JPS60226885A - Cephem derivative and its salt - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R1 is lower alkyl; Y1 is 5- or 6- membered heterocyclic group which may have substituent group such as lower alkyl, oxo, etc.; Y2 is aryl, or 5- or 6-membered heterocyclic group which may be substituted with lower alkyl or amino; n is 1 or 0) and its salt. EXAMPLE:7beta-[2-( 2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-{4-[(1H-imidazol-4-yl) methylthio]pyrazinio}methyl-3-cephem-4-carboxylate trihydrochloride. USE:An antibacterial agent exhibiting broad antibacterial spectrum and having strong antibacterial activity against Gram-negative bateria and Gram-positive bacteria including Pseudomonas aeruginosa. PREPARATION:The compound of formula I can be prepared by heating the compound of formula II (R2 is lower alkyl) or its salt and the compound of formula III corresponding to the compound of formula I, in the presence of minimum amount of water, etc.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention provides a compound of the general formula (I) useful as an antibacterial agent (wherein the ratio represents a lower alkyl group, and Y+ represents a 5- or 6-membered heterocycle). , the heterocycle may be substituted with a lower alkyl group, a hydroxyl group, an oxo group or an amino group.Yl represents an aryl group or a 5- or 6-membered heterocycle, and the aryl group and the heterocycle are substituted with a lower alkyl group, or a 5- or 6-membered heterocycle. It may be substituted with a group or an amide group.R represents 0.1 or 2.

) and its salts.

Here, the lower alkyl group is methyl.

Examples include ethyl, %-propyl and i-propyl. The 5-membered heterocycle is pyrazole.

Imidazole, thiazole, 1,8,4-thiadiazole, 1,2,4-triazole, oxazole.

Isoxazole, oxadiazole, pyrrolidine, 2
-pirulin, a-pirulin, imidacilline, thiazoline, and tetrazole. Examples of 6-membered heterocycles include pyridine and pyridazine! pyrimidine, pyrazine,
piperidine.

Examples include piperazine and morpholine.

In addition, as a salt of a compound represented by formula 1 (1), formic acid,
Organic acids such as methanesulfonic acid and hydrochloric acid.

Examples include salts with inorganic acids such as sulfuric acid, alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as magnesium salts and calcium salts of carboxylic acids.

The compounds represented by the general formula (I) of the present invention are all new compounds, and are manufactured by the manufacturing company shown below.

It can be manufactured by B or C.

Manufacturing company (wherein R1, Y, , Y2 and R are the same as above and & represents a lower alkyl group) Conversion of the acyloxyl group at the 8-position of the cephem ring of the compound of formula (1) to a substituted pyridinio group The reaction may be carried out by combining the compound of formula (n) or a salt thereof with a corresponding compound (200 million) in the presence of an inorganic salt such as sodium iodide, potassium thiocyanide or an organic salt such as sodium p-)toluenesulfonate. The desired compound of formula (I) can be produced by heating in a small amount of water or a mixture of water and a water-containing solvent such as acetonitrile, acetone or dioxane. This reaction is usually carried out at 40 to 100°C, preferably 60 to 80°C.
The reaction is carried out for 15 minutes to 8 hours, preferably for 80 minutes to 2 hours, and if necessary, the pH may be adjusted to a range of 4 to 8 using an inorganic acid such as hydrochloric acid.

Production method B (In the formula, R1 and L are the same as above, Z2 has a carboxyl protecting group + XI and k are the same or different halogen atoms, Yll may have a protecting group)
, Y21 represents Y2 which may have a protecting group, and Yl and Y2 are the same as above. ) In this production method, when Yl or Y2 has an amine 7 group as a substituent or has a nitrogen atom as a ring constituent atom and is a heterocycle in which the nitrogen atom is bonded to a hydrogen atom, generally It is desirable to carry out the reaction while protecting the amine group and the nitrogen atom with an amine-7 protecting group.

Examples of protecting groups for amino groups include formyl, trityl, tertiary butoxycarbonyl, and p-methoxybenzyloxycarbonyl.

