hz, 2H).

7) R = carbamoylmethyl, R ¹ = diphenylmethyl, X = chloro / iodo 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonyl) Vinyloxyimino) acetamido] -3- (1-carbamoylmethyl-4-pyridinio) thiomethyl-3-cephem-4-
7.39 g (7 mmol) of carboxylic acid p-methoxybenzyl ester 1-oxide chloride were dissolved in 70 ml of acetone and cooled to -20 ° C. 11.62 g (10 equivalents) of finely powdered potassium iodide, then 3 m of acetyl chloride
l (6 eq) is added and stirred at -20 to -10 ° C for 1.5 hours. The reaction solution is poured into a solution of 7.3 g (10 equivalents) of sodium hydrogen sulfite in 200 ml of ice water, and the precipitate is collected by filtration. This was dissolved in dichloromethane, dried over magnesium sulfate, and concentrated under reduced pressure to give 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino) acetamide].
7.15 g of a mixture of 3- (1-carbamoylmethyl-4-pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester chloride and iodide are obtained. IR ν (CHCl ₃ ) cm ⁻¹ : 1786, 1717, 1690sh.

8) R = 2-sulfamoylmethyl, R ¹ =
Diphenylmethyl, X = chloro / iodo Crude 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino) acetamide] -3- (1- (2-Sulfamoylethyl) -4-pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester
7.78 g of 1-oxide / chloride was dissolved in 70 ml of acetone and cooled to -20 ° C to obtain powdery potassium iodide 11.62.
g and 3.0 ml of acetyl chloride are added, and the mixture is stirred at -20 to -10 ° C for 1.5 hours. The reaction solution is sodium bisulfite 7.
It was poured into an aqueous solution of ice containing 3 g and the resulting precipitate was collected by filtration to obtain crude 7β- [2- (2-t-butoxycarbonylamino-
4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino) acetamido] -3- (1- (2-
Sulfamoylethyl) -4-pyridinio) thiomethyl-
7.69 g of a mixture of 3-cephem-4-carboxylic acid p-methoxybenzyl ester chloride and iodide are obtained. IR ν (CHCl ₃ ) cm ⁻¹ : 1784, 1717, 1628.

9) R = Boc amino, R ¹ = diphenylmethyl, X = chloro / iodo 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonyl) Vinyloxyimino) acetamido] -3- (1-t-butoxycarbonylamino-4-pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester / 1-
To a mixture of 1.10 g (1 mmol) of oxide / chloride, 1.66 g (10 mmol) of potassium iodide and 10 ml of acetone, 0.43 ml (6 mmol) of acetyl chloride was added at -30 ° C, and then -20 to -30. React at 2 ° C for 2 hours. The reaction solution was poured into 3% sodium hydrogen sulfite water under ice cooling,
After stirring for 20 to 30 minutes, the resulting precipitate was collected by filtration to obtain crude 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino). Acetamide] -3- (1-t-butoxycarbonylamino-4-pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester ester 1.16 g of a mixture of chloride and iodide is obtained.

¹ HNMR δ (CDCl ₃ -CD ₃ OD) ppm: 1.55 (s, 18
H), 3.46, 3.60 (ABq, J = 19Hz, 2H), 3.79 (s, 3H), 4.34,
4.49 (ABq, J = 13Hz, 2H), 4.90 (d, J = 5Hz, 1H), 5.20,
5.26 (ABq, J = 10Hz, 2H), 5.63 (d, J = 2Hz, 1H), 5.78 (d,
J = 5Hz, 1H), 5.83 (d, J = 2Hz, 1H), 6.86 (d, J = 8Hz, 2
H), 6.94 (s, 1H), 7.25 ~ 7.40 (m), 7.80 (d, J = 7Hz, 2
H), 8.38 (d, J = 7Hz, 2H).

Example 3 Deprotection The compound prepared in Preparation Example 2 is deprotected to obtain the target compound I. A. Compound having pyridin-2-ylthio group

[Chemical 9]

1) R = methyl, R ¹ = diphenylmethyl → H → Na, X = iod 5.49 g (6 equivalents) of aluminum chloride was added to anisole 5
Dissolve in a mixture of 5 ml and 28 ml of dichloromethane, -50 ° C
Cooled to 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino) acetamide] -3- (1-
Methyl-2-pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester iodide 7.5
A solution of 0 g (6.87 mmol) in 28 ml of dichloromethane is added. After stirring at -50 to -40 ° C for 1 hour, a mixed solution of 100 ml of methanol and 100 ml of N-hydrochloric acid was added to the reaction solution. Separate the aqueous layer, wash with dichloromethane and ether,
The residual organic solvent was distilled off under reduced pressure, and the column was passed through a 300 ml column of a styrene-divinylbenzene copolymer adsorbent. 5 to 5
Elute with 10% aqueous acetonitrile and dry under reduced pressure.
The residue was washed with methanol and dried to give 7β- [2- (2-amino-4-thiazolyl) -2- (1-
Carboxyvinyloxyimino) acetamide] -3-
(1-Methyl-2-pyridinio) thiomethyl-3-cephem-
2.85 g of 4-carboxylate are obtained. Yield: 72
%.

This carboxylic acid was added to 100 ml of water, and N-sodium hydroxide was gradually added under ice cooling to adjust the pH to 5.6.
Adjusted to 7, filtered with a Millipore filter and lyophilized to give 7β- [2- (2-amino-4-thiazolyl) -2- (1-
Sodiooxycarbonylvinyloxyimino) acetamido] -3- (1-methyl-2-pyridinio) thiomethyl-
3.19 g of 3-cephem-4-carboxylate are obtained.

¹ HNMR δ (D ₂ O) ppm: 3.49, 3.73 (ABq, J =
17.4Hz, 2H), 4.22 (s, 3H), 4.28, 4.48 (ABq, J = 13.4H
z, 2H), 5.14 (d, J = 1.8Hz, 1H), 5.15 (d, J = 4.6Hz, 1
H), 5.30 (d, J = 1.8Hz, 1H), 5.82 (d, J = 4.6Hz, 1H), 7.
19 (s, 1H), 7.64 ~ 8.66 (m, 4H). IR ν (KBr) cm ^-1 : 1763, 1660sh, 1594. Elemental analysis Calculated as C ₂₂ H ₁₉ N ₆ O ₇ S ₃ Na ・ 2.6H ₂ O C, 40.94; H, 3.78; N, 13.02; S, 14.90; Na,
3.56; H ₂ O, 7.26%. Experimental value C, 40.82; H, 3.92; N, 13.27; S, 15.29; Na,
3.58; H ₂ O, 7.16%.

This compound is a Bud-coccus Smith strain (0.8
μg / ml), Klebsiella oxytoca SR 696 strain (0.013 μg / ml), Proteus vulgaris S
It has an excellent minimum inhibitory concentration such as R3 strain (0.05 μg / ml) and has strong antibacterial activity.

