JPS6052714B2 - Novel antibacterial compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel antibacterial compound, more specifically a compound having the general formula [1] [wherein R1 is a carboxyl group or a cyano group, and R2 is a hydrogen atom, a cyano group, a sulfamoyl group, or a lower alkyl group] group, lower alkoxy group, aroyl group, optionally substituted aryl group, optionally substituted monocyclic heterocyclic group, RCO1 or R-S(0)n=(in the formula R
represents a lower alkyl group which may have a hydroxyl group or may be interrupted by a heteroatom, and n represents 0.1 or 2.

), R3 is a hydrogen atom or a methoxy group, R4
represents a lower alkyl group which may have a hydroxyl group or may be interrupted by a heteroatom. ] The present invention relates to a novel cephalosporin derivative and a salt thereof.

The lower alkyl group in general formula [1] is a methyl group,
A straight chain or branched group having 1 to 6 carbon atoms such as an ethyl group, an isopropyl group, a butyl group, or a hexyl group is meant.A lower alkoxy group means a methoxy group, an ethoxy group, an isopropoxy group, or a butoxy group. It means a straight chain or branched chain having 1 to 6 carbon atoms.

In addition, monocyclic heterocyclic groups include pyrrolyl group, pyrrolidinyl group,
It means a 5- or 6-membered ring group containing a sulfur atom and/or a nitrogen atom, such as an imidazolyl group, a thienyl group, a thiadiazolyl group, a pyridyl group, and a piperidino group. Examples of the aroyl group include a benzoyl group, and examples of the aryl group include a phenyl group and a naphthyl group. The monocyclic heterocyclic group and aryl group may be substituted with a hydroxyl group, a lower alkyl group, or the like. Compound [1] provided by the present invention is a compound [1] of the CefI allosporin nucleus.
It is a chemically structurally completely new cephalosporin derivative in that it has a 1,3-dithiethane ring in its side chain, and it exhibits excellent antibacterial activity, making it promising as an antibacterial agent.

The antibacterial activity (minimum effective inhibitory concentration) of compound [1] in comparison with commercially available 7cefazoline (CEZ) is as follows. The compound [1] of the present invention exhibits antibacterial activity against a wide range of pathogenic bacteria, and as is clear from Table 1 above, it is particularly effective against several important pathogenic bacteria belonging to Gram-negative bacteria. .

Therefore, the compound [1] of the present invention is useful as a pharmaceutical, especially an antibacterial agent, a feed additive, a preservative, and the like. The compound [1] of the present invention is available as it is or as a salt thereof. Preferred salts include salts with pharmaceutically acceptable non-toxic bases, such as alkali metal salts such as sodium salts and potassium salts; ammonium salts, synchlohexylamine salts, cyclohexylamine salts, trimethylamine salts; Examples include salts with organic bases such as triethylamine salts, ethanolamine salts, ornithine salts, and lysine salts. The compound [1] of the present invention or a salt thereof is administered orally or parenterally as an antibacterial agent.

The dosage varies depending on symptoms, body weight, etc., but for adults it is usually about 250 to 3000 m9 per day, divided into 3 to 4 doses. Dosage forms suitable for administration include injections, tablets, capsules, and syrups, but these dosage forms must be prepared by adding excipients, preservatives, stabilizers, etc. used in manufacturing. , can be carried out by conventional methods.

According to the present invention, the compound [1] can be produced by the following method. First Method This method is shown by the following reaction formula.

(In the formula, R5 means a hydrogen atom or a protecting group for a carboxyl group.

Moreover, R,, R2, R3 and R4 have the above meanings. ) This method involves reacting a 7-aminocephalosporin derivative (formerly or its salt) with 4-(substituted-methylene)-1,3-dithiethane-2-carboxylic acid [] or a reactive derivative of the carboxylic acid to form a compound [ ] and R1 of the compound
is a carboxyl group having a protecting group and/or R5 is a carboxyl group protecting group, such as a trityl group, T
When it is an ert-butyl group, benzhydryl group, etc.,
This is then done by removing it.

In the reaction between the above compound [] and [], the compound [] can be converted into a reactive derivative of its carboxylic acid and then subjected to the reaction.

Suitable reactive derivatives include acid halides, mixed acid anhydrides, active esters, active amides, acid anhydrides, acid azides, and the like. When the compound [] is used in a free state, a condensing agent may be used. As a condensing agent, N, N
"-dicyclohexylcarbodiimide, N,N"-diethylcarbodiimide, etc. are suitable. Also, the compound []
When R1 is a carboxyl group, in order to avoid side reactions between these active groups and the compound [], these active groups may be protected in advance with a protecting group such as a tert-butyl group or a benzhydryl group. good.

The reaction between the compound [] and the compound [] or its reactive derivative is carried out under heating or cooling, but in the case where the compound [] in which R3 is a methoxy group is used as a raw material, this methoxy group is reacted during the reaction. In order to avoid epimerization, it is preferable to carry out the reaction at a low temperature, particularly at -20°C or lower.

4-(substituted-methylene)-1,
The cephalosporin compound [] having a 3-dithiethane-2-carboxamide group can then be led to the target compound [1] by removing the protecting group. Second method The compound of the present invention [1] can also be produced by the reaction of the following formula.

(In the formula, R6 represents an acetyl group or a carbamoyl group.

