JPH01216997A - Novel cephem compound and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is (protected) amino; R<2> is R or lower alkyl; R<3> is (protected) carboxy; R<4> is 4-oxo-1,4- dihydropyrimidinyl having lower alkyl, etc., 4-oxo-3,4-dihydropyrimidinyl having lower alkyl, etc., 3-oxo-2,3-dihydropyridazinyl having lower alkyl, 4-oxo-1,4- dihydropyridaziniyl having lower alkyl, etc.; X is N or CH]. EXAMPLE:7-[2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1-methy l-4-oxo-5- hydroxy-1,4-dihydropyrimidin-2-yl)thiomethyl-3-cephem-4-carboxylic acid. USE:An antimicrobial agent against Gram-postive, Gram-negative bacteria, etc. PREPARATION:A compound expressed by formula II is reacted with a compound expressed by formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION "Field of Industrial Application" The present invention relates to novel cephalosporin compounds and salts thereof, which are useful in the pharmaceutical field.

A means to solve one problem.

Although many types of cephalosporin compounds have been known,
The present invention provides further superior cephalosporin compounds.

The cephalosporin compound of the present invention has the following general formula (I):
It can be shown as

(In the formula, R1 is an amine group or a protected amino group, R2 is hydrogen or a lower alkyl group, R3 is a carboxy group or a protected carboxy group, and R4 is a lower alkyl group or a hydroxy group.
4-dihydropyrimidinyl group; 4-dihydropyrimidinyl group; 4-dihydropyrimidinyl group; 4-dihydropyrimidinyl group; 4-dihydropyrimidinyl group;
4-dihydropyrimidinyl group; 3-year-old xo-2,3-dihydropyridazinyl group having a lower alkyl group or hydroxy group; 4-oxo-1,4-dihydro which may have a lower alkyl group or halogen Pyridazinyl group; 4-year-old xo 4 which may have a hydroxy group
H-1,3-thiazinyl group; or 4-year-old xo5.6
-Shihydro4H-1,3-thiazinyl group, and X means N or CH, respectively. ) The object compound (I) of the present invention or its salts can be produced by the method shown below.

1. (I) or a reactive derivative at its carboxy group or a salt thereof + or a reactive derivative at its amino group or a salt thereof ± or a salt thereof or a salt thereof + R-5H(V) Soil or a salt thereof Method 3 or its salts or its salts Process 4 or its salts or its salts Process 5 ↑ or its salts or its salts (wherein, R1, R2, R3, R4 and X each have the same meaning as above, and R1 is a protected R3 represents a protected carboxy group and Y represents a leaving group.

) Compound (I[[) is novel and can be produced by the method shown below.

Method A + R'-5R(V) ↓ or salts thereof (wherein R3 and R4 each have the same meaning as before and 2 means a leaving group), some of the compounds (V) and some of the compounds (VI ) are new and can be produced by the method disclosed in the production examples below or a method analogous thereto.

Compound (V) has tautomers based on its partial structure. These are in an equilibrium relationship expressed by the following equation.

(A) (B) For convenience, in the reaction formulas in the explanation of each production method above, compound (V) is expressed as R'-S H assuming that it exists in the thiol form represented by formula (A). Ta.

In the object compound (I) of the present invention and various starting compounds, the partial structure represented by the following formula % shall include both of the two types of geometric isomers represented by the following formulas (C) and (D).

In this specification, among all the compounds having the above partial structure, the compound having the geometric structure represented by formula (C) is referred to as a 1-syn isomer, and the compound represented by formula (D>) is referred to as
called the anti-isomer.

Suitable salts of the target compound (1) include commonly used non-toxic salts. For example, salts with inorganic or organic bases such as sodium salts, potassium salts, calcium salts, magnesium salts, triethylamine salts, lysine salts, and inorganic or organic acids such as hydrochlorides, sulfates, acetates, methanesulfonates, etc. Examples include salt.

In the description above and below in this specification, suitable examples included in the various definitions are as follows.

Lower terms have 1 to 6 carbon atoms, unless otherwise specified.
shall mean a group of individuals.

Suitable amine-protecting groups for the 1-protected amino group include those commonly used in this field, such as acyl groups (e.g., formyl, acetyl,
lower alkanoyl groups such as propionyl, butyryl, imbutyryl, valeryl, pivaloyl, hexanoyl, etc.)
can be mentioned.

Suitable lower alkyl groups include methyl, ethyl,
Examples include propyl, butyl, t-butyl, pentyl, hexyl, etc., but more preferred are (C1-C
,) The most preferred alkyl groups include methyl and ethyl.

Suitable "protected carboxy groups" include those protected by protective groups commonly used in this field, and include, for example, esterified carboxy groups. Examples of the ester moiety include al (lower) alkyl esters [e.g., phenyl (lower) alkyl esters such as benzyl esters, diphenyl (lower) alkyl esters such as benzhydryl esters, triphenyl (lower) alkyl esters such as trityl esters] (lower) alkyl esters, etc.

"Carboxy group protected" by such a protecting group
As a preferable example, an al (lower) alkyl dicarbonyl group is used, and a more preferable example is a diphenyl (lower)
The most preferred example of the alfkidicarbonyl group is a benzhydryloxycarbonyl group.

Suitable halogens include fluorine, chlorine, bromine and iodine.

Examples of the "4-year-old xo-1,4-dihydropyrimidinyl group having a suitable 1-lower alkyl group or hydroxyl group" include, for example, 1-methyl-4-oxo-5-hydroxy-1,4-dihydropyrimidinyl group. 1-(lower)alkyl-4-hydroxy-5-hydroxy-1,4-dihydropyrimidinyl group [more preferably 1-(C1-
C4) Alkyl-4-year-old xo-5-hydroxy-1,4
-dihydropyrimidin-2-yl group, most preferably
1-methyl-4-oxo-5-hydroxy-1,4-dihydropyrimidin-2-yl group], for example 1-methyl-4-oxo-6-hydroxy-1,4-dihydropyrimidinyl group. -(lower)alkyl-4-hydroxy-6-hydroxy-1,4-dihydropyrimidinyl group [
More preferably, 1-(C1''-C4)alkyl-4-
6-hydroxy-1,4-dihydropyrimidic-2-yl group, most preferably 1-methyl-4-hydroxy-1,4-dihydropyrimidine-2
-yl group], 4-oxo-5-hydroxy-1,4-dihydropyrimidinyl group (more preferably, 4-oxo-5-hydroxy-1,4-dihydropyrimidin-2-yl group), etc. can.

Suitable "4-xo-3,4-dihydropyrimidinyl group having lower alkyl group or hydroxyl group" includes, for example, 3-methyl-4-xo-5-hydroxy-3,4-dihydropyrimidinyl group. 3-(lower)alkyl-4-hydroxy-5-hydroxy-3,4-dihydropyrimidinyl group [more preferably 3-(C1-
C4) Alkyl-4-year-old xo-5-hydroxy-3,4
-dihydropyrimidin-2-yl group, most preferably
Examples include 3-methyl-4-oxo-5-hydroxy-3,4-dihydropyrimidin-2-yl group.

Suitable "3-year-old xo-2,3-dihydropyridazinyl group having a lower alkyl group or hydroxy group" includes, for example, 2-methyl-3-year-old xo-6-hydroxy-2,3-dihydro 2-(lower)alkyl-3-hydroxy-6-hydroxy-2,3- such as pyridanyl group
dihydropyridazinyl group [more preferably 2-(C1
-C4) alkyl-3-year-old xo-6-hydroxy-2,
3-cyhydropyridazin-5-yl group, most preferably 2-methyl-3-hydroxy-6-hydroxy-2,3-
dihydropyridazin-5-yl group].