B. Compound having pyridin-4-ylthio group

[Chemical 10]

1) R = methyl, R ¹ = diphenylmethyl➝H➝Na, X = chloro / iod 1.6 g (12 mmol) of aluminum chloride aniso-
20 ml solution at 30 ° C. with 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino) acetamido] -3- (1-methyl-4 -Pyridinio) thiomethyl-3-
A solution of 2.08 g of a mixture of cephem-4-carboxylic acid p-methoxybenzyl ester chloride and iodide in 20 ml of dichloromethane was added, and the mixture was stirred at -30 to -15 ° C for 1.5 hours. To the reaction solution are added 25 ml of methanol and 25 ml of 1N hydrochloric acid, the mixture is washed with dichloromethane, the methanol in the aqueous layer is distilled off, and the adsorbent column of styrene-divinylbenzene copolymer is passed through. The adsorbate was eluted with water to 80% methanol and the eluate was concentrated to give 7β- [2- (2-amino-4-thiazolyl) -2- (1-carboxyvinyloxyimino) acetamide] -3. -(1-Methyl-4-pyridinio) thiomethyl-
514 mg of 3-cephem-4-carboxylate are obtained. IR ν (KBr) cm ^-1 : 1770, 1670, 1630.

514 mg (0.89 mmol) of this carboxylic acid was dissolved in 9 ml of 0.1N sodium hydroxide and lyophilized to give 7β- [2- (2-amino-4-thiazolyl) -2- (1 -Sodioxycarbonylvinyloxyimino) acetamido] -3- (1-methyl-4-pyridinio) thiomethyl-3-cephem-4-carboxylate 5
Get 53 mg.

¹ HNMR δ (D ₂ O) ppm: 3.46, 3.70 (ABq, J =
18Hz, 2H), 4.17 (s, 3H), 4.18, 4.36 (ABq, J = 14Hz, 2
H), 5.16 (d, J = 5Hz, 1H), 5.17 (d, J = 2Hz, 1H), 5.30
(d, J = 2Hz, 1H), 5.80 (d, J = 5Hz, 1H), 7.15 (s, 1H),
7.79 (d, J = 7Hz, 2H), 8.36 (d, J = 7Hz, 2H). IR ν (KBr) cm ^-1 : 1765, 1660, 1630, 1595.

This compound is a bud-coccus Smith strain (0.8
μg / ml), Klebsiella oxytoca SR696 strain (0.025 μg / ml), Proteus vulgaris S
It shows excellent minimum inhibitory concentration such as R3 strain (0.1 μg / ml) and has strong antibacterial activity.

2) R = ethyl, R ¹ = diphenylmethyl → H → Na, X = chloro / iodo 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1- Diphenylmethoxycarbonylvinyloxyimino) acetamide] -3- (1-ethyl-4-
Pyridinio) thiomethyl-3-cephem-4-carboxylic acid p
-8.1 g of a mixture of methoxybenzyl ester / chloride and iodide was dissolved in 160 ml of dichloromethane, and 6.40 g (48 mmol) of aluminum chloride was added as anisole 5.
Add 0 ml solution and stir at -50 ° C for 1 hour. 150 ml of 1N hydrochloric acid, 150 ml of methanol and ether 30 were added to the reaction solution.
Add 0 ml. The aqueous layer is separated and passed through a column of styrene-divinylbenzene copolymer adsorbent (500 ml). 2 adsorbates
Elute with 5% to 10% acetonitrile in water and evaporate the solvent. If the residue is washed with methanol, 7β- [2- (2-
2.75 g of amino-4-thiazolyl) -2- (1-carboxyvinyloxyimino) acetamido] -3- (1-ethyl-4-pyridinio) thiomethyl-3-cephem-4-carboxylate are obtained. Yield: 58.1%.

This carboxylic acid (4.9 mmol) was dissolved in a solution of 391 mg of sodium hydrogencarbonate in 60 ml of water, isopropanol was added, and the resulting precipitate was collected by filtration to give 7β.
-[2- (2-Amino-4-thiazolyl) -2- (1-sodiooxycarbonylvinyloxyimino) acetamide]-
1.68 g of 3- (1-ethyl-4-pyridinio) thiomethyl-3-cephem-4-carboxylate are obtained.

¹ HNMR δ (D ₂ O) ppm: 1.54 (t, J = 7Hz, 3
H), 3.45, 3.70 (ABq, J = 17Hz, 2H), 4.17, 4.37 (ABq, J
= 14Hz, 2H), 4.43 (q, J = 7Hz, 2H), 5.14 (d, J = 2Hz, 1
H), 5.16 (d, J = 5Hz, 1H), 5.30 (d, J = 2Hz, 1H), 5.80
(d, J = 5Hz, 1H), 7.15 (s, 1H), 7.80 (d, J = 7Hz, 2H),
8.43 (d, J = 7Hz, 2H). IR ν (KBr) cm ^-1 : 1765, 1630, 1595, 1535. Elemental analysis Calculated as C ₂₃ H ₂₁ N ₆ S ₃ O ₇ Na ・ 4H ₂ O C, 40.34; H, 4.27; N, 12.28; S, 14.05; Na,
_{3.36; H 2 O, 10.53%} . Experimental value C, 40.99; H, 4.23; N, 12.68; S, 14.51; Na,
_{3.45; H 2 O, 10.49%} .

This compound is a bud-coccus Smith strain (0.8
μg / ml), Klebsiella oxytoca SR 696 strain (0.013 μg / ml), Proteus vulgaris S
It shows excellent minimum inhibitory concentration such as R3 strain (0.1 μg / ml) and has strong antibacterial activity.

3) R = isopropyl, R ¹ = diphenylmethyl → H → Na, X = chloro / iodo 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1- Diphenylmethoxycarbonylvinyloxyimino) acetamido] -3- (1-isopropyl-4-pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester-a mixture of chloride and iodide (1.07 g) in dichlorometha Melted to 20 ml,
Aluminum chloride 0.80 g (6 mmol) at -50 ° C
Add 7 ml of anisole solution of
Stir for hours. To the reaction solution, 1N hydrochloric acid 20ml, methanol 2
A mixture of 0 ml and 60 ml ether is added. The aqueous layer is concentrated under reduced pressure to about half the volume and passed through a column of styrene-divinylbenzene copolymer adsorbent. After washing the column with water, the adsorbate is 8% to 10%.
% Β- [2- (2-amino-4-thiazolyl) -2- (1-carboxyvinyloxyimino) acetamide] -3- (1-isopropyl-4-
Pyridinio) thiomethyl-3-cephem-4-carboxyl
-To obtain 434 mg.