Moreover, R1, R2, R3 and R4 have the above meanings.
) This method uses 7β-[4-(substituted-methylene)-1,3
-dithietan-2-yl] carboxamidose cephalosporin derivative [] or a salt thereof with a 1H-tetrazole-5-thiol derivative [] or an alkali metal substituted for the hydrogen of its mercapto group. The reaction is carried out at room temperature to elevated temperature, usually in a solvent. The solvent is one that does not participate in this reaction, such as acetone, dimethylformamide, methanol, ethanol, water, or phosphate buffer, and these may be used in combination if necessary. The reaction is preferably carried out near neutrality. When using the 1H-tetrazole-5-thiol derivative [] in its free state as a starting material, it is best to carry out the reaction in the presence of a base such as alkali hydroxide, alkali carbonate, alkali hydrogen carbonate, trialkylamine, pyridine, dimethylaniline, etc. suitable. In order to isolate the product after the reaction is completed, the reaction solution is made acidic and the precipitated product is collected, or a method using solvent extraction is used. The production of the compound [1] of the present invention will be specifically explained below with reference to Examples.

Example 1 (a) 4-[1-(Tert-butoxycarbonyl)ethylidene]-1,3-dithiethane-2-carboxylic acid 0.
340 da and 0.206 y of pyridine in methylene chloride 15
Dissolve in m1.

Phosphorus pentachloride 0.284 while stirring while cooling in an ice water bath.
Add y. The reaction was carried out for 1 hour at 10°C or lower, and then the reaction solution was cooled to -50°C, and 7β-amino-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cephemu-4-carboxylic acid benzhydryl ester 0 A solution of .690y dissolved in 10 mt of methylene chloride is added dropwise.

Then, 1.6 ml of pyridine was added dropwise for 1 hour.
React at 40°C. After the reaction is completed, 10 ml of 5N hydrochloric acid is added dropwise at 0° C. or lower, and the mixture is extracted with methylene chloride. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous calcium chloride, and methylene chloride was distilled off to obtain a residue 1.1y. This was subjected to silica gel column chromatography, and a caramel-like 7β-(4-[1-(T
ert-butoxycarbonyl)ethylidene]-1,3-
0.490y (yield: 47%) of dithietan-2-yl) carboxamide 7α-methoxy 3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cefemu 4-carboxylic acid benzhydryl ester is obtained. Nuclear magnetic resonance spectrum (D6-DMSO) δ (Ppm); 1.4
4(9H..tert-butyl)3.49(3H,...
...0CH3) (b) 0.44y of the product obtained in (a) is dissolved in 25ml of anisole, and 7.5ml of trifluoroacetic acid is added dropwise while cooling to below 5°C with ice water.

The reaction is carried out at 5 to 10°C for 1 hour, and then anisole and excess trifluoroacetic acid are distilled off under reduced pressure, and ether is added to the residue to powder it.

After cleaning, thoroughly wash with ether to obtain pale yellow powdered 7β.
-[4-(1-carboxyethylidene)-1,3-dithietan-2-yl]carboxamide 7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cefemu-4-carboxylic acid 0.271y (yield 867%). Nuclear magnetic resonance spectrum (D6-DM
SO) Infrared spectrum (KBr) (Cm-1) 1870 (lactam) Production of raw materials 40 ml of dimethoxyethane, which had been previously distilled to remove oxygen, and 10 ml of tetrahydrofuran were placed in a 100 ml three-necked flask and heated in a dry ice acetone bath in a nitrogen stream. -70
After cooling to below 0.degree. C., 1 mt of N-isopropylcyclohexylamine and 3.43 ml of 15% n-butyllithium (n-hexane solution) are added.

Next, 0.65 y of tert-butyl propionate is added, and while stirring, reaction is carried out at -7 (s) or less for about 3 minutes. Add 0.332 ml of carbon disulfide to the reaction solution at -75 to -73
It takes about 3 drops to add at ℃. The mixture was allowed to react for 10 minutes at -70°C or lower, and then 3.4 ml of 15% n-butyllithium (n-hexane solution) was added dropwise at -70°C or lower in about 3 drops.

1. After reacting at -70°C or lower, add 0.24y of 50% sodium hydride (oil-based) and 1.56y of short acetic acid in advance.
Short sodium acetate obtained by reacting y in dimethoxyethane under ice cooling is added, and the mixture is returned to room temperature and stirred overnight.

The solvent of the reaction solution was distilled off under reduced pressure, and the residue was added with cold ether, acidified with 1N hydrochloric acid, and extracted. The ether extract was thoroughly washed with a cold saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the ether was distilled off to form a brown oil.
．． Get 42y. This was subjected to silica gel column chromatography, and oily 4-
(1-Tel-butoxycarbonylethylidene)-1,
0.5y of 3-dithiethane-2-carboxylic acid is obtained. Nuclear magnetic resonance spectrum (D6-DMSO) δ (Ppm); 1
．． 42 (9H..tert-butyl) infrared spectrum (
Cffl-1) 2970 (Tert-butyl) 2520-2650 (-COOH) 1640-1740 (-COO-Tel-butyl, -C
OOH) 1360, 12501840 (Tert-butyl) Example 2 (a) 7β-amino-7α-methoxy 3
-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cephemu 4-carboxylic acid benzhydryl ester 0.7y and 4-[(Tert-butoxycarbonyl)
Dissolve 0.35 y of (methoxy)methylene]-1,3-dithiethane-2-carboxylic acid in 5 ml of tetrahydrofuran, add 0.3 y of synchhexylcarbodiimide under ice cooling, and stir at room temperature for 2 hours to remove insoluble materials. Concentrate the p solution under reduced pressure.