4-year-old xo 1,4-dihydropyridazinyl group which may have a suitable 1-lower alkyl group or halogen.”
For example, 1-(lower)alkyl-3-halo-4-oxo-1,4-dihydropyridazinyl group such as 1-methyl-3-chloro-4-oxo-1,4-dihydropyridazinyl group. dazinyl group [more preferably 1-(C1-C4)
Alkyl-3-halo 4-year-old xo-1,4-dihydropyridazin-6-yl group, most preferably 1-methyl-
Examples include 3-chloro-4-xo-1,4-dihydropyridazin-6-yl group.

Examples of the "4-year-old xo 4H-1,3-thiazinyl group which may have a suitable 1-hydroxy group" include, for example, 4-
Oxo-4) (-1,3-thiazinyl group, 5-hydroxy-4-xo-4H-1,3-thiazinyl group, etc. (more preferably 4-xo-4H-1,3-thiazin-2)
-yl group, 5-hydroxy-4-hydroxy-4H-1,3
-thiazin-2-yl group).

Preferred C4-dihydro-5,6-cyhydro-4H-1,3
-thiazinyl group", for example, 4-year-old xo5.
A 6-sihydro 4H-1,3-thiazin-2-yl group is mentioned.

Suitable leaving groups include the aforementioned halogens, acyloxy groups (e.g., lower alkanoyloxy groups such as acetoxy groups), di(lower) alkylsulfonio groups (
For example, dimethylsulfonio group) and the like can be mentioned.

The method for producing the target compound (1) will be explained in detail below.

The target compound (1) or a salt thereof is a compound (I[) or a reactive derivative thereof at the carboxy group or a salt thereof; It is produced by reacting.

Suitable reactive derivatives for the carboxy group of compound (It) include those commonly used in the art, such as acid halides, acid anhydrides, activated amides, activated esters, etc., and particularly preferred ones include Examples include acid chloride, alkylsulfonic acid mixed acid anhydride (for example, methanesulfonic acid mixed acid anhydride), and the like. These reactive derivatives are appropriately selected depending on the type of compound (II).

Suitable salts for compound (IF) include those exemplified for compound (I).

Suitable reactive derivatives at the amine group of compound (I[[) include reactive derivatives commonly used in amidation reactions,
For example, compound (III) and bis(trimethylsilyl)
Examples include silyl derivatives obtained by reaction with silyl compounds such as acetamide and trimethylsilylacetamide.

Suitable salts of compound (III) include compound (I);
The following are examples.

This reaction usually involves water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride,
It is carried out in conventional solvents such as tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine, and other solvents that do not adversely affect the reaction. Among these, hydrophilic solvents can be used in combination with water.

In this reaction, when compound (1) is used in the form of a free acid or a salt thereof, for example, N.

Preferably, the reaction is carried out in the presence of a customary condensing agent such as N'-dicyclohexylcarbodiimide, the so-called Vilsmeier reagent.

This reaction includes alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, alkali metal acetates, tri(lower)alkylamines (e.g., triethylamine), pyridine, N-(lower)alkylmorpholines, N,N-di(
The reaction can be carried out in the presence of an inorganic or organic base such as lower) alkylbenzylamine or N,N-di(lower) alkylaniline. When the base or condensing agent is liquid,
It may also be used as a solvent.

Although the reaction temperature is not particularly limited, it is usually carried out under cooling or around room temperature in many cases.

1 迭1 Target compound (I) or a salt thereof is produced by reacting compound (IV) or a salt thereof with compound (V).

Suitable salts for compound (IV) include those exemplified for compound (1).

This reaction consists of water, phosphate buffer, acetone, chloroform, nitrobenzene, methylene chloride, ethylene chloride, N,N-dimethylformamide, methanol,
The reaction can be carried out in ethanol, ether, tetrahydrofuran, dimethyl sulfoxide, or other solvents that do not adversely affect the reaction, of which polar solvents are preferred. Among the above solvents, hydrophilic solvents can be used in combination with water. .

This reaction occurs in the presence of bases such as alkali metal hydroxides, alkali metal halides (e.g. sodium iodide), alkali metal carbonates, alkali metal acetates (e.g. sodium acetate), alkali metal bicarbonates and trialkylamines, etc. It is desirable to carry out the reaction below.

Although the reaction temperature is not particularly limited, it is usually carried out at room temperature, with heating, or with slight heating.

The compound (Ib>) or a salt thereof is produced by subjecting the compound (Ia) or a salt thereof to an amino-protecting group elimination reaction.

Suitable salts of compound (Ia) include salts with bases exemplified for compound (1).

Suitable salts for compound (Ib) include those exemplified for compound (I).

The elimination reaction can be carried out by a method commonly used for eliminating an amine protecting group, such as a hydrolysis reaction.

Examples of the hydrolysis reaction include a method using an acid, and suitable acids include formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, salt #
Mention may be made of specific organic and inorganic acids, of which particularly preferred are formic acid, trifluoroacetic acid, hydrochloric acid. A suitable acid can be selected depending on the type of protecting group to be removed.

The acid elimination reaction is carried out in the presence or absence of a solvent. Suitable solvents include commonly used organic solvents (
Examples include methanol), water, and mixtures thereof. When using trifluoroacetic acid, the elimination reaction is preferably carried out in the presence of anisole.

Although the reaction temperature is not particularly limited, it is preferable to carry out the reaction under mild conditions such as cooling, room temperature, or slightly warming.

Method 4 Target compound (Id) or its salt is compound (Ic)
or by subjecting its salts to an elimination reaction of the carboxy protecting group.

Examples of salts of compound (Ic) include salts with acids exemplified for compound (I), and examples of salts of compound (Id) include those exemplified for compound (I).

This reaction is carried out by methods commonly used for removing carboxy protecting groups, such as hydrolysis.

Hydrolysis is preferably carried out in the presence of a base or an acid. Suitable bases include alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, their hydroxides, carbonates or bicarbonates, trialkylamines such as trimethylamine and triethylamine, picoline, 1. 5-diazabicyclo[4,3,0
]-5-nonene, 1,4-diazabicyclo[2,2,2
co-octane, 1,8-diazabicyclo[5,4,O]-
Inorganic or organic bases such as 7-undecene are included.

Suitable acids include organic acids such as formic acid, acetic acid, propionic acid, and trifluoroacetic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and aluminum halides (eg, aluminum chloride). When trifluoroacetic acid or aluminum halide is used, the elimination reaction is preferably carried out in the presence of anisole.

This reaction is usually carried out in a solvent such as water, an alcohol such as methanol or ethanol, methylene chloride, nitromethane, a mixture thereof, or any other solvent that does not adversely affect the reaction. A liquid base or acid may also be used as a solvent. Although the reaction temperature is not particularly limited, it is usually carried out under cooling or heating.

1. The gem compound (I) or its salts is produced by subjecting the compound (VI) or its salts to a reduction reaction.

Suitable salts for compound (VI) include those exemplified for compound (1).

Reducing agents used in this reaction include those commonly used for converting sulfinyl groups to thio groups, such as phosphorus halides (e.g., phosphorus trichloride, phosphorus pentachloride, etc.), stannous halides (e.g., (e.g., stannous chloride), silicon halides (e.g., silicon tetrachloride), excessive amounts of lower alkanoyl halides (e.g., acedel bromide, acetyl chloride, etc.)
Acid halides, alkali metal halides (such as
Examples include combinations of acid anhydrides such as sodium iodide (eg, sodium iodide) and halo(lower) alkanoic anhydrides (eg, trifluoroacetic anhydride, etc.).