430 mg of this carboxylic acid was dissolved in 10 times the amount of water containing 1.0 equivalent of sodium hydrogen carbonate,
A 15-fold amount of isopropanol was added, and the resulting precipitate was collected by filtration to obtain 7β- [2- (2-amino-4-thiazolyl) -2.
-(1-Sodiooxycarbonylvinyloxyimino) acetamido] -3- (1-isopropylpyridinio-4-yl) thiomethyl-3-cephem-4-carboxylate 40
0 mg are obtained. ¹ HNMR δ (D ₂ O-CD ₃ OD) ppm: 1.57 (d, J = 6Hz, 6H), 3.4
3, 3.68 (ABq, J = 18Hz, 2H), 4.15, 4.40 (ABq, J = 15Hz, 2
H), 5.13 (d, J = 2Hz, 1H), 5.14 (d, J = 5Hz, 1H), 5.28
(d, J = 2Hz, 1H), 5.79 (d, J = 5Hz, 1H), 7.15 (s, 1H),
7.80 (d, J = 7Hz, 2H), 8.49 (d, J = 7Hz, 2H). IR ν (KBr) cm ^-1 : 3400, 1765, 1625, 1595.

This compound is a bud-coccus Smith strain (0.8
μg / ml), Klebsiella oxytoca SR 696 strain (0.01 μg / ml), Proteus vulgaris SR
It shows excellent minimum inhibitory concentration such as 3 strains (0.2 μg / ml) and has strong antibacterial activity.

4) R = allyl, R ¹ = diphenylmethyl → H → Na, X = chloro / iodo 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1- Diphenylmethoxycarbonylvinyloxyimino) acetamide] -3- (1-allyl-4-
Pyridinio) thiomethyl-3-cephem-4-carboxylic acid p
-Methoxy benzyl ester-1.04 g of a mixture of chloride and iodide was dissolved in 20 ml of dichloromethane and -50.
A solution of 0.80 g (6 mmol) of aluminum chloride in 7 ml of anisole was added at .degree. 20 ml of 1N hydrochloric acid, 20 ml of methanol and 40 ml of ether are added to the reaction solution. The aqueous layer is separated and passed through a column of styrene-divinylbenzene copolymer adsorbent (80 ml). The adsorbate is eluted with 25% to 10% aqueous acetonitrile, and the solvent is distilled off. If the residue is washed with methanol, 7β- [2-
(2-Amino-4-thiazolyl) -2- (1-carboxyvinyloxyimino) acetamide] -3- (1-allyl-4-
Pyridinio) thiomethyl-3-cephem-4-carboxyl
-Get 414 mg.

347 mg of this carboxylic acid was dissolved in aqueous sodium hydrogen carbonate and lyophilized to give 7β- [2- (2-amino-4-thiazolyl) -2- (1-sodiooxycarbonylvinyloxyimino) acetamide]. 321 mg of 3- (1-allyl-4-pyridinio) thiomethyl-3-cephem-4-carboxylate are obtained. ¹ HNMR δ (D ₂ O-CD ₃ OD) ppm: 3.45, 3.67 (ABq, J = 17Hz,
2H), 4.17, 4.36 (ABq, J = 14Hz, 2H), 5.50 (d, J = 6Hz, 2
H), 5.14 (d, J = 2Hz, 1H), 5.15 (d, J = 5Hz, 1H), 5.28 (d,
J = 2Hz, 1H), 5.40 (d, J = 16Hz, 1H), 5.48 (d, J = 10Hz,
1H), 5.79 (d, J = 5Hz, 1H), 5.96 ~ 6.16 (m, 1H), 7.14
(s, 1H), 7.81 (d, J = 7Hz, 2H), 8.39 (d, J = 7Hz, 2H). IR ν (KBr) cm ^-1 : 3380, 1762, 1625, 1590.

This compound is a bud-coccus Smith strain (0.4
μg / ml), Klebsiella oxytoca SR 696 strain (0.01 μg / ml), Proteus vulgaris SR
It shows excellent minimum inhibitory concentration such as 3 strains (0.1 μg / ml) and has strong antibacterial activity.

5) R = cyclopropyl, R ¹ = diphenylmethyl → H → Na, X = chloro / iodo 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1 -Diphenylmethoxycarbonylvinyloxyimino) acetamido] -3- (1-cyclopropyl-4-pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester-a mixture of chloride and iodide (7.96 g) After dissolving in 140 ml of dichloromethane, a solution of 5.60 g (42 mmol) of aluminum chloride in 50 ml of anisole was added, and the mixture was stirred at -50 ° C for 2 hours. 120 ml of 1N hydrochloric acid, 120 ml of methanol and 250 ml of ether were added to the reaction solution. Separate the water layer and remove styrene-
Pass through a column of divinylbenzene copolymer adsorbent (400 ml). The adsorbate is eluted with 25% to 10% aqueous acetonitrile, and the solvent is distilled off. If the residue is washed with methanol,
7β- [2- (2-Amino-4-thiazolyl) -2- (1-carboxyvinyloxyimino) acetamide] -3- (1-
Cyclopropyl-4-pyridinio) thiomethyl-3-cephem-
2.86 g of 4-carboxylate are obtained.

To a suspension of 2.52 g (4.18 mmol) of this carboxylic acid in 40 ml of water was added 351 mg of sodium hydrogencarbonate.
(4.18 mmol) was added to form a sodium salt, isopropyl alcohol was added, and the resulting precipitate was collected by filtration to give 7β- [2- (2-amino-4-thiazolyl) -2- (1-
1.67 g of sodiooxycarbonylvinyloxyimino) acetamido] -3- (1-cyclopropyl-4-pyridinio) thiomethyl-3-cephem-4-carboxylate are obtained.

¹ HNMR δ (D ₂ O) ppm: 1.28 (d, J = 5Hz, 4
H), 3.46, 3.70 (ABq, J = 18Hz, 2H), 4.10 (quint, J = 5H
z, 1H), 4.20, 4.35 (ABq, J = 14Hz, 2H), 5.16 (d, J = 2H
z, 1H), 5.17 (d, J = 5Hz, 1H), 5.30 (d, J = 2Hz, 1H), 5.79
(d, J = 5Hz, 1H), 7.14 (s, 1H), 7.78 (d, J = 7Hz, 2H), 8.
51 (d, J = 7Hz, 2H). IRS ν (KBr) cm ^-1 : 1760, 1660, 1620, 1595, 1530. Elemental analysis calculated as C ₂₄ H ₂₁ N ₆ S ₃ O ₇ Na ・ 5H ₂ O, C, 40.33; H, 4.37; N, 11.76; S, 13.46; Na,
_{3.22; H 2 O, 12.61%} . Experimental value C, 40.45; H, 4.36; N, 12.14; S, 13.70; Na,
_{3.26; H 2 O, 13.14%} .

This compound is a bud-coccus Smith strain (0.8
μg / ml), Klebsiella oxytoca SR 696 strain (0.013 μg / ml), Proteus vulgaris S
It shows excellent minimum inhibitory concentration such as R3 strain (0.1 μg / ml) and has strong antibacterial activity.