The residue was subjected to column chromatography to obtain 7β(4-(Tert-butoxycarbonyl)(methoxy)methylene)-1,3-dithiethane-2- using a benzene-ethyl acetate mixture (volume ratio 85:15) as the eluent. )
Carboxamide 7α-methoxy 3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cephemu 4-carboxylic acid benzhydryl ester 0.36f is obtained. Nuclear magnetic resonance spectrum (CDCl3) δ (Ppm); 1.50 (9H..tert-butyl)
3.59(3H)C,...0CH3 and V1-
ViV\
．． ．． E. 3(b) The product obtained in (a) 0.
Dissolve 23y in 1.7ml of anisole, -5 to -10
While cooling to 0.degree. C., 5.1 ml of trifluoroacetic acid is gradually added and stirred at 0 to 8 degrees Celsius.

The reaction solution was concentrated under reduced pressure, ether was added to the residue, and the resulting slightly brown powder was collected. After thorough washing with ether and drying under reduced pressure, 7β-(4-[(carboxy)(methoxy)methylene]-1,3-dithiethane-2-yl)carboxamide 7α-methoxy3-(1-methyltetrazol-5-yl) was obtained. ) Thiomethyl-Δ3-cefemu4-
0.12f of carboxylic acid is obtained. Nuclear magnetic resonance spectrum (
D6-DMSO) (a) 7β-amino-7α-methoxy 3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cefemu 4-carboxylic acid benzhydryl ester 0.8y and 4-[(benzoyl)(Tert-butoxy) 0.8y of carbonyl)methylene]-1,3-dithiethane-2-carboxylic acid was treated in the same manner as in Example 2-(a) to obtain 7β-(4-[(benzoyl)(Tert-butoxycarbonyl)methylene]-1 ,3-dithiethane-2
-yl) carboxamide 7α-methoxy 3-(1-
methyltetrazol-5-yl)thiomethyl-Δ3-cephemu-4-carboxylic acid benzhydryl ester 0.3
Get 5y.

Nuclear magnetic resonance spectrum (CDCl3) (a) 4-[(Tert-butoxycarbonyl)(methylthio)methylene]-1,3-dithiethane-2-carboxylic acid 0.3y1 synchrohexylcarbodiimide 0.
2y and 7β-amino-7α-methoxy-3-(1-methyltetrazol-5-y(b)) 0.23y of the product obtained in (a) was treated in the same manner as in Example 2-(b) to give 7β- (4-[(benzoyl)(carboxy)methylene]-1,3-dithiethane-2-yl)carboxamide 7α-methoxy3-(1-methyltetrazole-5-
yl)thiomethyl-Δ3-cefemu-4-carboxylic acid 0
．． 13f is obtained.

Nuclear magnetic resonance spectrum (D6-DMSO) δ (Ppm)
;3.46(3H1...0CH3)thiomethyl-Δ3-cefemu 4-carboxylic acid benzhydryl ester (0.5y) is dissolved in 10ml of anhydrous tetrahydrofuran and stirred at room temperature for 1 hour.

The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and 7β-(4-[(Ter
t-butoxycarbonyl)(methylthio)methylene]-
1,3-dithietan-2-yl)carboxamide 7α
-Methoxy3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cefemu 4-carboxylic acid benzhydryl ester 0.3y is obtained. Nuclear magnetic resonance spectrum (CDCl3) δ (Ppm); 1.52 (9H, tert-butyl)
(b) Dissolve 0.3y of the product obtained in (a) in 1.5mt- of anisole and stir at -5°C to produce triple (a) 4-[(Tert-butoxycarbonyl)(ethylthio)methylene]-1 , 3-dithiethane-2-carboxylic acid 0.15y1 synchhexyl carposi. imide 0.1q and 7β-amino-7α-methoxy 3-(1
-Methyltetrazol-5-yl)thiomethyl-Δ3-
Cefemu 4-carboxylic acid benzhydryl ester 0.
26y was treated in the same manner as in Example 4-(a) to obtain 7β-(4
-[(Tert-・butoxycarbonyl)(ethylthio)methylene]-1,3-dithietan-2-yl)carboxamide 7α-methoxy3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-*5 ml of oral acetic acid - Add dropwise at 5--3°C, then stir at 0-3°C for 1 hour.

Evaporate to dryness under reduced pressure, add ether to the residue, take it off, and wash thoroughly with ether. Vacuum drying over phosphorous pentoxide overnight gave 7β-(4-[(carboxy)(methylthio)methylene]-1,3-dithiethane-2-yl)carboxamide 7α-methoxy-3-(1-methyltetrazol-5-yl). ) 0.17y of thiomethyl-Δ3-cefemu-4-carboxylic acid is obtained. Nuclear magnetic resonance spectrum (D6-
DMSO) Cefemu 4-carboxylic acid benzhydryl ester 0.14y is obtained.