The reaction is usually carried out in the presence of lower alkenes (eg, 2-methyl-2-butene, etc.), lower alkylene oxides (1 series, ethylene oxide, propylene oxide, etc.), or other acid scavengers.

The reaction is also generally carried out in conventional solvents that do not adversely affect the reaction, such as chloroform, methylene chloride, tetrahydrofuran, benzene, N,N-dimethylformamide, etc., or mixtures thereof.

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

The method for producing the raw material compound (I[[) will be explained below.

Method A Compound (I[) or a salt thereof is produced by reacting compound (■) or a salt thereof with compound (V).

Suitable salts for compound (■) include those exemplified for compound (I).

This reaction can be carried out in substantially the same manner as described in m.

"Effects of the Invention" The object compound (I) of the present invention and its salts are novel compounds that have excellent antibacterial activity, inhibit the growth of a wide range of pathogenic microorganisms including Durum-positive bacteria and Durum-negative bacteria, and are antibacterial. It is useful as a drug.

When administering the object compound (1) of the present invention for therapeutic purposes, the compound (1) containing the above-mentioned compound as a main component is combined with a pharmaceutically acceptable carrier, such as an organic or inorganic solid suitable for oral, parenteral or external use. Alternatively, it can be used in the form of a preparation obtained by adding a liquid excipient. Such formulations include solids such as capsules, tablets, granules, and ointments, and liquids such as solutions, suspensions, and emulsions. Furthermore, if necessary, adjuvants, stabilizers,
It can contain wetting agents or emulsifying agents, buffering agents, and other commonly used additives.

The dose of the compound varies depending on the patient's age, condition, type of disease, type of compound CI>, etc., but the average dose of the compound (I) of the present invention is about 50 mg per dose.

It may be administered in amounts of 100mg, 250mg or 500mg.

Generally, the daily dosage ranges from 5 mg to about 30 mg.
00 mg or more can be administered to the patient.

"Examples" Next, the present invention will be explained in detail with reference to production examples and examples.

Sodium hydride (7.9g), methyl formate (17.8g)
g) and sodium metal (100 mg) in tetrahydrofuran (600 mQ) at room temperature, 2-benzyloxyacetic acid methyl ester is added dropwise, and then sodium metal (500 mg) is further added. After stirring for 2 hours, the tetrahydrofuran is distilled off under reduced pressure. After adding cooled IN hydrochloric acid (4 oomu) and diethyl ether (200 m) to the residue, the diethyl ether layer was separated, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to vacuum distillation to give 2-benzyloxy-
2-formylacetic acid methyl ester (45.4 g) is obtained as a colorless oil.

b, p, 120-125℃ (<lmmHg>NMR(
DMSO-ds, 8)' 3-63 (3H9s)
, 4.77 (2H1s), 7.1-7.4 (5H
).

J11 main metal sodium (9.2g) in ethanol (300-)
After adding 2-benzyloxy-2-formylacetic acid methyl ester (al, 6 g) to the solution dissolved in the solution at room temperature, N-methylthiourea (13.5 g) is added.6 The reaction mixture is refluxed for 3 hours. After cooling, water (300ml) was added to the reaction solution, and the pH was adjusted to 3.0 with 6N hydrochloric acid. The precipitate was collected by filtration, and 1-methyl-2-thioxo-4-thioxo-5-benzyloxy-1,2°3.4-tetrahydropyrimidine (abbreviated as compound A) and 2-deoxo-3-methyl were collected. -4-oxo-5-benzyloxy-1,2,3,4
A mixture (26.1 g) of -tetrahydropyrimidine (abbreviated as compound B) is obtained.

This mixture is recrystallized from ethanol (1j) and then from ethyl acetate (200111Q) to obtain a pure compound A (10.2 g). Both the ethanol and ethyl acetate filtrates from the filtration are combined, After concentration under reduced pressure, the residue was subjected to column chromatography using silica gel and eluted with a mixture of ethyl acetate and benzene (1:4) to obtain compound B (5.0 g) and compound A (3.8 g). )
get.

Kanno Toyohito Seal 1 mp: 202℃ IR (Suji 1-le): 1680. 1630.
13tO, 1230am-INMR (DMSO-da
, l; )' 3.51 (3H0s), 4.86
(2H1s), 7.33 (5)1. s), 7.6
7 <IH, s) Elemental analysis (as C1□H1□N20□S) Calculated value F C58,05,) I 4.87. N
11.28. S 12.91 Actual value: C58,3
2, H4, 94, N 11.27.512.97 Supervising plan l Second Seal 1 mp: 188-190°C IR (Streak 3-L) i 3160. 1650.
1640. 1540. 1310°1220 am
-1 NMR (DMSO-da, δ): 3.54 (3H
,s), 4.96 (2H.

s), 7.20 (IH, s), 7.36 (
5H,s).

1 Meng'1 In the same manner as in Production Example 2, 2-benzyloxy-2-formylacetic acid methyl ester (26 g) and thiourea (8,
2g) to form 2-mercapto-4-oxo-5-benzyloxy-1t4-dihydropyrimidine (t
6.6 g) is obtained.

NMR (DMSO-H6, δ): 5.0 (2H,
s), 7.20 (LH, s).

7.337.66 (61, m).

Production Example 4 Anhydrous aluminum chloride (10.8 g) was mixed with nitromethane (
Anisole (20 companies) was added to a solution dissolved in 200mQ), and then l-methyl-2-thioxo-4-
Oxo-5-benzyloxy-1,2,3°4-tetrahydropyrimidine (Log) is added at 0-5°C with stirring. The reaction solution was stirred at 5-10°C for 30 minutes and then at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the resulting precipitate was collected by filtration, washed with a small amount of nitromethane, and then mixed with a mixture of cold water and tetrahydrofuran ( 1:1) and then add sodium chloride to this solution until saturation. The tetrahydrofuran layer is separated, dried over magnesium sulfate, and then concentrated under reduced pressure. The crystalline residue is suspended in diethyl ether and then filtered. Recrystallized from ethanol (200 proof) to give 1-methyl-2-thioxo-4-year-old xo5.
-Hydroxy-1,2,3,4-tetrahydropyrimidine (2,05 g) is obtained as colorless crystals.

mp: 248-249°C (decomposition) IR (streak 1-l): 3280. 1690.
1650. 1510. 1320°1260clI
I-1 NMR (DMSO-H6, δ): 3.53 (3H
,s), 7.38 (11°S) Elemental analysis (as C5H6N20S) Calculated value: C37,97,H3,82,N 17.71
．． S 20.27°Actual measurement: C38,69,H3,
78, N 17.65. S 20.29゜Production Example 5 In the same manner as in Production Example 4, 2-deoxo-3-methyl-4
- 2-thioxo-3-methyl-4-thioxo-5 -Hydroxy-1,2,3,4-tetrahydropyrimidine (1,8) is obtained.

mp: 313°C (decomposition) IR (7 dils)' 3320. 3120.
1650. 1540. 1310°1250CII
I-1 NMR (DMSO-H6, δ): 3.5B (3H
,s), 7.0 <IH,d.

J=6Hz).

Elemental analysis (as C5H6N20S) Calculated value: C37,97,H3,82,N 17.71
．． S 20.27° Actual measurement: C38, 29, H3,
79, N 17.56. S 20.10゜Justo Week 1 In the same manner as in Production Example 4, 2-mercapto-4-year-old xo-5-benzyloxy-1,4-dihydropyrimidine (8
, Og) with anhydrous aluminum chloride (8.8 g) to give 2-mercapto-4-year-old xo-5-hydroxy-
1,4-dihydropyrimidine (2,5 g) is obtained.
.

NMR (DMSO-H6, δ): 6.9B (IH
,s).