6) R = cyclopentyl, R ¹ = diphenylmethyl → H → Na, X = chloro / iodo 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1- Diphenylmethoxycarbonylvinyloxyimino) acetamido] -3- (1-cyclopentyl-4-pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester-A mixture of chloride and iodide 5.40 g was added to 100 ml of dichloromethane. Then, a solution of 4.16 g (31.2 mmol) of aluminum chloride in 40 ml of anisole was added and the mixture was stirred at -50 ° C for 1 hour. 80 ml of 1N hydrochloric acid and 80 ml of methanol were added to the reaction mixture.
Add 160 ml of tell. The aqueous layer is separated and passed through a column of styrene-divinylbenzene copolymer adsorbent (300 ml). The adsorbate is eluted with 25% to 10% aqueous acetonitrile, and the solvent is distilled off. If the residue is washed with methanol, 7β-
[2- (2-Amino-4-thiazolyl) -2- (1-carboxyvinyloxyimino) acetamido] -3- (1-cyclopentyl-4-pyridinio) thiomethyl-3-cephem-
2.46 g of 4-carboxylate are obtained. When 2.96 g of this carboxylic acid was dissolved in a solution of 328 mg (3.9 mmol) of sodium hydrogen carbonate in 30 ml of water and freeze-dried, 7β-
[2- (2-Amino-4-thiazolyl) -2- (1-sodiooxycarbonylvinyloxyimino) acetamide]-
3- (1-Cyclopentyl-4-pyridinio) thiomethyl-
2.34 g of 3-cephem-4-carboxylate are obtained.

¹ HNMR δ (D ₂ O) ppm: 1.7 to 2.0 (m, 6H),
2.25 ~ 2.45 (m, 2H), 3.45, 3.68 (ABq, J = 19Hz, 2H), 4.
18 to 4.37 (ABq, J = 13Hz, 2H), 4.8 to 4.95 (m, 1H), 5.16
(d, J = 2Hz, 1H), 5.17 (d, J = 5Hz, 1H), 5.30 (d, J = 2Hz,
1H), 5.80 (d, J = 5Hz, 1H), 7.14 (s, 1H), 7.80 (d, J = 7H
z, 2H), 8.47 (d, J = 7Hz, 2H). IRS ν (KBr) cm ^-1 : 1762, 1660, 1625, 1590, 1532. This compound is a Bud-coccus Smith strain (0.4 μg / ml),
Klebsiella oxytoca SR696 strain (0.013
μg / ml), Proteus vulgaris SR3 strain (0.
It has an excellent minimum inhibitory concentration such as 1 μg / ml) and has a strong antibacterial activity.

7) R = 2-hydroxyethyl, R ¹ = diphenylmethyl → H → Na, X = chloro / iodo 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-Diphenylmethoxycarbonylvinyloxyimino) acetamide] -3- (1- (2-hydroxyethyl) -4-pyridinio) thiomethyl-3-cephem
Dissolve 7.55 g (7.3 mmol) of 4-carboxylic acid p-methoxybenzyl ester chloride in dichloromethane, cool to -40 ° C, and stir aluminum chloride 5.8.
After dropwise adding a solution of 6 g of anisole in 50 ml, the mixture was stirred at the same temperature for 60 minutes. 140 ml of N-hydrochloric acid and 14 ml of methanol were added to the reaction solution.
Add 0 ml cold mix at once. The aqueous layer is separated, washed with ether and passed through a column of styrene-divinylbenzene copolymer adsorbent. The adsorbate was eluted with 10% aqueous acetonitrile and concentrated under reduced pressure to give 7β- [2- (2-amino-4-thiazolyl) -2- (1-carboxyvinyloxyimino) acetamide] -3- (1- 3.1 g of (2-hydroxyethyl) -4-pyridinio) thiomethyl-3-cephem-4-carboxylate are obtained.

If 1.80 g of this carboxylic acid was neutralized with 2% aqueous sodium hydrogen carbonate and lyophilized, 7β- [2-
(2-Amino-4-thiazolyl) -2- (1-sodiooxycarbonylvinyloxyimino) acetamide] -3- (1
-(2-Hydroxyethyl) -4-pyridinio) thiomethyl
1.70 g of -3-Cephem-4-carboxylate are obtained. ¹ HNMR δ (D ₂ O) ppm: 3.45, 3.71 (ABq, J = 17.6Hz, 2H),
3.99 (t, J = 5.0Hz, 2H), 4.19, 4.38 (ABq, J = 13.5Hz, 2
H), 4.52 (t, J = 5.0Hz, 2H), 5.15 (d, J = 2.0Hz, 1H), 5.1
6 (d, J = 4.8Hz, 1H), 5.30 (d, J = 2.0Hz, 1H), 5.81 (d, J
= 4.8Hz, 1H), 7.17 (s, 1H), 7.83 (d, J = 7.0Hz, 2H), 8.4
3 (d, J = 7.0Hz, 2H).

This compound is a bud-coccus Smith strain (0.8
μg / ml), Klebsiella oxytoca SR696 strain (0.025 μg / ml), Proteus vulgaris S
It shows excellent minimum inhibitory concentration such as R3 strain (0.2 μg / ml) and has strong antibacterial activity.

8) R = 1-hydroxy-2-propyl, R ¹
= Diphenylmethyl → H → Na, X = chloro / iodo 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino) acetamide] -3- ( 1- (1-hydroxy-2-propyl) -4-pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester
6.7 g (6.42 mmol) of chloride was added to dichloromethane 1
It was dissolved in 20 ml, cooled to -40 ° C., a solution of 5.13 g (6 equivalents) of aluminum chloride in 45 ml of anisole was added dropwise, and the mixture was stirred at the same temperature for 60 minutes. N-hydrochloric acid 120 in the reaction solution
ml, 120 ml of methanol cold mixture is added at once. The aqueous layer is separated, washed with ether and passed through a column of styrene-divinylbenzene copolymer adsorbent. The adsorbate was eluted with 10% aqueous acetonitrile and concentrated under reduced pressure to give 7β- [2- (2-amino-4-thiazolyl) -2- (1-carboxyvinyloxyimino) acetamide] -3- (1- ( 2.56 g of 1- (1-hydroxy-2-propyl) -4-pyridiniothio) methyl-3-cephem-4-carboxylate are obtained.

250 mg of this carboxylic acid was adjusted to pH 6.0 with sodium hydrogen carbonate and lyophilized to give 7β- [2-
(2-Amino-4-thiazolyl) -2- (1-sodiooxycarbonylvinyloxyimino) acetamide] -3- (1
-(1- (1-hydroxy-2-propyl) -4-pyridinio) thiomethyl-3-cephem-4-carboxylate 23
5 mg are obtained.