Nuclear magnetic resonance spectrum (CDCl3) δ (Ppm): 1.22 (3H1CHICH2S-)1
．． 52 (9H.Stert-Butyl) 2.68 (2H.
．． CH3C milk S-) 3.58 (5H,.C2 -CH2- and...
・0CH3) 3.82 (3H1...0CH3)4.
38 (2H..C3-ClI2S-)
S4.7O (1H1-go7CH-) S 5.08 (1H,.C6 H) 6.92 (1H1-CU(C6H5)2) 7.32 (1
0H1-CH(C6?)2)7.79(1H1-CON
H-) (b) Example 4-
7β-(4-[(carboxy)
(ethylthio)methylene]-1,3-dithiethane-2-
0.07y of carboxamide 7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cephemu-4-carboxylic acid is obtained.

Nuclear magnetic resonance spectrum (D6-DMSO) δ (Ppm)
;1.14(3H,CH3CH2S-)2.62(2H
、． CH3C River S-) 3.43 (3H1...0
CH3) 3.61 (2H, -CH2- of .C2) 4.28 (-CH2S- of 2H, .C3) 5.08 (1
H. ．． H at C6) 9.64 (1H1-00NH-) Example 6 (a) 7β-amino-7α-methoxy 3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cefemu 4-carboxylic acid benzhydryl ester 0. 43y
was dissolved in 12 ml of methylene chloride, cooled to -40°C, and 0.65 y of pyridine was added.

Next, 0.2 g of 4-(dicyanomethylene)-1,3-dithiethane-2-carboxylic acid was dissolved in 8 ml of methylene chloride, 0.21 y of phosphorus pentachloride was added, and the two powders were stirred at room temperature. Dropped at -25℃, -30℃
Stir at ~-20°C for 1 hour. After the reaction, 60 ml of chloroform is added, and the mixture is washed with 1% hydrochloric acid, water, and then a saturated aqueous sodium chloride solution, and the organic layer is dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 7β-[4-(dicyanomethylene)-1,3-dithiethane- 2-yl]carboxamide 7α-methoxy 3-
(1-methyltetrazol-5-yl)thiomethyl-Δ
0.37 g of 3-cefemu-4-carboxylic acid benzhydryl ester is obtained. Nuclear magnetic resonance spectrum (CDCl3
) δ (Ppm); 3.54 (5H, -CH2- of C2 and
・・・・・・・・・0CH3)4.30(2H,C3-
CH2S-) 6.90 (1H, -CH(C6H5)2) 7.30 (1
0H, -CH(C6H5)2) (b) 0.37 g of the product obtained in (a) is dissolved in 10 ml of methylene chloride, 0.5 ml of anisole is added and the mixture is cooled to -20°C.

2 ml of trifluoroacetic acid was added dropwise at -20 to -10°C,
Stir for 30 minutes at -10 to -5°C. The solvent was distilled off under reduced pressure, 20 ml of ether was added to the residue, and the mixture was stirred for 30 minutes. The resulting precipitate was then filtered under reduced pressure, and the resulting precipitate was thoroughly washed with ether and dried under reduced pressure to obtain 7β-[4-(dicyanomethylene)-1,3-dithiethane-2-yl]carboxamide 7α-methoxy 3-(1- Methyltetrazole-5
-yl)thiomethyl-Δ3-cephemu-4-carboxylic acid 0.21 V is obtained. Nuclear magnetic resonance spectrum (D6-DM
SO) δ (Ppm): 3.44 (3H1...0CH
3) 3.64 (2H, C2 -CH2-) 4.30 (2
H, C3 -CH2S-) 5.18 (1H, C6 H) Example 7 (a) 4-(Tert-butoxycarbonylmethylene)
Dissolve 0.714y of -1,3-dithiethane-2-carboxylic acid in 20ml of methylene chloride, and dissolve 0.454g of pyridine.
is added and cooled to below 5°C, 0.630f of phosphorus pentachloride is added and reacted at below 10°C for 1 hour.

The reaction solution was cooled to about -50°C, and 1.5y of 7β-amino-7α-methoxy3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cefemu-4-carboxylic acid benzhydryl ester was dissolved in 15ml of methylene chloride. Drop the solution. Then add 3 ml of pyridine and-
React at 30 to -35 for 1 hour. After the reaction is completed, 20 ml of 6N hydrochloric acid is added at a temperature below 0°C. The methylene chloride layer is separated, and the aqueous layer is further extracted with 20 mL of methylene chloride. Combine the methylene chloride layer 1 and add 20 ml of saturated sodium chloride aqueous solution.
mL twice, dried over anhydrous magnesium sulfate, and distilled off the solvent to obtain brown caramel 1.89f. This was subjected to silica gel column chromatography using a mixture of ethyl acetate and n-hexane (volume ratio 2:1) as an eluent to 7β-[(4-Tert-butoxycarbonylmethylene)-1,3-dithiethane-2-yl. ] 0.308 q of carboxamide 7α-methoxy 3-(1-methyltetrazol-5-ylthiomethyl)-Δ3-cephemu 4-carboxylic acid benzhydryl ester is obtained. Nuclear magnetic resonance spectrum (D6-DMSO) δ (Ppm); 1
．． 40 (9H, tert-butyl) 3.44 (3H, ・
・・・・・・・・・0CH3)5.23(1H, H of C6
)6.88(1H, -CH(C6H3)2)9.66(
1H, -CONH-) (b) Dissolve 0.3 g of the product obtained in (a) in 1.7 nt of anisole, cool to below -5°C, and add 5.1 ml of trifluoroacetic acid dropwise at below 0°C. .