Also, as a protecting group for the carboxyl group mentioned above.

Examples include p-nitrobenzyl, tertiary butyl and benzhydryl.

As is clear from the above chemical reaction formula, production method B consists of a substitution reaction, a deoxidation reaction, and a deprotection group reaction, and each reaction will be explained below.

Formula (W) is obtained by reacting the compound of substitution reaction formula (w) with the compound of formula (V) in a solvent that does not participate in the reaction, such as acetone, methyl ethyl ketone, dichloromethane, tetrahydrofuran, or acetonitrile, or a mixed solvent thereof.
Compounds of can be produced. The reaction is usually 0-5o
``C9'' Preferably carried out at 10-30°C for 8-24 hours.

The compound of deoxidation reaction formula) is converted into N,N-dimethylformamide or N
The compound of formula (b) can be produced by reacting with a deoxidizing agent such as phosphorus chloride or phosphorus tribromide in a solvent that does not participate in the reaction, such as N-dimethylacetamide. The reaction is usually carried out at -70 to 0''C, preferably -50 to -20C for 15 minutes to 8 hours, preferably 80 minutes to 60 minutes.

The deprotection reaction of the protecting group in the compound of formula (2) proceeds in an inorganic acid such as hydrochloric acid, an organic acid such as formic acid, trifluoroacetic acid, or a mixture thereof.

The desired compound of formula (1) can be produced.

The reaction is usually carried out at 0 to 50°C, preferably 15 to 80°C, for 15 minutes to 8 hours, preferably 80 minutes to 60 minutes.

Production method C (In the formula, r RI+ Y11+ Y21 and mist are the same as above.) As is clear from the chemical reaction formula, this production method consists of a condensation reaction and, if necessary, a deprotection reaction. Each reaction will be explained below.

The condensation reaction between the compound of formula (2) and the compound of formula (2) can be carried out by treating the compound of formula (2) with phosphorus pentachloride, 7-thionyl chloride, oxalyl tetralide, etc. The acid halide obtained by treating the compound of Formula 9 (2) with a Beers reagent prepared with dimethylformamide and phosphorus oxychloride, etc., in a solvent that does not participate in the reaction, such as ethyl acetate, acetonitrile, dichloromethane, etc. .

The compound of formula (2) can be produced by reacting in the presence of N,O-bis(trimethylsilylacetamide), triethylamine, sodium bicarbonate, propylene oxide, or the like. The reaction is usually -50 to 50
It is preferably carried out at -20 to 80°C.

Deprotection reaction The deprotection reaction of the protecting group in the compound of formula (1) thus produced proceeds in an inorganic acid such as hydrochloric acid, an organic acid such as formic acid, trifluoroacetic acid, or a mixture thereof, The desired compound (I) can be produced. The reaction is usually carried out at a temperature of θ to 50°C, preferably 15 to 30°C.

Raw material manufacturing method The raw material compound (to) in manufacturing method C can be manufactured as follows.

That is, 7-amituse7allosborane acid or a salt thereof is mixed with trimethylsilyl halide, sodium iodide, potassium thiocyanide, etc. in the presence of a halosulfonic acid such as trifluoromethanesulfonic acid or trichloromethanesulfonic acid in an organic solvent such as dichloromethane or acetonitrile. Let it react.

The compound of formula (4) can then be produced by reacting with the compound of formula (V).

Alternatively, 7-acylaminocephalosporanic acid may be mixed with a mixture of an organic solvent such as acetonitrile and water, and a compound of formula (V), sodium iodide, and thiocyanide-8-(substituted pyridiniomethyl)-8-cephem-4-carboxylate. can be manufactured. This compound is esterified with a silylating agent such as N,O-bis(trimethylsilylacetamide), and then reacted with an iminochlorinating agent such as phosphorus pentachloride and an iminoetherifying agent such as 1,8-butanediol in order. It is also possible to produce a compound of formula (1) by eliminating the acyl group. In this case, ordinary acyl groups can be used, and phenylacetyl, chenylacetyl, aminoadipyl, etc. are preferably used.