1. Ethyl acetate (20mu) of pyruvic acid (6.5g)
Trityloxyamine (10.7 g) is added to a mixture of and water (50 mfl) under stirring at room temperature. Continue stirring at the same temperature for 3 hours. The ethyl acetate layer is separated, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. Diisopropyl ether was added to the residue, the precipitate was collected by filtration, and 3-bromo-2-
Trityloxyiminopropionic acid (5.8 g) is obtained.

mp: 122-125°C IR: 2600-2500.
1690. 1590 cm-1HMR (DMSO-
ds, 8)' 4.36 (2H1s), 7.3 (
158, s).

1 child's week 1 3-bromo 2-trityloxyiminopropionic acid (
4.24 g), ethyl acetate (30 mQ) and water (10
Ammonium dithiocarbamate (1.1 g) is added to the mixture of mQ '') at room temperature under stirring.

Continue stirring at the same temperature for 3 hours. Separate the ethyl acetate layer,
After washing with a saturated aqueous sodium chloride solution and drying over magnesium sulfate, the solvent is distilled off under reduced pressure. Diisopropyl ether was added to the residue, and the resulting precipitate was collected by filtration to obtain 3-thiocarbamoylthio-2-trityloxyiminopropionic acid (3.6 g).

mp: 130 (35℃ (decomposition) IR (Sujoor)' 3300. 1620.
1490. 1220 am'NMR (DMSO-
da, l; ) ' 4.12 (2H, s), 7-
3 (15H1s).

1.3-Dicyclohexylcarbodiimide is added to a solution of 3-thiocarbamoylthio-2-trityloxyiminopropionic acid (872 mg) and anhydrous 1-hydroxybenzotriazole (306 mg) in tetrahydrofuran at room temperature with stirring. Continue stirring at the same temperature for 1 hour. Insoluble matter is filtered off. Concentrate the filtrate under reduced pressure. Benzene was added to the residue, and the resulting precipitate was collected by filtration to give 2-thioxo-4-thioxo-5-
Trityloximinobarhid O-2H-1,3-thiazine (535 mg) is obtained.

mp 14g-152℃ (decomposition) IR (streak 1-l): 3300, 31
00, 1700. 1620.

1580 am' NMR (DMSO-ds.8)' 4-50
(2H,s), 7. 3 (15H.

s).

Production Example 10 Anhydrous aluminum chloride (3.5 g: M) nitromethane (
60a2) was added with anisole (61119) for 10 minutes, then 2-thioxo-4-year-old xo-5-trityloxyimino-perhydro-2H-1,3-thiazine (5
．． 4g) at 0-5°C while stirring. 5-10℃
Continue stirring for 30 minutes. The reaction solution was diluted with ethyl acetate (t
Pour into a mixture of oomu) and cold water (100+Ilfl). The organic layer is separated, dried over magnesium sulfate, and concentrated under reduced pressure until the volume reaches IOInQ. The precipitate was collected by filtration and washed with diisopropyl alcohol and diisopropyl ether to give 2-thioxo-4.
-Sakiso-5-hydroxyimino-perhydro-2H-
1.3-thiazine (1.6 g) is obtained.

mp: 138 (42℃ (decomposition) IR (suji meal): 3280. 170
0. 1600. 1405 am-1HMR
(DMSO-ds,l; )' 4-18 (2H
, s) 97, 23 (15H.

s).

Titanium trichloride (2
Add a 5% aqueous solution (444 mQ) dropwise at 8°C while stirring. After addition, continue stirring at the same temperature for 1 hour.
Insoluble materials are filtered off, the filtrate is concentrated to remove dioxane, and the residue is extracted with ethyl acetate. Concentrate the extract under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate and benzene (3:1).
Collect the fractions containing the target compound and evaporate the solvent under reduced pressure. The crystalline residue was recrystallized from diisopropyl alcohol to give 2-thioxo-4-oxo-5-hydroxy-3
．． 4-dihydro-2H-1,3-thiazine (4.05g
) is obtained as a pale yellow mass.

mp: 175-176°C (decomposition) IR (streak rule): 3500. 16
70. 1610 cm″″INMR (DMSO
-ds. δ): 6.70 (LH.s).

1 Soot vector j 161 (M”) Elemental analysis (C4
H3NO□S2) Calculated value i C 29.80.
H 1.88, N 8.69. S 39.77.

Actual measurements: C 29.67, H 1.85. N8
．． 42, S 39.50.

115B 1-methyl-3,6-dichloro-4-oxo-1,4-
To a solution of dihydropyridazine (1.8 g) in dimethyl sulfoxide (10 fflll) is added sodium hydrosulfide (NaSH) (1.1 g) at 5°C with stirring. After stirring at 10°C for 1 hour, ethyl acetate (30 mEI) and water (30 ml!) were added to the reaction solution.
) and adjust the pH to 2.0 with IN hydrochloric acid! It is. Yes 1
Separate the first layer, wash with water and saturated aqueous sodium chloride solution, dry over magnesium sulfate, and evaporate the solvent under reduced pressure. Diisopropyl ether was added to the crystalline residue, the precipitate was collected by filtration, and 1-methyl-3-chloro-4-
Oxo-6-mercabuto 1,4-dihydropyridazine (1.2 g) is obtained.

mp' 131-133℃ IR (v;a-L>=1630.155
0. 1480 am-1NMR (DMSO-d6
．． δ) = 3.93 (3H, s), 6.80 (L
H,s) Production Example 13 In the same manner as Production Example 12, 2-methyl-3-year-old xo 5
-Chloro-6-hydroxy-2,3-dihydropyridazine (3,21 g) to 2-methyl-3-year-old xo-5-
Mercapto-6-hydroxy-2,3-dihydropyridazine (2,7 g) is obtained.

mp: 220-225°C (decomposition) IR (streak 1-l) 2 1620. 1560.
1490 am-1HMR (DMSO-d6.l;
): 3.40 (s), 3.43 (s).

(Ratio = 1:3), 4.23 (S), 6.62
(s), (ratio=2:3).

Production Example 14 7-Amitusephalosboranic acid (2,72g) and 1-methyl-2-thioxo-4-year-old xo-5-hydroxy-1
,2,3,4-tetrahydropyrimidine (1,58g)
Boron trifluoride, diethyl ether complex (4.26 g) is added to a solution of the above in trifluoroacetic acid (5011Q) at room temperature. After stirring the reaction solution at the same temperature for 5 hours, the solvent was distilled off under reduced pressure. The residue was triturated in diisopropyl ether and filtered to obtain a crude product. Add this to cold water (l
0IILII) and adjusted to pH 3.2 using a 14% aqueous ammonium hydroxide solution under water cooling. The formed precipitate was collected by filtration and washed successively with cold water, acetone, and diisopropyl ether to give 7-amino-3-(1-methyl-4-hydroxy-5-hydroxy-1,4-dihydropyrimidine-2- yl)thiomethyl-3-cephem-4
-carboxylic acid (1°55 g) is obtained.

mp: 168-172°C (decomposition) IR (sugital)' 1800. 1650.
1600. 1240 cn+-' mass spectrum: 371 (M+1) NMR<o2o+Nauco3
．． S)' 3-60 (3H1s), 3.50 and 3.43 (2H, ABq, J=18Hz>, 4
．． 35 and 4.08 (2H,ABq,,C14Hz
>, 5.05 (IH.

dJ=5Hz>, 5.40 (IH, d, J=5Hz
>, 7.13 (LH.

s).

7-amino-3-(3-methyl-4-oxo-5-hydroxy-3,4-dihydropyrimidin-2-yl)-thiomethyl-3-cephem-4 was prepared in the same manner as in Jusan Echo Production Example 14.
- obtain carboxylic acid.

mp: 172-175°C (decomposition) IR (striped tool) 2 1800. 1650. 1
610. 1410°1380 am-1 NMR (C20+DC1, δ): 3.6g (3H
,s), 3.73 (2H.