¹ HNMR δ (D ₂ O) ppm: 1.60 (d, J = 6.8Hz, 3
H), 3.44, 3.70 (ABq, J = 18.0Hz, 2H), 3.76-4.0 (m, 2
H), 4.16, 4.43 (ABq, J = 14.0Hz, 2H), 4.70 (m, 1H), 5.
14 (d, J = 2.0Hz, 1H), 5.15 (d, J = 5.0Hz, 1H), 5.29 (d, J
= 2.0Hz, 1H), 5.83 (d, J = 5.0Hz, 1H), 7.20 (s, 1H), 7.
83 (d, J = 7.0Hz, 2H), 8.50 (d, J = 7.0Hz, 2H). This compound is a Bud-coccus Smith strain (0.8 μg / ml),
Klebsiella oxytoca SR696 strain (0.2 μg
/ Ml), Proteus vulgaris SR3 strain (0.2μ
(g / ml) and shows an excellent minimum inhibitory concentration, and has a strong antibacterial activity.

9) R = carbamoylmethyl, R ¹ = diphenylmethyl → H → Na, X = chloro / iod 5.5 g (6 equivalents) of aluminum chloride was added to 60 m of anisole.
It was dissolved in a mixed solution of 1 and dichloromethane (20 ml) and cooled to -50 ° C, and 7β- [2- (2-t-butoxycarbonylamino-
4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino) acetamido] -3- (1-carbamoylmethyl-4-pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester chloride And iodide mixture 7.15 g dichloromethane 60 m
Add the solution and stir at -50 to -40 ° C for 1 hour. The reaction solution was treated with 100 ml of cold methanol and 100 ml of dichloromethane.
It is poured into a mixed solution of ml, washed with dichloromethane and ether, the dissolved organic solvent is distilled off, and then 200 ml of a styrene-divinylbenzene copolymer adsorbent is passed through. The adsorbate is eluted with water, 5% aqueous acetonitrile and 10% aqueous acetonitrile. The desired product fraction was concentrated to dryness, disentangled with methanol and collected by filtration to obtain 7β- [2- (2-amino-4-thiazolyl) -2- (1-
Carboxyvinyloxyimino) acetamide-3- (1
-Carbamoylmethyl-4-pyridinio) thiomethyl-3-
2.79 g of cephem-4-carboxylate are obtained.

2.6 g of this carboxylic acid was suspended in 50 ml of cold water, adjusted to pH 5.5 with N-sodium hydroxide, and filtered with a Millipore filter. 100 ml of isopropanol was added to the filtrate and stirred for 1 hour. The resulting precipitate is collected by filtration, washed with isopropanol and ether, and dried under reduced pressure to give 7β- [2- (2-amino-4-thiazolyl) -2-
1.6 g of (1-sodiooxycarbonylvinyloxyimino) acetamido] -3- (1-carbamoylmethyl-4-pyridinio) thiomethyl-3-cephem-4-carboxylate are obtained.

¹ HNMR δ (D ₂ O) ppm: 3.43, 3.70 (ABq, J =
17.0Hz, 2H), 4.18, 4.42 (ABq, J = 14.0Hz, 2H), 5.15
(d, J = 4.5Hz, 1H), 5.16 (s, 1H), 5.26 (s, 3H), 5.82
(s, 3H), 5.82 (d, J = 4.5Hz, 1H), 7.18 (s, 1H), 7.85 (d,
J = 6.4Hz, 2H), 8.36 (d, J = 6.4Hz, 2H). IR ν (KBr) cm ^-1 : 1764, 1689. Elemental analysis _{C 23 H 20 N 7 O 8} S 3 Na · 2.7H 2 O Calculated C, 40.07; H, 3.70; N, 14.23; S, 13.95; Na,
3.34; H ₂ O, 7.05%. Experimental value C, 40.27; H, 3.84; N, 14.64; S, 14.30; Na,
_{3.45; H 2 O, 6.74%} .

This compound is a bud-coccus Smith strain (0.4
μg / ml), Klebsiella oxytoca SR 696 strain (0.013 μg / ml), Proteus vulgaris S
It shows excellent minimum inhibitory concentration such as R3 strain (0.1 μg / ml) and has strong antibacterial activity.

10) R = 2-methylthioethyl, R ¹ = diphenylmethyl → H → Na, X = chloro / iodo 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-Diphenylmethoxycarbonylvinyloxyimino) acetamido] -3- (1- (2-methylthioethyl) -4-pyridinio) thiomethyl-3-cephem
1.8 g of -4-carboxylic acid p-methoxybenzyl ester chloride was dissolved in 32 ml of dichloromethane and cooled to -40 ° C. A solution of 1.36 g of aluminum chloride in 12 ml of anisole was added to this, and the mixture was stirred at the same temperature for 1 hour. To the reaction solution was added a cold mixed solution of 40 ml of N-hydrochloric acid and 40 ml of methanol all at once. The aqueous layer is separated, washed with ether, and styrene-
Pass the divinylbenzene copolymer adsorbent column. 1 adsorbate
By elution with 0% acetonitrile water and concentration under reduced pressure, 7β
-[2- (2-Amino-4-thiazolyl) -2- (1-carboxyvinyloxyimino) acetamide] -3- (1- (2-
0.59 g of methylthioethyl) -4-pyridinio) thiomethyl-3-cephem-4-carboxylate is obtained.

350 mg of this carboxylic acid was neutralized with 1% aqueous sodium hydrogen carbonate, added dropwise to 50 ml of isopropanol with stirring, and the precipitate formed was collected by filtration to give 7β- [2-
(2-Amino-4-thiazolyl) -2- (1-sodiooxycarbonylvinyloxyimino) acetamido-3- (1-
350 mg of (2-methylthioethyl) pyridinio-4--4-yl) thiomethyl-3-cephem-4-carboxylate are obtained.

¹ HNMR δ (D ₂ O) ppm: 2.05 (s, 3H), 3.06
(t, J = 5.8Hz, 2H), 3.44, 3.70 (ABq, J = 17.8Hz, 2H), 4.
17, 4.40 (ABq, J = 13.2Hz, 2H), 5.14 (d, J = 1.4Hz, 1H),
5.16 (d, J = 4.5Hz, 1H), 5.30 (J = 1.4Hz, 1H), 5.82 (d,
J = 4.5Hz, 1H), 7.18 (s, 1H), 7.83 (d, J = 7.0Hz, 2H), 8.
47 (d, J = 7.0Hz, 2H). This compound is a Bud-coccus Smith strain (0.4 μg / ml),
Klebsiella oxytoca SR696 strain (0.01 μ
g / ml), Proteus vulgaris SR3 strain (0.2
It has an excellent minimum inhibitory concentration such as μg / ml) and has a strong antibacterial activity.