The compound of formula (1) of the present invention and its intermediates have an oximino group, and these compounds have syn isomers and anti-isomers shown below.

In general, the syn isomer shows superior antibacterial activity.

I've finished the whole thing! (In the formula, R1 and Y21 are the same as above.) When the syn isomer and the anti isomer are expressed in one expression for convenience in this specification, they are expressed by the following partial structure.

Y□“c-cosH- OR.

(In the formula, Fb and Yzdt are the same as above.) Also,
The target compound (1) and its intermediates may include tautomers. For example, when Y2 is 2-aminothiazole, the equilibrium relationship can be shown as follows.

(In the formula, R3 represents hydrogen or a protecting group for amine 7 group.

) Since tautomers can be converted into each other, they can be considered as substantially the same compound.

〔Effect of the invention〕

The compounds of the present invention exhibit a broad antibacterial spectrum and exhibit strong antibacterial activity against Gram-negative bacteria including Pseudomonas aeruginosa and Durham-positive bacteria. The results were expressed as MIC values using se7-otaxime as a control drug.

Minimum inhibitory concentration (MIC, μg/-) [Amount of inoculum:
10'/+/, culture conditions: 287°C, 218 hours] Compound A near β-(2-(2-aminothiazol-4-yl)
-2-methoxyiminoacetamide)-8-(4-((
LH-imidazol-4-yl)methylthio)pyridiniocomethyl-8-cephem-4-carboxylade normal hydrochloride (syn isomer) Compound B nia β-(2-(2-aminothiazole-4-
yl)-2-methoxyiminoacetamide)-8-(
4-(2-pyrrolidinoethyl)thiopyridiniocomethyl-3-cephem = 4-carboxilade normal hydrochloride (syn isomer) Compound C nia β~(2-(2-aminothiazole-4-
yl)-2-methoxyiminoacetamide)-3-(4
-(2-oxopyrrolidin-3-yl)thiopyridinio]methyl-a~cephem-4-carboxilade (syn isomer) Compound D nia β-(2-(2-aminothiazole-4-
yl)-2-methoxyiminoacetamide)-a-(4
-4(inoxazol-8-yl)methylthio)pyridiniocomethyl-3-cephem-4-carboxylade (syn isomer) Compound Enia β-(2-(2-aminothiazole-4-
yl)-2-methoxyiminoacetamide]-8-(4
-(2-Amino-1,8,4-thiadiazol-5-yl)thiopyridiniocomethyl-8-cephem-4-carboxilade normal hydrochloride (syn isomer) (Example) Example 1 7β- (2-(2-aminothiazol-4-yl)-2
-methoxyiminoacetamide]-8-(4-((IH
-imidazol-4-yl)methylthio)pyridiniocomethyl-8-cephem-Fuku-carboxilald normal hydrochloride (syn isomer) 1L) Dissolve 1.56 g of pyridine-4-thiol in 80 g Lt of acetonitrile and cool with water. Triethylamine 1
．． Add 97-. Then, a solution of 4-chlorodimethyl-1-trityl-IH-imidazole 4.0B9 dissolved in 120 tnt of acetonitrile was added dropwise, and the mixture was cooled with water for 40 min.
Stir for a minute. The solvent is evaporated and the residue is partitioned between water and chloroform. The chloroform layer was washed with water, dried with Glauber's salt, and then the solvent was distilled off. The resulting oily residue was subjected to silica gel column chromatography, and 4-(1-)lythyl-IH with a melting point of 170-172°C was obtained from the lyloloform eluate.
-imidazol-4-yl)methylthiopyridine 1.0
Obtain 7g.