Broad s), 4.33 (2H, Broad
! ! >, 5.31 (IH, d.

J=5Hz), 5.48 (LH, d, J=5Hz>
, 8.07 (IH, 5) 11 and 7-amino-3-(1-methyl-4-year-old xo-6-hydroxy-1,4-dihydropyrimidin-2-yl) Thiomesol-3-cephem-4-
Obtain carboxylic acid.

mp: 172-174°C (decomposition) NMR (C20, δ): 3.30 (3H, s),
4.43 and 4.07 (2H, ABq, J:14
Hz>, 4.53 and 4.77 (2H, ABq, J
= 18Hz), 5.00 (5Hz for LH, d).

5.37 (LH, d, J=5Hz).

Production Example 17 2-thioxo-4-year-old xo-5-hydroxy-3,4-
In a solution of dihydro-2H-1,3-thiazine (3.0 g) and sodium bicarbonate (6.3 g) in water (60 m),
Bis(trifluoromethanesulfonic acid) salt of 7-amino-3-dimethylsulfoniomethyl-3-cephem-4-carboxylate <12. '8g) was added little by little at 5°C while stirring. The reaction solution was stirred for 1 hour at 5-8°C and adjusted to pH 3.0 using 6N hydrochloric acid.

The obtained precipitate was collected by filtration and washed with acetone and diisopropyl ether to give 7-amino-3-(4-oxo-5-hydroxy-4H-1,3-thiazin-2-yl)thiomethyl-3- Cephem-4-carboxylic acid (2,8
g) is obtained.

mp: 205-210°C (decomposition) IR (sugital): 3300. 1780.
1640. 1610 cm-INMR (DMSO
-d6. ): 4.13 and 4.43 (
2H.

ABq, J=14Hz, 4.70 (IH,
d, J=5Hz>, 4.93 (IH, d, J=5
Hz>, 7.03 (IH,s).

Production Example 18 In the same manner as in Production Example 17, 7-amino-3-(2-methyl-3-year-old xo-6-hydroxy-2,3-dihydropyridazin-5-yl)-thiomethyl-3-cephem-4
- Obtain carboxylic acid.

mp: 168-173℃ (decomposition) IR (streak seal) '3300. 1800.
1620. 1540 am-'NMR(D O"
NaHCO3,8)' 3.43 and 3.70 (
2H.

ABq, J=18Hz>, 3.48 (3H,s),
4.02 and 3.78 (2H, ABq, 14
Hz, 4.70 (LH, d.

J=5Hz>, 5.05 (IH, d, J=5Hz)
, 6.52 (IH, s).

Manufacturing example 19? -[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamide]-3
-Iodomethyl-3-cephem-4-carboxylic acid benzhydryl ester 1-oxide (14,4 g) and 2-thioxo-4-oxo-perhydro-2H-1,3-thiazine (2,6 g) N.

Anhydrous potassium carbonate (1.38 g) is added to a solution in N-dimethylformamide (100 IIQ) at 5-10 DEG C. with stirring. After stirring at the same temperature for 2 hours, ethyl acetate (200 ml) and water (200 mQ) were added to the reaction mixture. The ammonium is collected, washed twice with water, and then concentrated under reduced pressure. The precipitate formed is collected by filtration and washed with a small amount of acetone and ethyl acetate to give 7-[2-(5-amino-1
,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamidoco-3-(4-year-old xo5,6-cyhydro-4H-1,3-thiazin-2-yl)thiomesol-3-cephem-4- Carboxylic acid benzhydryl ester 1-oxyto (7.3 g) is obtained.

mp: 168-171°C (decomposition) IR (striped fur): 3400. 3150.
1790. 1720. 1690°1620, 15
10 am” NMR (DMSO-ds, S)' 127 (3H
, t, J=7Hz), 2.4-2.6 (2H, m)
, 3.3-3.5 (2H, m), 3.83 (2
H.

Broad s), 3.90 (IH, d, J=1
4Hz), 4.50 (IH.

d, J: 14Hz>, 4.20 (2H, q, J=7
Hz>, 5.01 (IH.

d, J=5Hz), 6.02 (IH, dd, J=8
Hz and J=5Hz), 6.93 (IH,s),
7.1-7.5 (IOH).

8.07 (2H, broad s), 8.90
(LH, d, J: 8Hz).

Production Example 20 In the same manner as Production Example 19, 7-[2-(5-amino-1
,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamide]-3-(4-year-old xo4H-1,
3-thiazin-2-yl)thiomethyl-3-cephem-
4-Carboxylic acid benzhydryl ester l-oxyto is obtained.

mp: 161-165°C (decomposition) IR (sudicol): 3300. 1790.
1650. 1620 am-INMR (DMSO
-d6. δ): 1.25 (3H, t, J=7Hz
>, 3.83 (2H, broad s), 4.18
(2H,q, 7Hz>, 4.00(IH,d
, J-14)1z), 4.63 (IH, d, J=1
4Hz>, 5.01 (LH, d, J=5Hz), 6
．． 00 (IH, dd, J = 8 Hz and J = 58 Hz, 6.58 (1) 1. d, J = 10 Hz),
6.97 (IH.

s), 7.1-7.5 (IOH), 8.05 (
lH, d, J-10Hz>.

8.13 (2H, broad s), 8.87
(IH, d, J: 8Hz).

A solution of 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer) (1.0 g) in N,N-dimethylformamide (10 fflll) was added under stirring to a solution of -20 methanesulfonyl chloride (1.1 g
) and then diimpropylethylamine (1,
3g). Thereafter, stirring was continued for 1 hour at -20 to -25°C. This reaction solution (6IQ) was converted into 7-amino-
3-(1-methyl-4-year-old xo-5-hydroxy-1,
4-dihydropyrimidin-2-yl)thiomethyl-3-
Cephem-4-carphonic acid (740 mg) and trimethylsilylacetamide (4.0 g) in methylene chloride (2
01M) solution at -20°C with stirring. After stirring the reaction solution at the same temperature for 1 hour, it was concentrated under reduced pressure. After washing the residue three times with diethyl ether, water (5ml)
was added, and the pH was adjusted to 7 with dilute aqueous sodium bicarbonate solution to obtain a clear solution. This solution was adjusted to pH 3.0 with IN hydrochloric acid under water cooling. The formed precipitate is collected by filtration and washed with cold water,
After washing with acetone and diimpropyl ether, 7-
[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-(1-methyl-4-year-old xo-5-hydroxy-1,4-dihydropyrimidine-
2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (220 mg) is obtained.

mp: 152 (55℃ (decomposition) IR (X di*-IL): 3300. 1760
．． 1650. 1610. 1550°1540 a
m-1 NMR (DMSO-ds-8): 3-47 (3H,
s), 3-67 (2H.

Broad s), 3.80 (3H, s),
4.40 and 4.13 (2H, ABq, J:1
4Hz), 5.13 (IH, d, J=5Hz>.

5.77 (IH, dd, J=8Hz and J=5)1
z), 6.73 (IH, s), 7.17 (2
H, Broad s), 7.40 (IH, s).

9.53 (IH, d, J=8Hz>.

In the same manner as in Example 1, the following compounds (Examples 2 to 5)
get.

Toka] Nia-(2-(2-aminothiazol-4-yl)-2-
methoxyiminoacetamide]-3-(3-methyl-4
-xo-5-hydroxy-3,4-dihydropyrimidin-2-yl)thiomethyl-3-cephem-4-carvone # (syn isomer) rnp: 14g-153°C (decomposition) IR (suji meal): 1760. 1-640. 1510
am″″INMR (DMSO-ds, δ): 3.
40 (3H,s), 3.46 and 3.70 (2
H, ABq, J:=18Hz), 3.80 (3H,
s).