11) R = 2-sulfamoylethyl, R ¹
= Diphenylmethyl->H-> Na, X = chloro / iod. Aluminum chloride (5.6 g) was dissolved in a mixture of 60 ml of anisole and 20 ml of dichloromethane, and the mixture was cooled to -50 ° C. to give 7
β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino) acetamide] -3- (1- (2-sulfamoylethyl) -4- Pyridinio) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester / mixture of chloride and iodide 7.69 g of dichloromethane 60 m
Add the solution and stir at -50 to -40 ° C for 1 hour. To the reaction solution was added a mixed solution of 100 ml of cold methanol and 100 ml of N-hydrochloric acid. The aqueous layer is taken, washed with ether, concentrated to remove the residual organic solvent, and then passed through a 200 ml column of a styrene-divinylbenzene copolymer adsorbent. The adsorbate was eluted with water, 5% acetonitrile, 10% acetonitrile, and the target stream was concentrated with dry lye, crushed with methanol and collected by filtration to obtain 7β-
[2- (2-Amino-4-thiazolyl) -2- (1-carboxyvinyloxyimino) acetamide] -3- (1- (2-
Sulfamoylethyl) -4-pyridinio) thiomethyl-
2.75 g of 3-cephem-4-carboxylate are obtained.

2.5 g of this carboxylic acid was suspended in 50 ml of water, and the pH was adjusted to 5.5 with N-sodium hydroxide while stirring and cooling with ice, followed by filtration with Millipore. Add 100 ml of isopropanol to the filtrate and stir for 1 hour. The precipitate is collected by filtration, washed with isopropanol and ether, and dried under reduced pressure,
7β- [2- (2-Amino-4-thiazolyl) -2- (1-sodiooxycarbonylvinyloxyimino) acetamido] -3- (1- (2-sulfamoylethyl) -4-pyridinio) thiomethyl 1.83 g of -3-Cephem-4-carboxylate are obtained.

IR ν (KBr) cm ^-1 : 1761, 1660 (sh), 162
8, 1593. ¹ HNMR δ (D ₂ O) ppm: 3.40, 3.64 (ABq, J = 17.6Hz, 2H),
3.87 (t, J = 6.6Hz, 2H), 4.15, 4.35 (ABq, J = 14.1Hz, 2
H), 4.84 (t, J = 6.6Hz, 2H), 5.10 (s, 1H), 5.11 (d, J =
4.6Hz, 1H), 5.25 (s, 1H), 5.77 (d, J = 4.6Hz, 1H), 7.1
3 (s, 1H), 7.80 (d, J = 7Hz, 2H), 8.47 (d, J = 7Hz, 2H). This compound is a Bud-coccus Smith strain (0.8 μg / ml),
Klebsiella oxytoca SR696 strain (0.01 μ
g / ml), Proteus bulgaris SR3 strain (0.1
It has an excellent minimum inhibitory concentration such as μg / ml) and has a strong antibacterial activity.

12) R = t-butoxycarbonylamino, R ¹ = diphenylmethyl → H → Na, X = chloro /
Yodo. 7β- [2- (2-t-Butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino) acetamide] -3- (1-t-butoxycarbonylamino-4-pyridinio) thiomethyl 1.15 g of a mixture of 3-cephem-4-carboxylic acid p-methoxybenzyl ester / chloride and iodide was added to dichloromethane 2
Melt to 0 ml, and add aluminum chloride 1.1g at -50 ℃.
Add 7 ml of anisole solution (8 mmol) to -35
Stir at ~ -45 ° C for 1 hour. 20m of 1N hydrochloric acid in the reaction solution
l, 20 ml of methanol and 40 ml of ether are added. The aqueous layer is separated and passed through a column of styrene-divinylbenzene copolymer adsorbent (70 ml). The adsorbate is eluted with 25% to 10% aqueous acetonitrile, and the solvent is distilled off. The residue was washed with methanol to give 7β- [2- (2-amino-4-thiazolyl) -2- (1-carboxyvinyloxyimino) acetamido] -3- (1-amino-4-pyridinio) thiomethyl. -
255 mg of 3-cephem-4-carboxylate are obtained.

254 mg of this carboxylic acid was dissolved in a solution of 37 mg of sodium hydrogencarbonate in 2.5 ml of water to give isopropanol.
The resulting precipitate was collected by filtration and dried to give 7β- [2- (2-amino-4-thiazolyl) -2- (1-
Sodiooxycarbonylvinyloxyimino) acetamido] -3- (1-amino-4-pyridinio) thiomethyl-3
-191 mg of cephem-4-carboxylate are obtained.

¹ HNMR δ (D ₂ O) ppm: 3.45, 3.70 (ABq, J =
17.5Hz, 2H), 4.14, 4.38 (ABq, J = 14.5Hz, 2H), 5.15
(d, J = 5Hz, 1H), 5.16 (d, J = 2Hz, 1H), 5.30 (d, J = 2Hz,
1H), 5.81 (d, J = 5Hz, 1H), 7.17 (s, 1H), 7.76 (d, J = 7H
z, 2H), 8.39 (d, J = 7Hz, 2H). This compound is a Bud-coccus Smith strain (0.4 μg / ml),
Klebsiella oxytoca SR696 strain (0.013
μg / ml), Proteus vulgaris SR3 strain (0.
(2 μg / ml) and shows an excellent minimum inhibitory concentration, and has strong antibacterial activity. The method for producing the raw material compounds used in the above examples is shown below.

Production Example 1 Amidation

[Chemical 11]

1) R ¹ = t-butyl 7β-amino-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester hydrochloride (purity: 9
(6.1%) 5.06 g (12 mmol) was suspended in 100 ml of dichloromethane and 2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-t-butoxycarbonylvinyloxyimino) acetic acid 5 was added. After adding 0.11 g (12.4 mmol) and cooling to -35 ° C, 7.9 ml (72 mmol) of N-methylmorpholine was added and melted. Further, 2.24 ml of phenylphosphoric acid dichloride was added and -20 to -35.
Stir at 80 ° C. for 80 minutes. 10% Citric acid is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The extract is washed with 5% sodium hydrogen carbonate and saturated brine, dried and the solvent is evaporated. The residue is subjected to silica gel column chromatography (toluene /
If purified with ethyl acetate = 3/1), 7β- [2- (2-
t-butoxycarbonylamino-4-thiazolyl) -2-
5.67 g of (1-t-butoxycarbonylvinyloxyimino) acetamido] -3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester are obtained. Yield: 57%.

¹ HNMR δ (CDCl ₃ ) ppm: 1.48 (s, 9H), 1.5
3 (s, 9H), 3.48, 3.63 (ABq, J = 18.5Hz, 2H), 3.82 (s, 3
H), 4.46, 4.51 (ABq, J = 13.0Hz, 2H), 5.06 (d, J = 5Hz,
1H), 5.21, 5.25 (ABq, J = 11.5Hz, 2H), 5.60 (d, J = 1.6H
z, 1H), 5.76 (d, J = 1.6Hz, 1H), 5.94 (dd, J = 5Hz, J = 8.
6Hz, 1H), 6.90 (d, J = 8.8Hz, 2H), 7.36 (d, J = 8.8Hz, 2
H), 7.46 (s, 1H), 7.99 (d, J = 8.6Hz, 1H), 8.44 (bs, 1
H).