After the completion of the dropwise addition, the 3 powders were reacted at 0 to 5°C, then 5 to 10°C.
Incubate at ℃ for 3 minutes. After the reaction solution was finished, anisole and trifluoroacetic acid were distilled off under reduced pressure, ether was added to the residue to make it into a powder, and the mixture was thoroughly washed with ether and dried to give a pale yellow powder of 7β-[4-(carboxymethylene)-1, 3-
dithietan-2-yl]carboxamide 7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cefemu-4-carboxylic acid 0.1584 g
get.

Nuclear magnetic resonance spectrum (D6-DMSO) 0●υυ(1
Production method of raw materials for AA~υυA1 80 ml of dimethoxyethane, which had been distilled in advance to remove oxygen, and 20 ml of tetrahydrofuran, cooled to below -70 in a nitrogen stream, and 2 ml of N-isopropylcyclohexylamine.
1 and 15% n-butyllithium (n-hexane solution) 6
．． 86 ml and then 1.16 g of tert-butyl acetate are added dropwise.

React at -70℃ or below for 30 minutes, carbon disulfide 0.66
Add 4 nt for about 3 minutes at -72°C or below.

The reaction solution turned pale yellow. After reacting the two powders at below 70°C, 15% n-butyllithium (n-hexane solution) was added to 15,+(a)7β-amino-7α- at below -JmoVC. Methoxy-3-(1-methyltetrazol-5-yl)thiomethyl. 0.32f of Δ3-cefemu 4-carboxylic acid benzhydryl ester is dissolved in 8ml of methylene chloride, cooled to -30°C, and 0.48y of pyridine is added.
Then 4-[(Tert-butoxycarbonyl)(methylsulfonyl)methylene]-1,3-dithiethane-2-
Dissolve 0.37 g of carboxylic acid in 8 ml of methylene chloride,
A solution prepared from 0.25y of phosphorus pentachloride and 0.18y of pyridine is added dropwise at -40 to -30°C. -30 to -20
Stir at ℃ for 1 hour and add dropwise over 7 minutes. After the dropwise addition, the two powders were reacted at -70°C or lower to form one part of dimethoxyethane.
5T! Add a short sodium acetate crystal precipitate synthesized from 0.48y of 50% sodium hydride and 3.12y of short acetic acid in LL. Return to room temperature and allow to react overnight.
50ml of cold ether was added to the dark brown oil obtained by distilling off the solvent.
Add 20 ml of 1 and 1N hydrochloric acid for extraction. The aqueous layer is further extracted with 30 ml of cold ether, and the ether layers are combined and washed twice with 30 ml of saturated aqueous sodium chloride solution. Dry over anhydrous magnesium sulfate and distill off the ether to obtain brown oil 3f1. This was subjected to silica gel column chromatography using a chloroform-methanol-formic acid mixture (volume ratio 95:5:2) as an eluent.
-(Tert-butoxycarbonylmethylene)-1,3
-dithiethane-2-carboxylic acid 0.564q is obtained. After nuclear magnetic resonance spectroscopy (D6-DMSO), 50 mt of chloroform is added, washed with 1% hydrochloric acid, water, then saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 7β-(4
-[(Tert-butoxycarbonyl)(methylsulfonyl)methylene]-1,3-dithietan-2-yl)carboxamide 7α-methoxy3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cefemu 4
-0.25y of carboxylic acid benzhydryl ester is obtained. Nuclear magnetic resonance spectrum (CDCl3) (b) The raw I6.2y obtained in (a) was anisole 2
．． 5nt5, cooled to -20°C, added 10mt of trifluoroacetic acid dropwise at -20 to -10°C, stirred two powders at the same temperature, and then stirred four powders at 10°C.

The solvent was distilled off under reduced pressure, and 30 ml of ether was added to the residue to give 0.6 y of 4-(α-Tert-butoxycarbonyl-4-Tert-butoxybenzylidene)-1,3-dithiethane-2-carboxylic acid. methylene chloride 1.
Dissolve the solution in 5 ml, add 0.2 mL of pyridine, then add 0.285 y of phosphorus pentachloride under ice cooling and stir for 7 minutes. Zeru. This solution was mixed with 7β-amino-7α-methoxy 3-(
1-methyltetrazol-5-yl)thiomethyl-Δ3
-Cefemu 4-carboxylic acid benzhydryl ester 0
．． Dissolve 5V in 15ml of methylene chloride and -30 to -40
Add to the solution obtained by adding 0.45 ml of pyridine cooled to 0.degree. C., and stir the two powders at that temperature. Add 60 ml of chloroform to the reaction solution, add about 30 ml of water, and about 3 ml of 1-2% hydrochloric acid.
Wash with 0 ml then 30 ml of water and stir for * minutes with anhydrous magnesium sulfate. Next is decompression? The precipitate obtained was thoroughly washed with ether and dried under reduced pressure to obtain 7β-(
4-[(carboxy)(methylsulfonyl)methylene]
-1,3-dithietan-2-yl)carboxamide 7
α-Methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cephemu-4-carboxylic acid 0.
Get 08y. Nuclear magnetic resonance spectrum (D6-DMSO
) After drying, the solvent is distilled off under reduced pressure.