4.43 and 4.67 (2H, ABq, J=14H
z), 5.08 (IH, d, J=5Hz>, 5.7
3 (IH, dd, J=8Hz and J=5Hz),
6.70 (IH,s), 7.13 (2H
, Broad s).

7.46 (LH, s), 9.50 (IH, d, J
=8Hz).

1 7-[2-(2-aminothiazol-4-yl)-2-
methoxyiminoacetamide]-3-(4-year-old xo5
-Hydroxy-4H-1,3-thiazin-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) tnp: 162-167°C (decomposition) IR (x di*-
4)' 3300. 17g0. 1630.
1540 am-1HMR (DMSO-ds, l;
): 3.63 (2H, broad s),
3.83 (3H,s), 4.10 and 4.47
(2H, ABq.

J-14Hz>, 5.13 (IH, d, J=5H
z>, 5.85 (IH.

dd, J=8)1z and J=5Hz), 6.73
(IH, s).

7.03 (IH,s), 9.53 (1)1. d
, J=8Hz).

Tue J11± 7-[2-(2-aminothiazol-4-yl)-2-
methoxyiminoacetamide]-3-(1-methyl-4
-oxo-6-hydroxy-1,4-dihydropyrimidin-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) mp: 145-149°C (decomposition) NMR (DMSO-ds, δ) : 3.32 (3H
,s), 3.83 (3H.

s), 3.6-4.0 (2H, m), 4.0-4
．． 5 (2H, m).

5.10 (IH, d, J=5Hz>, 5.40 (
IH, s), 5.47 (IH, dd, J: 8Hz and J=5Hz), 6.81 (IH.

s), 7.13 (2H, broad s), 9
．． 82 (IH, dJ=8Hz).

Phantom 1μ 7-[2-(2-aminodeazol-4-yl)-2-
Methoxyiminoacetamidoco-3-(2-methyl-3
-oxo-6-hydroxy-2,3-dihydropyridazin-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) mp: 148-152°C (decomposition) IR (X di+-4) : 3300. 1770
．． 1620. 1530 cm-INMR (DMS
O-ds, δ): 3.40 (3H, s), 3.
67 and 3.50 (2H, ABq, J=18Hz>
, 3.82 (3H, s), 4.02 (2H, broad s), 5.15 (IH, d, J=8Hz
), 5.73 (IH, dd, J=8Hz and J=
5Hz), 6.50 (IH.

s), 6.70 (IH, s), 7.13
(2H, broad s), 9.52 (IH, d,
J=8Hz).

υei (16 two-amino-3-(4-year-old xo-5-hydroxy-4H
-1,3-thiazin-2-yl)thiomethyl-3-cephem-4-carboxylic acid (650 mg) in water (6,51
119) and a suspension in acetone (13 mQ),
Triethylamine (182 mg) was added at -5 to 0°C, and then 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetyl chloride hydrochloride (syn isomer) (518 mg> is added little by little. At this time, by adding triethylamine, p
After stirring for 1 hour at 0-5° C., keeping H at 6.0-6.5, ethyl acetate (tomn) is added to the reaction solution. A small amount of insoluble matter was filtered off, and the filtrate was adjusted to pH 3.8 with IN hydrochloric acid. After separating the aqueous layer and distilling off the remaining ethyl acetate under reduced pressure, the pH of the solution was adjusted to 2.0 with IN hydrochloric acid. The formed precipitate was collected by filtration to give 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-
Ethoxyiminoacetamidoco-3-(4-year-old xo5)
-Hydroxy-4H-1,3-thiazin-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (250 mg) is obtained.

mp: 162-167℃ (decomposition) IR (sujiwor): 3300. 1?70.
1680. 1620°1520 cm-1 NMR (DMSO-d6.δ): 1.23 (3H
, t, J=7Hz>, 3.70 and 3.53 (2
H, ABq, J=18Hz), 4.13 (2H.

ABq, J=14)1z), 5.10 (LH,d
, J=5Hz>, 5.77 (LH, dd, J=8H
z and J=5Hz), 7.00 (IH.

s), 8.05 (2H, broad s),
9.45 (IH, d.

J=8Hz).

1st place The following compounds are obtained in the same manner as in Example 6.

7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamide]-3
-(2-methyl-3-year-old xo-6-hydroxy-2,3
-dihydropyridazin-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) mp: 162-165°C (decomposition) IR(Xdi*-A)' 3300. 1770.
1660. 1620°1530 am-1 NMR (DMSO-d6.δ): 1.25 (3H
, t, J=7Hz), 3.70 and 3.50 (2
H, ABq, J=18Hz), 3.40 (3H.

s), 4.03 (28, broad s),
4.15 (2H, q.

J near Hz>, 5.15 (IH, d, J-5Hz>
, 5.78 (IH, dd.

J=5Hz and J=8Hz), 6.63 (IH,
s), 8.05 (2H9io-r s), 9.
47 (IH, dJ=8Hz>.

Tue 11Fl Dan7-[2-(2-formamidothiazol-4-yl)
-2-Methoxyiminoacetamide]-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer) (3.9 g) and 1-methyl-3-chloro-4-year-old xo-6-mercabuto To a solution of 1,4-dihydropyridazine (1,3 g) in N,N-dimethylformamide (201d) at 5-10°C is added sodium acetate (492 mg) under stirring. After stirring at the same temperature for 2 hours, ethyl acetate (100mM) and water (100mM) were added to the reaction mixture. Yes! The calendar is taken out, washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was triturated in diisopropyl ether to give 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamide]-3-(1-methyl-3-chloro-4-year-old xo1. 4-dihydropyridazin-6-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer) (4.0 g) is obtained.

mp: 139-142°C (decomposed) NMR (DMSO-d6.8): 3.40 and 3.27 (2H.

ABq, J=18Hz), 3.77 (3H,s),
3.90 (3H, s).

4.10 (2M, broad s), 5.25
(IH, d, J=5Hz).

5.95 (IH, dd, J=8Hz and J-5Hz
>, 6.40 (IH, s), 6.90 (IH, s
), 7.1-7.6 (IOH).

8.48 (IH, s), 9.67 (LH, d, J
-8Hz>.

Fortress 1 The following compound is obtained in the same manner as in Example 8.

7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamide]-3
-(1-Methyl-3-chloro-4-dihydropyridazin-6-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (syn isomer) mp: 172-175°C ( Disassembly) IR (streak): 3300. 1770.
1715. 16g0. 1600°1520 am
'NMR (DMSO-d6.δ): 1.23 (3H
, t, J=7Hz), 3.47 and 3.70 (2
H, ABq,, Cl8Hz>, 3.75 (3H.

s), 4.07 (2H, broad s),
4.15 (2H, q.

J=7Hz), 5.22 (IH, d, J:5Hz
>, 5.90 (IH, dd.

J=8Hz and J=5Hz), 6.40 (IH,
s), 6.88 (LH, s), 7.1-7.5
(10B), 8.07 (2H, Broads)
, 9.53 (IH, d, JJ) Iz).