2) R ¹ = diphenylmethyl 7β-amino-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester hydrochloride 53.1 g (purity: 97.0%: 0.127 mol) And 2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino) acetic acid dicyclohexylamine salt 99.4 g (0.141 mol) were suspended in 800 ml of dichloromethane and − After cooling to 35 ° C, N
-Methylmorpholine 42 ml (0.382 mol) is added to form a solution. 25 ml of phenylphosphoric acid dichloride in this solution
(0.167 mol) is added dropwise at -30 ° C or lower. -30
After stirring at ~ -25 ° C for 1.5 hours, 10% citric acid 200m
Add l and raise the temperature to 0 ° C. The reaction solution is concentrated under reduced pressure to remove dichloromethane, and 1.2 l of ethyl acetate and 700 ml of water are added. The organic layer was separated, 5% hydrochloric acid, 5
% Sodium hydrogencarbonate and saturated saline solution in that order, dried over magnesium sulfate, and evaporated to remove 7β- [2-
(2-t-butoxycarbonylamino-4-thiazolyl)-
2- (1-Diphenylmethoxycarbonylvinyloxyimino) acetamido] -3-chloromethyl-3-cephem-
A foamy residue of 4-carboxylic acid p-methoxybenzyl ester is obtained.

¹ HNMR δ (CDCl ₃ ) ppm:
1.53 (s, 9H), 3.25, 3.45 (A
Bq, J = 18.5 Hz, 2H), 3.80.
(S, 3H), 4.36, 4.58 (ABq,
J = 12 Hz, 2H), 4.84 (d, J = 5.
0Hz, 1H), 5.20, 5.24 (ABq,
J = 13 Hz, 2H), 5.69 (d, J =
2.0 Hz, 1H), 5.84 (dd, J = 8.
8Hz, J = 5.0Hz, 1H), 5.90 (d,
J = 2.0 Hz, 1H), 6.89 (d, J =
10Hz, 2H), 6.94 (s, 1H),
7.15-7.50 (m, 13H).

Production Example 2 Sulfoxidation

[Chemical 12]

1) R ¹ = t-butyl 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-t-butoxycarbonylvinyloxyimino) acetamido] -3-chloromethyl -3-Cephem
-4-carboxylic acid p-methoxybenzyl ester 3.38 g
(4.42 mmol) was dissolved in 35 ml of dichloromethane and cooled with dry ice-acetone to give 950 mg (4.40 mmol) of m-chloroperbenzoic acid (purity: 80%).
Add. After 10 minutes, the temperature was raised to -40 ° C, and the mixture was stirred at the same temperature for 40 minutes. 5% Sodium thiosulfate water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The extract was washed with water and saturated saline and the solvent was distilled off to give 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-t-butoxycarbonylvinyloxyimino) acetamide. ] -3-
3.23 g of chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 1-oxide are obtained. Yield: 94%. Colorless crystals.

¹ HNMR δ (CDCl ₃ ) ppm: 1.50 (s, 9H), 1.5
3 (s, 9H), 3.40, 3.77 (ABq, J = 18.0Hz, 2H), 3.82 (s, 3
H), 4.26, 5.00 (ABq, J = 15.0Hz, 2H), 4.65 (d, J = 5.0H
z, 1H), 5.24, 5.30 (ABq, J = 12.0Hz, 2H), 5.47 (d, J =
1.8Hz, 1H), 5.59 (d, J = 1.8Hz, 1H), 6.20 (dd, J = 5.0Hz,
J = 10.0Hz, 1H), 6.92 (d, J = 8.8Hz, 2H), 7.36 (d, J = 8.
8Hz, 2H), 7.39 (s, 1H), 7.79 (d, J = 10.0Hz, 1H), 8.88
(bs, 1H).

2) R ¹ = diphenylmethyl 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino) acetamido] -3-chloromethyl-3 -
Cephem-4-carboxylic acid p-methoxybenzyl ester was dissolved in 1 liter of dichloromethane, -70 to -75.
Cooled to ℃, m-chloroperbenzoic acid (Purity: 80%: 2
(7.4 g: 0.127 mol) is added in 4 to 5 portions.
After stirring at -60 to -55 ° C for 1 hour, 500 ml of 5% sodium thiosulfate was added and the mixture was stirred at 5 ° C or lower for about 15 minutes.
The residue obtained by distilling dichloromethane under reduced pressure from the reaction solution was dissolved in ethyl acetate, washed successively with water, 5% hydrochloric acid, 5% sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate and the solvent was distilled off. The residue was crystallized from ethyl acetate-ether to give 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxyimino) acetamide] -3-. 102 g (90.2%) of chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 1-oxide are obtained. Decomposes gradually from about 140 ° C.

¹ HNMR δ (CDCl ₃ ) ppm: 1.52 (S, 9H), 2.7
3, 3.37 (ABq, J = 19.5Hz, 2H), 3.80 (s, 3H), 4.12 (d, J
= 6.6Hz, 1H), 4.18, 4.94 (ABq, J = 13Hz, 2H), 5.20, 5.
31 (ABq, J = 12Hz, 2H), 5.52 (s, 1H), 5.73 (s, 1H), 6.1
5 (dd, J = 6.6Hz, J = 10Hz, 1H), 6.90 (d, J = 8.2Hz, 2H),
6.91 (s, 1H), 7.26 (s, 1H), 7.30-7.39 (m, 12H).

Production Example 3 Pyridyl thiolation

[Chemical 13]

1) R ¹ = t-butyl, n = 0 4-mercaptopyridine 113 mg (1.2 mmol) was dissolved in ethanol 2 ml and 1N sodium ethylate 1.0 ml (1.0 mmol) was added. In addition to sodium salt,
The solvent was distilled off, and the residue was dissolved in 2 ml of dimethylformamide,
Cool to 40 ° C. 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-t-butoxycarbonylvinyloxyimino) acetamide] -3-
Chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 764 mg (1.0 mmol) was added,
Stir for 50 minutes at -30 to -40 ° C. 5% Citric acid and ethyl acetate are added to the reaction solution. The organic layer is separated, washed with water and saturated brine, dried over magnesium sulfate, and evaporated to remove 7β- [2- (2-t-butoxycarbonylamino).
825 mg of -4-thiazolyl) -2- (1-t-butoxycarbonylvinyloxyimino) acetamido] -3- (pyridin-4-yl) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester are obtained. Yield: 98%. Foam.