The residue was subjected to silica gel column chromatography,
As an eluent, a benzene-ethyl acetate mixture (volume ratio 11:
2) using 7β-[4-(α-TerL-butoxycarbonyl-4-Tert-butoxybenzylidene)-1
,3-dithietan-2-yl]carboxamide 7α-
Methoxy-3-(1-methyltetrazol-5-yl)
0.4y of thiomethyl-Δ3-cephemu 4-carboxylic acid benzhydryl ester is obtained. Nuclear magnetic resonance spectrum (CDCl3) δ (Ppm): 1.35 (9H) Tel-butyl
1.47 (9H) 3.60 (5H1...0CH3 and -CH2- of C2) 7.15 (2H) (b) 0.4y of the product obtained in (a) was mixed with 10ml of trifluoroacetic acid and anisole. Dissolve the mixture with 2mt under ice cooling and stir at 10°C for about 3 minutes.

The solvent was distilled off under reduced pressure, and 40 ml of ether was added to the residue.
The resulting precipitate was collected and then washed with ether to obtain 7β-
[4-(α-carboxy4-hydroxybenzylidene)-1,3-dithietan-2-yl]carboxamide 7α-methoxy3-(1-methyltetrazole-5-
About 0.2 f of yl)thiomethyl-Δ3-cephemu-4-carboxylic acid is obtained. Nuclear magnetic resonance spectrum (D6-DMS
O) Example 10 (a) 4-(α-Tert-butoxycarbonylbenzylidene)-1,3-dithiethane-2-carboxylic acid 0.5
Dissolve y in 15mt of methylene chloride, and add 0.2m of pyridine.
Add t, further dissolve, add 0.2 mt of pyridine, and further add 0.285 y of phosphorus pentachloride under ice cooling, and stir for about 2 minutes.

The following procedure was carried out in the same manner as in Example 9-(a), except that the eluent used for silica gel column chromatography was a benzene-ethyl acetate mixture (volume ratio 9:2).
4-(α-Tert-butoxycarbonylbenzylidene)-1,3-dithietan-2-yl]carboxamide 7α-methoxy 3-(1-methyltetrazole-5-
Approximately 0.4 g of 4-carboxylic acid benzhydryl ester is obtained. Nuclear magnetic resonance spectrum (CDCl3) (b) obtained in (a); product 0.4 blue Example 9-(b
) to give 7β-[4-(α-carboxybenzylidene)-1,3-dithietan-2-yl]carboxamide 7α-methoxy3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cephemu 4 - About 0.2y of carboxylic acid is obtained.

Nuclear magnetic resonance spectrum (D6-DMSO) (a) 4-[
(Acetyl)(Tert-butoxycarbonyl)methyln]-1,3-dithiethane-2-carboxylic acid 0.87f
Dissolved in 15 ml of methylene chloride, -pyridine 0.47
4y of phosphorus pentachloride was added under ice-cooling, and the mixture was stirred for 30 minutes.

This solution was mixed with 0.6% of 7β-amino-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cephemu-4-carboxylic acid benzhydryl ester.
y was dissolved in 20 ml of methylene chloride, cooled to -30'C, added to the solution obtained by adding pyridine, and stirred at that temperature for 1 hour. To the reaction solution were added 10 m of water, 11 L of normal hydrochloric acid, and 30 ml of chloroform, and the chloroform layer was washed with 1% hydrochloric acid until pyridine disappeared, then water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and 7β-(4-[(acetyl)(Tert-butoxycarbonyl)methylene]-1,3- dithietan-2-yl)carboxamide 7α-methoxy3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cephemu 4-carboxylic acid benzhydryl ester 0.55q
get. Nuclear magnetic resonance spectrum (CDCl3) ●● & WiV cheer●υv\AV-ー)\-V: NicoLIΩ
(b) Dissolve 0.55y of the product obtained in (a) in a mixed solution of 12 ml of trifluoroacetic acid and 3 ml of anisole at -5°C, and stir the two powders at 15°C.

The solvent was distilled off under reduced pressure, and 20 ml of ether was added to the residue.
Offshore the resulting sediment. Wash with ether to obtain 7β-(4
-1[(acetyl)(carboxy)methylene]-1,3-
0.33 V of dithietan-2-yl)carboxamide 7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cephemu-4-carboxylic acid is obtained. Nuclear magnetic resonance spectrum (D6-DMSO) (a) 4
- [(Tert-butoxycarbonyl)(5-methylthio1,3,4-thiadiazol-2-yl)methylene]-1,3-dithiethane-2-carboxylic acid (1.1 y) was dissolved in 20 ml of methylene chloride, and pyridine (0.462 y) was dissolved in it. In addition, 0.606 y of phosphorus pentachloride was added under ice-cooling, and the mixture was stirred for 3 minutes.

This solution was added to 7β-amino-7α-methoxy 3-(1
-Methyltetrazol-5-yl)thiomethyl-Δ3-
Cefemu 4-carboxylic acid benzhydryl ester 0.
9y was dissolved in 30 ml of methylene chloride, cooled to -30°C, added to the solution obtained by adding 0.75 mt of pyridine, and stirred at that temperature for 1 hour. After adding 10 ml of water and 40 ml of chloroform to the reaction solution, the chloroform layer was washed with 1% hydrochloric acid until pyridine disappeared, then water, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and 7β-(4-[(Tert-butoxycarbonyl)
(5-methylthio1,3,4-thiadiazole-2-
yl)methylene]-1,3-dithiethane-2-yl)carboxamide 7α-methoxy 3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cephemu 4-carboxylic acid benzhydryl ester 0.2y is obtained. Nuclear magnetic resonance spectrum (CDCl3) δ (Ppm); 1.58 (9H..tert-butyl)
(b) 0.2 of the product obtained in (a)? Dissolve in a mixture of 8 mt of trifluoroacetic acid and 2 ml of anisole at -5°C, and stir at 17-18°C for 1 hour.