4.15 (2H,s, methylene group) 6.70 (IH,s, H at position 5 of imidazole ring) 7.0
0 to 7.80 (15H, m, ) lythyl group) 8.80
(2H, a, H at positions 2 and 6 of the pyrosine ring) b) 7β
-(2-(2-tritylaminothiazol-4-yl)
-2-methoxyiminoacetamide]-8-bromomethyl-8-cephem-4-carboxylic acid tertiary butyl ester-1-oxide 790 mg and 4-(1-)rityl-IH-imidazol-4-yl)methylthiopyridine 1.089 mg acetone 20- and tetrahydro-7rane 15-
- and stirred for 80 minutes while cooling with water. After stirring at room temperature for 16 hours and distilling off the solvent, the residue is treated with ether to solidify and filtered. This was dissolved in N,N-dimethylformamide 12-, cooled to -50 to -60°C, 0.86- of phosphorus trichloride was added dropwise, and at the same temperature 1.5-
Stir for an hour. Chloroform was added to the reaction mixture, washed with saturated brine, dried over Glauber's salt, the solvent was distilled off, ether was added to the residue, and insoluble matter was filtered off.

The obtained powder was dissolved in 90% formic acid (15-) under ice cooling, and stirred at the same temperature for 80 minutes and then at room temperature for 8.5 hours. Insoluble matter was filtered off, and the soy sauce was distilled off.

The resulting residue was dissolved in 2-anisole and 2-trifluoroacetic acid and stirred for 1 hour while cooling with water. The solvent is concentrated, isopropyl ether is added, and the precipitate is collected by filtration. Dissolve this in water, adjust the pH to 6-7 with sodium hydrogen carbonate, and apply it to Diaion HP-20 column chromatography to obtain a crude product from the portion eluted with a water-acetone (90:1G) mixture. is purified by reverse phase high performance liquid chromatography and developed with a mixture of water-methanol (95:5) adjusted to pH 8 with hydrochloric acid to obtain the desired title compound. Gradually decomposes from melting point 175℃.

8.80.8.75 (Each IH, d, Cephem ring 2-position H
) 4.09 (8H, s, methoxy group) 4.71 (2H, s, methylenethio group) 5, s O,
5,51 (each IH, cl, cephem ring 8th position 0H2) 5,
a s (IHI dl cephem ring 6th position H) 7.18
(IH, s, 5-position H of thiazole ring) 7.60 (LH,
s, imidazole ring 5-position H) 7.90.8.68 (each 28. d, pyridine ring H) 8.85 (IH, s, imidazole ring 2-position H) Example 2 7β-(2-(2- aminothiazol-4-yl)-2
-Methoxyiminoacetamide] -3-(4-(2-pyrrolidinoethyl)thiopyridiniocomethyl-8-cephem-4-carboxilade ternate salt (syn isomer) a) 4-(2-bromoethyl ) Thiopyridine 2.189
and 1.42 g of pyrrolidine is stirred at room temperature for 2 hours. Water and ethyl acetate are added to the reaction solution to separate the layers. The ethyl acetate layer was washed with water, dried over sodium sulfate, and then the solvent was distilled off. The residue was subjected to silica gel column chromatography.

0.88 g of oily 4-(2-pyrrolidinoethyl)thiopyridine was obtained from the fraction eluted with chloroform-methanol (95:5).

1.80 (4H, m, H at the 8th and 4th positions of the bisilidine ring
) 2.55 (4H, m, H at the 2nd and 5th positions of the pyrrolidine ring) L80, 8.10 (2H, m each, ethylene group) 7.
09 and 8.82 (each 1!H, +1-+1.pyridine ring H) b) 7β-(2-(2-)ditylaminothiazol-4-yl)-2-methoxyiminoacetamide]
-8-bromomethyl-8-cephem-4-carboxylic acid tertiary butyl ester-1-oxide 0.79 g and 4
-(2-pyrrolidinoethyl)thiopyridine 0.629 is dissolved in acetone 5@/ and stirred at room temperature for 6 hours. The reaction solution was added dropwise to 100 ml of ether, and the precipitate was collected by filtration.