] U1 mark 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3
-Chloromethyl-3-cephem-4=carboxylic acid (syn isomer) (0.86 g) in N,N-dimethylformamide (10 ffl12) was added with sodium iodide (0.1 g) and 2-mercapto-4 -Saikiso 5
-Hydroxy-1,4-dihydropyrimidine (0,28
Add g) and stir at room temperature for 3 hours. Pour the reaction mixture into a mixture of ethyl acetate (50ffI+1) and water (600111). Adjust the pH of the solution to 7.0 by adding saturated aqueous sodium bicarbonate solution. . After separating the aqueous layer and adjusting the pH to 4.0 with 10% hydrochloric acid, it was subjected to column chromatography using "Diaion HP-20"(trademark; manufactured by Mitsubishi Chemical Industries, Ltd.) and 10% aqueous isopropyl alcohol. Elute at . The eluates containing the target product were combined and lyophilized to give 7-[2-(5-amino-1,
2,4-thiadiazol-3-yl)-2-methoxyiminoacetamidoco-3-(4-year-old xo-5-hydroxy-1,4-dihydropyrimidin-2-yl)thiomethyl-3-cephem-4-carboxylic acid (Syn isomer) (0
, 15 g).

IR (Streak 3-L): 3300. 1760.
1600 am-1HMR (DMSO-d6.ε)
: 4.15 and 4.48 <2H.

ABq, J: 13Hz), 5.00 (IH, d, J
=5Hz>, 5.60 (LH, dd, J: 5Hz and 8Hz), 6.63 (IH, s).

7.10 (2H, broad s), 7.38
(IH, s), 9.35 (d, J=8Hz).

λ凰古dan7-(2-(2-aminothiazol-4-yl)-2-
Hydroxyiminoacetamide]-3-chloromethyl-
To a solution of 3-cephem-4-carboxylic acid benzhydryl ester (syn isomer) (4,0 g >
-thioxo-4-year-old xo-5-hydroxy-1,2,3
, 4-tetrahydropyrimidine (1.1 g) and sodium iodide (0.5 g) were added and stirred at room temperature for 3 hours.
The reaction solution was mixed with water (100 mQ) and ethyl acetate (80 mQ).
) and tetrahydrofuran (40 mQ), separate the organic layer, and concentrate under reduced pressure. The residue was triturated in diethyl ether to give 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamidoco-3-(1-methyl-4-hydroxy-5-hydroxy-
1,4-dihydropyrimidin-2-yl)thiomethyl-
3-cephem-4-carboxylic acid benzhydryl ester (syn isomer) (3.3 g) is obtained as a powder.

The obtained ester (3.3 g) was dissolved in methylene chloride (1f
Add trifluoroacetic acid (6,6mQ) under water cooling to a solution dissolved in a mixture of flQ) and anisole (3,31119). 6. Stir the reaction mixture at the same temperature for 2 hours, then pour into diisopropyl ether (100fflll). .

The resulting precipitate is collected by filtration and dissolved in a 5% aqueous sodium hydrogen carbonate solution. The pH of this solution was adjusted to 4 using 10% hydrochloric acid.
．． 0, and subjected to column chromatography using Diaion HP-20 (eluted with 10% aqueous isopropyl alcohol). Combine the eluates containing the target product,
Freeze-dry to give 7-[2-(2-aminothiazole-4
-yl)-2-hydroxyiminoacetamide]-3-
(1-methyl-4-year-old xo-5-hydroxy-1,4-
Dihydropyrimidin-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.2 g) is obtained.

IR (Sujicor): 3200. 1750.
1650 cm″″INMR (DMSO-d6.δ
): 3.93 (3H,s), 4.27 and 4
．． 62 (2H, ABq, J=14Hz), 5.12
(IH, d.

J: 5Hz>, 5.80 (LH, dd, J=5Hz
and 8Hz).

7.38 (IH,s), 8.10 (2H,
Broad s), 9.52 (tH, d, J=8Hz
).

East n exit? -[2-(2-formamidothiazol-4-yl)
-2-methoxyiminoacetamide]-3-(1-methyl-3-chloro-4-oxo-1,4-dihydropyridazin-6-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester (synisomer body) (4,0
g) in methanol (40 nQ) was added with concentrated hydrochloric acid (1
, 611LQ) at room temperature with stirring. 1 at the same temperature.
Stir for 5 hours.

Ethyl acetate (1oomu) and water (100ff) were added to the reaction solution.
lll), the organic layer is separated and washed with water and saturated aqueous sodium chloride solution. The residue obtained by distilling off the solvent was triturated in diethyl ether to give 7-[2
-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-3-(1-methyl-3-chloro-4-oxo-1,4-dihydropyridazin-6-yl)thiomethyl-3-cephem -4-J levonic acid benzhydryl ester (syn isomer) (2.8 g) is obtained.

mp: 147-152°C (decomposition) IR (nudial): 3300. 17
75, 1715. 1670, 1600.

1520 am-1 NMR (DMSO-d6.f; ): 3. 5
2 and 3.72 (2H.

ABq, J=18Hz), 3.78 (3H,s)
, 3.85 (3H,s).

4, 10 (2H.Broad s), 5.25
(1)1. d. J=5)1z).

5, 88 (LH.dd.J=8Hz and J=5Hz
), 6.43 (IH.s>, 6.73 (IH.
s), 6.90 (IH, s), 7.1~7,
5 (IOH), 9.58 (IH.d, J=8H
z).

Tue] Kuchisu 7-[2-(2-aminothiazol-4-yl)-2-
Methoxyiminoacetamidoco-3-(1-methyl-3
-chloro-4-xo-1,4-dihydropyridazine-
methylene chloride (28 rMi) of anisole (IIQ) and anisole (IIQ)
), add 0 to 5 of trifluoroacetic acid (41nQ) to the solution in
Add while stirring at °C. The reaction solution was stirred at 5°C for 1 hour and then at room temperature for 1 hour. Ethyl acetate (50) and water (501) were added to the residue obtained by distilling off the solvent m.
1111) and adjust the pH to 7.0 using saturated aqueous sodium hydrogen carbonate solution. Separate the aqueous layer, adjust the pH to 4.0 with IN hydrochloric acid, and filter off the precipitate. The filtrate was adjusted to pH 2.0 with IN hydrochloric acid. 5, and the resulting precipitate was collected by filtration and washed with water to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamide]-
3-(1-methyl-3-chloro-4-year-old xo1.4-
Dihydropyridazin-6-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (850 mg
).

mp: 162-167℃ (decomposition) IR (Sujoor) i 3300. 17
80. 1660. 1530 am-'NMR
(DMSO-d6, δ): 3.53 and 3.7
3 (2H.

ABq, J=18Hz>, 3.83 (3)1. s)
, 3.86 (3H.s).

4, 18 (2H. Broad s), 5.13
(IH.d.J=5)1z).

5, 75 (IH.dd, J=8) 1z and J=5H
z), 6.58 (IH, s), 6.73 (IH.
s), 9.55 (LH.d., C8Hz).

In the same manner as in Example 13, the following compounds (Examples 14 and 15) are obtained.

7-[2-(5-amino-1.2.4-thiadiazol-3-yl)-2-ethoxyiminoacetamide]-3
-(1-Methyl-3-chloro-4-dihydropyridazin-6-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) rnp: 148-153°C (decomposition) IR ( Streak 1-le): 3300. 1775. 16
g0. 1580 cra-'NMR (DMSO
-ds,S)' 1.23 (3H.t.J=7H
z), 3-70 and 3.53 (2H.ABq,J
J8Hz), 3.87 (3H.

s), 4.13 (2H.q.J near Hz),
4.20 (2H, broad s), 5.13 (
IH. d. J=5Hz), 5.78 (IH.dd.