The solvent was distilled off under reduced pressure, and 20 ml of ether was added to the residue.
Collect the resulting precipitate overnight. Wash with ether to obtain 7β-(4
-[(carboxy)(5-methylthio1,3,4-thiadiazol-2-yl)methylene]-1,3-dithiethane-2-yl)carboxamide 7α-methoxy 3
0.05y of -(1-methyltetrazol-5-yl)thiomethyl-Δ3-cephemu-4-carboxylic acid is obtained. Nuclear magnetic resonance spectrum (D6-DMSO) (a) 4-[(
Benzhydryloxycarbonyl) (sulfamoyl)
Methylene]-1,3-dithiethane-2-carboxylic acid 0.
2y17β-amino-7α-methoxy 3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cefemu 4-carboxylic acid benzhydryl ester 0.25y
and 0.1 y of synchhexylcarbodiimide were dissolved in 12 ml of anhydrous tetrahydrofuran and stirred overnight at room temperature.

Insoluble matter was removed, and the solvent of the licorice was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography using a chloroform-isopropanol mixture (volume ratio 9:
1) using Thiomethyl-Δ3-cefemu 4-carboxylic acid benzhydryl ester 0.095V is obtained. (b) Dissolve 0.095q of the product obtained in (a) in 10ml of methylene chloride,
Add 0.5 ml of anisole and cool to -200C.

2 mt of trifluoroacetic acid was added dropwise at -20 to -15°C, and the mixture was stirred at the same temperature.
butoxycarbonyl)(3-pyridyl)methylene]-1
, 800 ml of 3-dithiethane-2-carboxylic acid was dissolved in 40 ml of dichloromethane, and then 0.3 ml of pyridine was dissolved.
Add 440 mg of phosphorus pentachloride under ice cooling, stir for about 15 minutes, and then stir at 0 to 3°C for 1 hour. The solvent was distilled off under reduced pressure, and 15 ml of ether was added to the residue.
Stir up the confusion. It was then filtered under reduced pressure, and the resulting precipitate was thoroughly washed and dried under reduced pressure to give 7β-(4-[(carboxy)(sulfamoyl)methylene]-1,3-dithiethan-2-yl)carboxamide 7α-methoxy3. −(
1-methyltetrazol-5-yl)thiomethyl-Δ3
-0.034f of cefhemu 4-carboxylic acid is obtained. Nuclear Magnetic Resonance Spectrum (D6-DMSO) Mix.

This solution was added to 7β-amino-7α-methoxy 3-(1-
methyltetrazol-5-yl)thiomethyl-Δ3-cephemu-4-carboxylic acid benzhydryl ester 0.8
Dissolve f in 25 mt of dichloromethane, add to a solution containing 0.7 Tnt of pyridine at -30°C, and stir the mixture at that temperature to complete the reaction. Next, 200 ml of chloroform is added to the reaction solution, washed twice with 150 ml of 1.3% acetic acid aqueous solution, and further washed twice with 100 ml of water, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography using benzene-ethyl acetate (volume ratio 2:1) as an eluent.
7β-(4-[(Tert-butoxycarbonyl)(3
400 m
I got a 9. NMR spectrum (CDCl3) (b) Trifluoroacetic acid 15ml and anisole 3ml
7β-(4-[(Tert-butoxycarbonyl)(3-pyridyl)methylene]-1,3-dithiethane-2-yl)carboxamide 7α-methoxy3-(1-methyltetra** 400 m9 of sol-5-yl)thiomethyl-Δ3-cephemu-4-carboxylic acid benzhydryl ester are dissolved and stirred at 10-15°C for 40 minutes.

After distilling off the solvent under reduced pressure, about 50 ml of ether was added, and the resulting precipitate was collected and washed with ether.
7β-(4-[(carboxy)(
Approximately 100 m9 of 3-pyridyl)methylene-1,3-dithietan-2-yl)carboxamide 7α-methoxy 3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cephemu 4-carboxylic acid were obtained. NMR spectrum (D6-DMSO) Acid 610TrL9 was dissolved in 15mt of tetrahydrofuran, and 7β-amino-7α
-Methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cefemu-4-carboxylic acid benzhydryl ester 1.05y,. Add 0.5y of N,N''-dicyclohexylcarbodiimide and react at room temperature for 2 hours.

After the reaction, the precipitated urea was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting caramel was dissolved in 50 ml of ethyl acetate, and 1N
The ethyl acetate layer obtained by washing with 30 mL of monohydrochloric acid and then with water was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 450 m9 of brown caramel. Using a column packed with silica gel 30y, first benzene was used as the effluent solvent, then benzene-ethyl acetate (95:5), and then benzene-ethyl acetate (90:10) were used to collect the fraction containing the target product.
β-(4-(1-Tert-butoxycarbonylpropylidene)-1,3-dithietan-2-yl)carboxamide 7α-methoxy3-(1-methyltetrazol-5-yl)thiomethyl-Δ3-cefemu-4-carboxylic acid Obtain benzhydryl ester.

NMR spectrum (CDCl3) (b) 7β-(4-(1-Tert-butoxycarbonylpropylidene)-1,3-dithiethane-2-yl)carboxamide 7α-methoxy 3-(1-methyltetrazol-5-yl) Thiomethyl-Δ3-cefemu4
- 200 m9 of carboxylic acid benzhydryl ester is dissolved in 1.1 m1 of anisole and cooled to around 5°C in an ice water bath.