The obtained powder 880j119 is dissolved in N,N-dimethylformamide 8-, cooled to -50 to -60"C, added 0.25" of phosphorus trichloride, and stirred at the same temperature for 1.5 hours. Reaction liquid. Pour into ice water and extract with chloroform. The extract is washed with water, dried, and the solvent is distilled off. Ether is added to the remaining liquid and the precipitate is collected by filtration.

The above crude product was dissolved in 90% formic acid 14- and stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness, the residual solution was treated with ether, and the precipitate was collected by filtration. The obtained powder was dissolved in a mixture of 3 gnt of trifluoroacetic acid and 8-anisole, and 1
Stir for an hour.

The reaction solution was concentrated to dryness, the residue was treated with ether, and the precipitate was collected by filtration. Dissolve this in water and use Diamond Ion HP-2.
The mixture was applied to a 7o column of 0 and developed with a mixture of water and ethanol (9o:to). The obtained crude product was subjected to reverse phase high performance liquid chromatography and water-methanol (
90:10) is developed with a mixture of hydrochloric acid adjusted to pH 1.5-2.0 to obtain the desired title compound. Melting point 15
0-170°C (decomposition).

1.94-2.80 (4H, m, pyridine>llll
B position and 4-position H) 8.12-8.40 (8H, m, -8OTo group and 2-position H of the cephem ring) 8.60-8.86 (7H, m, -CAM group, pyrrolidine ring 2-position and 5-position H and cephem ring 2@H) 4.07 (8H, s, methoxy group) 5.28, 5.54 (each IH, d, -1 = 7! A ring 8-position a6) 5.88 (IH , d, cephem ring 6-position H)5.
8 o (IH, a, Cephem ring 7-position H) 7.17 (
IH,s, thiazole ring 5th position H) 7.91.8.68
(each 2H, 6, pyridine ring H) Example 8 7β-(g-(g-aminothiazol-4-yl)-2
-methoxyiminoacetamide]-21-(4-(2-
Oxopyrrolidin-8-yl)thiopyridiniocomethyl-8-cephem-4-carboxilade (syn isomer) a) 1.88 g of 4-mercaptopyridine, 14 g of 8-chloro-2-pyrrolidone and triethylamine 2- in acetonitrile Dissolve in 80gLt and stir at room temperature for 24 hours. The solvent is evaporated and the residue is partitioned between chloroform and water. The chloroform layer was washed with water, dried over Glauber's salt, and then subjected to silica gel column chromatography and eluted with a chloroform-methanol mixture to obtain 1.47 of 4-(2-oxopyrrolidin-8-yl)thiopyridine.

2.20-L90 (2H, m, H at position 4 of pyrrolidine ring)
8゜4 B (2)1. t, pyrrolidine ring 5th position H)4
．． 00 (1B, t, pyrrolidine lls position H) 7.2
a, s, a s (each 2H, d, pyridine ring H) b
) 7β-(2-(2-aminothiazol-4-yl)
-2-Methoxyiminoacetamide]-8-acetoxymethyl-8-cephem-4-carboxylic acid sodium 95
0I119. Sodium iodide 8.02 and 4-(2-
Add 1.4 g of oxopyrrolidin-8-yl)thiopyridine to a mixture of acetonitrile and water (8:1), and
Stir at °C for 2 hours. After cooling, the two reaction solutions were poured into acetone, and the precipitate was collected by filtration. The obtained powder was dissolved in water, subjected to column chromatography on Diaion HP-20, and developed with a mixture of water and tetrahydro7ran (95:5). Furthermore, it was subjected to reverse phase high performance liquid chromatography,
The desired title compound is obtained by developing with a mixture of water and acetonitrile (s8:+2). Melting point 160-175℃ (
Disassembly).