J=8Hz and J=5Hz), 6.57 (IH.
s), 8.05 (2H, broad s), 9.4
8 (IH.d.J=8Hz>.

and five trigrams 7-[2-(5-amino-1.2.4-thiadiazol-3-yl)-2-ethoxyiminoacetamide]-3
-(4-year-old xo-4H-1,3-thiazin-2-yl)
Thiomethyl-3-cepheme-4-carboxylic acid (syn isomer) mp: 149-153°C (decomposition) IR (sujiwor): 3300. 1770.
1660. 1620°1520 am-1 NMR (DMSO-da, S)' 1.25 (3
H9t, J near t(z), 3.57 and 3.73 (
2H, ABq, J=18Hz), 4.17 (2H.

q, J=7Hz>, 4.13 and 4.50 (2H
, ABq.

J=14Hz>, 5.13 (IH, d, J=5Hz
), 5.63 (IH.

dd, J=8H2, and J=5Hz), 6.63
(IH, d.

, Cl0Hz), 8.07 (LH, d, J: 10H
z), 8.08 (2H.

Broad s), 9.48 (IH, d, J: 8
Hz＞.

1■ Anhydrous aluminum chloride (800mg) and anisole (
2-) solution phase in nitromethane (20ffLQ), 7
-[2-(5-amino-1,2,4-thiadiazole-
3-yl)-2-ethoxyiminoacetamidoco-3-
(4-year-old
A solution of 5 g) in nitromethane (5 mjl) is added with stirring at 0-5°C. After stirring at the same temperature for 30 minutes,
Ethyl acetate (some) and cold water (50111
Q). The organic layer is separated, washed with water, and then extracted with a dilute aqueous sodium hydrogen carbonate solution. After adding ethyl acetate to the extract, the pH was adjusted to 2.0 with 6N hydrochloric acid. The organic layer is separated and washed with saturated aqueous sodium chloride solution.

After drying with magnesium sulfate, concentrate under reduced pressure. The formed precipitate was collected by filtration and washed with a small amount of ethyl acetate and diisopropyl ether to give 7-(2-(5-amino-1,2
,4-thiadiazol-3-yl)-2-ethoxyiminoacetamide]-3-(4-year-old xo5,6-sihydro-4H-1,3-deazin-2-yl)thiomethyl-
3-cephem-4-carvone # (syn isomer) (20
0 mg).

r! lp: 165-170°C (decomposition) IR (streak 9-l): 3300. 1775. 1670
．． 1610°1520 am-1 NMR (DMSO-ds, l; ) ' 1.23 (
3H9t-1J=7Hz), 2.6~2.8 (2H,
m), 3.3=3.5 (2H, m), 3.4
3-3.70 (2H, ABq, J: 18Hz), 4
．． 13 (2H, q, J=7Hz).

4.00 and 4.36 (2H, ABq, 14Hz
>, 5.17 (IH, d, J=5Hz), 5.78
(IH, dd, J=8Hz and J=5Hz>,
8.07 (2H, broad s), 9.46
(IH, d.

J=8Hz).

衷Jd1■? -[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamidoco-3
-(4-year-old xo-5.6-cyhydro-48-1.3-thiazin-2-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester 1-oxyto (syn isomer) (11,6 g) Nato 5'c de o franc (73
m1), N,N-dimethylformamide (39m1+
) and propylene oxide (31,411111)
Acetyl bromide (13.5 g) was added dropwise to the solution in the mixture at -30° C. while stirring. After stirring for 15 minutes, the reaction solution was poured into cold water (40011Q), and the precipitate formed was collected by filtration. The obtained material was diluted with tetrahydrofuran (3
QmQ ), ethyl acetate (50 m12) and water (2
011Q), the organic layer is separated and washed with a saturated aqueous sodium chloride solution. The residue obtained by distilling off the solvent was subjected to column chromatography using silica gel and eluted with ethyl acetate to obtain 7-[2-(5
-amino-1,2,4-thiadiazol-3-yl)-
2-Ethoxyiminoacetamide]-3-[4-oxo-5,6-cyhydro-4H-1,3-thiazin-2-yl)thiomethyl-3-cephem-4-hydruponic acid benzhydryl ester (syn isomer) (3.54 g) is obtained.

mp: recrystallized from tromethane at 161-165°C (decomposition) IR (stir 1-l): 3300. 17B0.
1720. 16B0. 1620°1520 cr
tr-' NMR (DMSO-d6.l; )' 1.23 (
3H9t, J'7Hz>, 2.5-2.7 (2H, m
), 3.3-3.5 (2H, m), 3.57 and 3.73 (2H, ABq, J=18Hz), 3.
87 (IH, d.

J=14Hz), 4.35 (IH, d, JJ4Hz
), 4.15 (2H.

q, J=7Mz), 5.17 (LH, d, J=5H
z), 5.90 (1) 1°dd, J=8Hz and J:5Hz>, 6.88 (IH,s).

7.1-7.5 (IOH), 8.07 (2
H, broad s), 9.50 (IH, d, J=8
)12).

Tue] D breasts L The following compound is obtained in the same manner as in Example 17.

7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamidoco-3
-(4-year-old xo-4H-1,3-thiazin-2-yl)
3300. 1780, 17
10. 1680. 1630.

1520 cm-1 NMR (DMSO-da.8)' 1. 23
(3H.t.J=7Hz>, 3.60 and 3.80
(2H, ABq, J=18Hz), 3.97 (I
H.

d, J=14Hz), 4, L7 (2)1. q. J＝
7Hz), 4.48 (IH.

d, J-14Hz), 5.18 (IH, d,, C5
Hz), 5.92 (IH.

dd. J=8Hz and J=5Hz), 6,60
(IH.d.

J=10Hz), 6.90 (LH,s), 7.1
~7.5 (101).

8, 05 (LH.d.J=10Hz), 8.1
0 (2H.Broad s).

9, 53 (IH, d, J = 8Hz).

Claims (1)

[Claims] 1) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 is an amino group or a protected amino group, R^2 is hydrogen or a lower alkyl group, R^ 3 is a carboxyl group or a protected carboxy group, R^4 is a 4-oxo-1,4-dihydropyrimidinyl group having a lower alkyl group or a hydroxy group; 4-oxo-3 having a lower alkyl group or a hydroxy group
, 4-dihydropyrimidinyl group; 3-oxo-2,3-dihydropyridazinyl group having a lower alkyl group or hydroxy group; 4-oxo-1,4- which may have a lower alkyl group or halogen Dihydropyridazinyl group; 4-oxo- which may have a hydroxy group
4H-1,3-thiazinyl group; or 4-oxo-5,
6-dihydro-4H-1,3-thiazinyl group and X each mean N or CH. ) Novel cephem compounds and their salts. 2) The compound according to claim 1, wherein R^1 is an amino group and R^3 is a carboxy group. 3) (i) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^2 and X each have the same meaning as in claim 1) Compounds represented by or its reactive derivatives at the carboxyl group or their salts have the general formula: ▲Mathematical formula, chemical formula, table, etc.▼ (In the formula, R^3 and R^4 each have the meaning in claim 1. (ii) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^ 2, R^3 and (same meaning as before), or (iii) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^2, R^3, R^4 and and R^1_a means a protected amino group) or its salts are subjected to an amino-protecting group elimination reaction to form the general formula: ▲Mathematical formula, chemical formula, table, etc. (iv) General formula: ▲ Numerical formula, chemical formula, table etc. ▼ (In the formula, R^1, R^2, R^4 and X each have the same meaning as before, and R^3_a means a protected carboxy group) or its salts is subjected to the elimination reaction of the carboxy protecting group, the general formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^2, R^4 and X each have the same meaning as before. ), or (v) General formula: ▲Mathematical formula, chemical formula, table, etc.▼ (In the formula, R^1, R^2, R^3, R^4 and (X has the same meaning as before) By subjecting the compound shown by or its salt to a reduction reaction, the general formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^2, R^ 3. R^4 and X each have the same meaning as above) A method for producing a novel cephem compound, which is characterized by obtaining a compound or a salt thereof.