3.3 ml of trifluoroacetic acid is added dropwise to the solution at a temperature below 10°C. After the dropwise addition was completed, the mixture was stirred and reacted at 5 to 10° C. for one hour. Next, 10 mt of water was added to the residue obtained by distilling off anisole and excess trifluoroacetic acid at room temperature or below under reduced pressure.
Extract with n-butyl alcohol/ethyl acetate (1:1 mixture). The organic layer was washed with saturated sodium chloride water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the resulting residue, 10 ml of ether was added and powdered to obtain 7β.
-(4-(Carboxypropylidene)-1,3-dithiethane-2-yl)carboxamide 7α-methoxy 3
54m9 of -(1-methyltetrazol-5-yl)thiomethyl-Δ3-cefemu-4-carboxylic acid is obtained. N.M.
R spectrum (D6-DMSO) 9.60 (1H1-N
UCO-) Reference Example 4-(1-Tel-butoxycarbonylpropylidene)-1,3-dithiethanecarboxylic acid used in Example 15 was produced by the following method.

Dimethoxyethane 120ml, tetrahydrofuran 30ml
The mixture of 1 ml was cooled to -74°C, and 4.0 ml of isopropylcyclohexylamine was added, followed by n-butyllithium (1 ml).
Add 13.72TfLt (5% n-hexane solution).
(The temperature rose from -73℃ to 62℃.)Te butyrate
Add 3.17f of rt-butyl and mix 3 times, -74 to -75
After reacting at °C, 664 μe of carbon disulfide was added dropwise over about 10 minutes, and the two powders were reacted at that temperature. Then n-
Butyllithium (15% n-hexane solution) 6.86m
After adding 1 dropwise to -Jmo VC or less, 332 μe of carbon disulfide reacted with 3 powders was added in the same manner, and after the 2 powder reaction, n-butyllithium (15% n - Hexane solution) 3.43 nt between 1 powder - 72% c or less after dropping 2
The reaction was carried out at -74 to -7 JC. Also carbon disulfide 1
66μe was added for 6 minutes at around -74°C. After about 2 powders of reaction, short sodium acetate salt prepared in advance from 0.84 f of 50% sodium hydride and 5.46 y of short acetic acid in 25 ml of dimethoxyethane is added. After addition 0~+
After reacting at 5° C. for 3 days, the reaction was allowed to proceed overnight at room temperature.
The solvent was distilled off under reduced pressure, and 50 ml of cold ether and 40 ml of cold 1N monohydrochloric acid aqueous solution were added to the residue for extraction. The obtained ether layer was extracted twice with 20 ml of saturated sodium bicarbonate water to obtain an aqueous layer. Furthermore, the aqueous layer was extracted with 1N monohydrochloric acid as PHL and extracted twice with 30 ml and 20 ml of ether, and then washed with water.
After drying over anhydrous magnesium sulfate, the ether was distilled off to obtain 1.08q of an oily product. If this oily substance is collected by silica gel column chromatography (emitted with a 10:1 mixed solvent of chloroformrimethanol and dichloromethane), the title compound 630Tf is obtained as a brown oil.
Obtain L9.

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. group, an optionally substituted aryl group, an optionally substituted monocyclic heterocyclic group,
RCO- or R-S(O)_n- (in the formula, R is a lower alkyl group which may have a hydroxyl group or may be interrupted by a hetero atom; n represents 0, 1 or 2) A group represented by R_3 is a hydrogen atom or a methoxy group, R
_4 represents a lower alkyl group which may have a hydroxyl group or may be interrupted by a hetero atom. ] Cephalosporin derivatives and salts thereof. 2 7β-[4-(1-carboxyethylidene)-1,
The cephalosporin according to claim 1, which is 3-dithiethan-2-yl]carboxamide-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-Δ^3-cephem-4-carboxylic acid. derivative. 3 7β-{4-[(carboxy)(methoxy)methylene]-1,3-dithiethane-2-yl}carboxamide-7α-methoxy-3-(1-methyltetrazol-5
2. The cephalosporin derivative according to claim 1, which is 3-cephalosporin-yl)thiomethyl-Δ^3-cephem-4-carboxylic acid. 4 7β{4-[(carboxy)(ethylthio)methylene]-1,3-dithiethane-2-yl}carboxamide-7α-methoxy-3-(1-methyltetrazole-5
2. The cephalosporin derivative according to claim 1, which is 3-cephalosporin-yl)thiomethyl-Δ^3-cephem-4-carboxylic acid. 5 7β-[4-(carboxymethylene)-1,3-dithiethan-2-yl]carboxamide-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-Δ^3-cephem-4-carvone The cephalosporin derivative according to claim 1, which is an acid. 6 7β-{4-[(carboxy)(methylsulfonyl)methylene]-1,3-dithiethan-2-yl}carboxamide-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-Δ^3 -CEFEM-4-
The cephalosporin derivative according to claim 1, which is a carboxylic acid. 7 7β-{4-[(carboxy)(methylthio)methylene]-1,3-dithiethane-2-yl}carboxamide-7α-methoxy-3-(1-methyltetrazole-
The cephalosporin derivative according to claim 1, which is 5-yl)thiomethyl-Δ^3-cephem-4-carboxylic acid.