2.30-2.95 (2B, trr, 4-position H of pyrrolidine ring) 8.21, 8.65 (each IH, d, cephem 1
12th position H) 8.55 (2H, ml, pyrrolidine ring 5th position H) 8.97 (8H, s, methoxy group) +, 7oDH1t, pyrrolidine ring 8th position H) 5.20,5
．． 42 (Each LH, d, Cephem! fIS rank C output) 5.2
8 (IH, a, Cephem ring 6-position H) 5.90 (IH
,+1. Cephem ring 7th position H) 7.00 (IH,s, thiazole ring 5th position H) Example 4 7β-(2-(2-aminothiazol-4-yl)-2
-methoxyiminoacetamide]-8-(4-((isoxazol-8-yl)methylthio)pyridiniocomethyl-8-77em-4-carboxilade (syn isomer)-)isoxazole-8-carvone ethyl acid 1o
, s9 was dissolved in 200-g of tetrahydro7ran, 8.25 g of lithium borohydride was added under water cooling, and 1 was added at the same temperature.
Stir for an hour. Water was added to the reaction solution, the precipitate was filtered off, and the tetrahydro7rane was distilled off, followed by extraction with ether. The extract was dried with Glauber's salt and the solvent was distilled off. The obtained oily residue was subjected to silica gel column chromatography,
4.859 of 3-hydroxymethylisoxazole is obtained as a colorless oil from the chloroform eluate.

4.70 (2M, s, isoxazole ring 8th position C1
H2) 6.85 (IH, d, H at position 4 of isoxazole ring) s, go (IH, a, H at position 5 of inoxazole ring) b) 8-hydroxymethylisoxazole 240
m19 was dissolved in pyridine 2-, p-toluenesulfonic acid chloride 690119 was added under water cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was dried under reduced pressure, water was added to the residue, and the mixture was extracted with ether. The extract is washed with 10% hydrochloric acid, dried over magnesium sulfate, and then the solvent is distilled off. The residue is subjected to silica gel column chromatography and eluted and separated with chloroform to obtain 8-(p-)luenesulfonyloxy)methylisoxazole 2B5119. Melting point 66-67°C02,48 (8H,s, methyl group) 5.10 (2H,s, isoxazole ring 8-position 0H2
)6.85 (IH, d, H at position 4 of isoxazole ring)
7.25.7.75 (each 2H, d, benzene ring H) 8
．． 80 (IH, +1.Isoxazole ring 5th position H)C
) 4-mercaptopyridine 62119 was dissolved in acetonitrile 8-, and triethylamine 601119 was added thereto. A solution of 140 μm of 8-(p-toluenesulfonyloxy)methylisoxazole dissolved in 2 g Rt of cetonitrile was added to the above solution and stirred at room temperature for 1.5 hours. The solvent was distilled off, water was added to the residual liquid, and the mixture was extracted with chloroform.

After drying the extract with Glauber's salt, the solvent is distilled off and the resulting residue is subjected to silica gel column chromatography to obtain 4-(isoxazol-8-yl)methylthiopyridine 90s9 from the chloroform eluate. Melting point 56-58°C
04,21 (2H,s, isoxazole ring 8th position CH2
)8.81 (1)1. d, H at the 4th position of the isoxazole ring) 7.15 (2H, a, H at the 8th and 5th positions of the pyridine ring
) 8.80 to 8.40 (3H, m, pyridine ring positions 2 and 6, isoxazole ring 5th position H) d) 7β-(2-(2-)ditylaminothiazole-
4-yl)-2-methoxyiminoacetamide]-8-
Bromomethyl-8-cephem-4-carboxylic acid tertiary butyl ester-1-oxide 1.589 and 4-(isoxazol-8-yl)methylthiopyridine 764
'm9 was dissolved in acecin 8- and stirred at room temperature for 8 hours and then at 40°C for 8 hours. The solvent was distilled off, water was added to the residue, and the mixture was extracted with chloroform. The extract was dried with mirabilite,
After distilling off the solvent, the residue is treated with ether and the precipitate is collected by filtration.

1.85 g of this powder was mixed with 1 ml of N,N-dimethylformamide.
Dissolve phosphorus trichloride at 0°C and cool to -40 to -80°C to remove phosphorus trichloride.
．． 9- was added dropwise and stirred at the same temperature for 1 hour. Chloroform was added to the reaction mixture, washed with water, dried over sodium sulfate, the solvent was distilled off, the residue was treated with ether, and the precipitated crystals were collected by filtration.