¹ HNMR δ (CDCl ₃ ) ppm: 1.48 (s, 9H), 1.5
3 (s, 9H), 3.46, 3.59 (ABq, J = 18.0Hz, 2H), 3.81 (s, 3
H), 4.11, 4.21 (ABq, J = 14.0Hz, 2H), 5.02 (d, J = 5.0H
z, 1H), 5.22 (bs, 2H), 5.56 (d, J = 1.6Hz, 1H), 5.75
(d, J = 1.6Hz, 1H), 5.90 (dd, J = 5.0Hz, J = 10.0Hz, 1H),
6.89 (d, J = 9.0Hz, 2H), 7.12 (d, J = 6.4Hz, 2H), 7.35
(d, J = 9.0Hz, 2H), 7.45 (s, 1H), 8.00 (d, J = 10.0Hz, 1
H), 8.36 (d, J = 6.4Hz, 2H), 8.52 (bs, 1H).

2) R ¹ = t-butyl, n = 1 In the same manner as in the above example, 195 mg of 4-thiopyridone (1.75)
Mmol) and 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-t-butoxycarbonylvinyloxyimino) acetamido] -3-chloromethyl
From 7-β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- () from 3-14-cephem-4-carboxylic acid p-methoxybenzyl ester 1-oxide 1.14 g (1.46 mmol) There is obtained 1.24 g of 1-t-butoxycarbonylvinyloxyimino) acetamido] -3- (pyridin-4-yl) thiomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 1-oxide. Yield: 99
%.

¹ HNMR δ (CDCl ₃ ) ppm: 1.49 (s, 9H). 1.5
3 (s, 9H), 3.36, 3.83 (ABq, J = 20.0Hz, 2H), 3.80 (s, 3
H), 3.86, 4.58 (ABq, J = 14.0Hz, 2H), 4.60 (d, J = 5.0H
z, 1H), 5.24 (bs, 2H), 5.46 (d, J = 1.6Hz, 1H), 5.59
(d, J = 1.6Hz, 1H), 6.15 (dd, J = 5.0Hz, J = 10.0Hz, 1H),
6.89 (d, J = 8.8Hz, 2H), 7.07 (d, J = 6.2Hz, 2H), 7.36
(d, J = 8.8Hz, 2H), 7.39 (s, 1H), 7.75 (d, J = 10.0Hz, 1
H), 8.36 (d, J = 6.2Hz, 2H), 9.20 (bs, 1H).

3) R ¹ = diphenylmethyl, n = 1-4 mercaptopyridine 9.34 g (84 mmol) and sodium ethylate (1M solution: 77 ml) prepared by dissolving mercaptopyridine sodium salt in 40 ml of dimethylformamide. , -30 ℃, 7β- [2-
(2-t-butoxycarbonylamino-4-thiazolyl)-
2- (1-Diphenylmethoxycarbonylvinyloxyimino) acetamido] -3-chloromethyl-3-cephem-
4-Carboxylic acid p-methoxybenzyl ester 1-oxide 62.3 g (70 mmol) of dimethylformamide in 200 ml of solution was added, and the mixture was stirred at -30 to -20 ° C for 1 hour. 10% Citric acid and ethyl acetate are added to the reaction solution. The organic layer is separated, washed successively with diluted hydrochloric acid, water and saturated brine, dried and the solvent is distilled off. By purifying 68.5 g of the reddish brown residue by column chromatography (600 g of silica gel, ethyl acetate), 7β- [2- (2-t-butoxycarbonylamino-4-thiazolyl) -2- (1-diphenylmethoxycarbonylvinyloxy) was obtained. Imino) acetamido] -3- (4-pyridyl) thiomethyl-3-cephem-4-
52.2 g of carboxylic acid p-methoxybenzyl ester 1-oxide are obtained. Yield: 77.3%.

¹ HNMR δ (CDCl ₃ ) ppm: 1.51 (s, 9H), 2.7
3, 3.46 (ABq, J = 18Hz, 2H), 3.78 (s, 3H), 4.02 (d, J =
4.5Hz, 1H), 3.72, 4.52 (ABq, J = 11Hz, 2H), 5.19, 5.2
7 (ABq, J = 12Hz, 2H), 5.52 (d, J = 2.0Hz, 1H), 5.72 (d,
J = 2.0Hz, 1H), 6.10 (dd, J = 4.5Hz, J = 9.0Hz, 1H), 6.87
(d, J = 9.0Hz, 2H), 6.89 (s, 1H), 7.03 (d, J = 6.2 Hz, 2
H), 7.26 to 7.37 (m, 13H), 8.37
(D, J = 6.2Hz, 2H)

Antibacterial activity of the compounds described in the examples (MI
C) was determined by the agar dilution method at a bacterial concentration of 10 ⁶ cells / ml.

The antibacterial activity of the compound of the present invention determined in the same manner is shown in Table 1.

[Table 1] Antibacterial activity of Compound I Minimum inhibitory concentration (μg / ml) Test bacterial compound (R =) B. aureus Smith SR696 ¹⁾ SR3 ²⁾ Methyl (2nd) 0.8 0.013 0.05 Methyl ³⁾ 0.8 0.025 0.1 Ethyl 0.8 0.013 0.1 Isopropyl 0.8 0.01 0.2 Allyl 0.4 0.01 0.1 Cyclopropyl 0.8 0.013 0.1 Cyclopentyl 0.4 0.013 0.1 Hydroxyethyl 0.8 0.025 0.2 Hydroxyisopropyl 0.8 0.2 0.2 Carbamoylmethyl 0.4 0.013 0.1 Methylthioethyl 0.4 0.01 0.2 Sulfamoylethyl 0.8 0.01 0.1 Amino 0.4 0.013 0.2 Control ⁴⁾ 1.56 0.1 0.1 1) Klebsiella oxytoca SR696 2) Proteus bulgaris SR3 3) Unless otherwise specified, refers to the 4-position substituent. 4) Compounds described in JP-A-64-85

[Chemical 14]

[0123]

INDUSTRIAL APPLICABILITY The compound of the present invention represented by the formula I shows an excellent antibacterial action against various bacteria, especially Gram-negative bacteria, and can be used as a medicine, an animal drug, a bactericide, an antiseptic and the like. . The route of administration may be oral or parenteral, but parenteral administration is preferred.

Claims (6)

[Claims] 1. Formula I: (Wherein R is optionally substituted alkyl, alkenyl, cycloalkyl or amino; R ¹ and R ³ are independently hydrogen, an ester-forming group or a salt-forming group; R ² is optionally protected amino) Group; n represents 0 or 1), and carboxyvinyloxyiminocephalosporins. 2. R is an optionally substituted alkyl, cycloalkyl, alkenyl or amino, R ¹ is an alkali metal atom, R ² is an amino group, R ³ is a salt-forming group, and n is 0. Compound of. 3. The compound according to claim 2, wherein R is optionally substituted methyl or ethyl. 4. Formula II: The compound of claim 1 is prepared by starting from a compound represented by the formula (wherein R ³ is as defined above) and applying amidation, sulfoxidation, reduction of sulfoxide, pyridinithioation and deprotection in combination. Method. 5. An antibacterial composition containing the compound of claim 1 as an active ingredient. 6. A sterilizing or bacteriostatic method comprising contacting the compound of claim 1 with a bacterium.