1.2 g of this powder is dissolved in 90% formic acid 25- and stirred at room temperature for 2 hours. Filter off insoluble matter.

The residual liquid obtained by distilling off the solvent is solidified with ether, and the precipitated crystals are collected by filtration. This was dissolved in a mixture of anisole 4- and trifluoroacetic acid 8- and stirred at room temperature for 70 minutes. The reaction solution was dried under reduced pressure.

The residual liquid was solidified with ether to obtain a powder of 880 μm, which was dissolved in water, subjected to column chromatography on Diaion HP-20, and developed with water-acetone (80:20). The obtained crude product was subjected to reverse phase high performance liquid chromatography and developed with water-methanol (80:20) to obtain the desired title compound. Gradually decomposes from melting point 168°C.

8.1? , 3.6.1 (each IH, cl, 2nd H of cephem ring) 8.98 (8H, s, methoxy group) 4.62 (2)! , s, isoxazole ring 3-position C
H2) 5.1? , 5.87 (each IH, d, cephem ring 3
position 0H2) 5.80 (LH, α, cephem fi 6th position H
) 5.84 (LH, d, Cephem ring 7th position H) 6.62
(18,a, isoxazole ring 4-position H) 7.00
(IH, s, thiazole gA5-H) 7.85 (2H
, d, H at the 3- and 5-positions of the pyridine ring) 8.60 (2H
, cl, H at the 2nd and 6th positions of the pyridine ring) 8.65 (I
H, a, isoxazole ring 5th position H) Br I Rvmax (cl: 1770 (β-lactam C-0) Example 5 7β-(a-(2-aminothiazol-4-yl)-2
-methoxyiminoacetamide] -8-(4-(2-amino-1,8,4-thiadiazol-6-yl)thiopyridiniocomethyl-8-cephem-4-carboxilade trisalt salt (synisomer a) 4-Chlorpyridine hydrochloride 2.09,2-amino-5-mercapto-1,8,4-thiadiazole 2.2
59 and triethylamine 4.559 are added to N,N-dimethylformamide 20- and refluxed for 1 hour. The reaction solution was dried under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After drying the extract with Glauber's salt and distilling off the chloroform, the residue was treated with ether and the precipitate was collected by filtration to give 4-(2-amino-1,
8,4-thiadiazol-5-yl)thiopyridine2.
Obtain 16g.

7.15 (2H, d, pyridine ring 8th and 5th H)
7.69 (2H,s, amino group, disappeared by addition of D20) 8.88 (2H,a, H at 2- and 6-positions of pyridine ring) b) 7β-(2-(2-aminothiazole-4-
1.0 g of sodium iodide)-2-methoxyiminoacetamide]-8-acetoxymethyl-8-cephem-4-carboxylate, 2.5 g of sodium iodide and 4-(2-
0.889 of amino-1,8,4-thiadiazol-5-yl)thiopyridine is added to a mixture of water and acetonitrile (1:3) 1- and stirred at 70-80°C for 1 hour. from now on.

The reaction solution was poured into acetone, and the precipitate was collected by filtration.

The obtained powder was dissolved in water and subjected to column chromatography using Diaion HP-20.
The crude product obtained by developing with a mixture of water-methanol (85
:15) is developed with a mixture adjusted to pH 2 with hydrochloric acid,
The desired title compound is obtained. Gradually decomposes from melting point 202°C.

Claims (1)

[Claims] General formula (r in the formula: R1 represents a lower alkyl group. Yl represents a 5- or 6-membered heterocycle, and the heterocycle is a lower alkyl group, a hydroxyl group, an oxo group, or an amine 7 group) Yl represents an aryl group or a 5- or 6-membered heterocycle, and the aryl group and heterocycle may be substituted with a lower alkyl group or an amino group.
゜Represents 1 or 2. ) and its salts.