JPH01258685A - Cephem based compound - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> represents (protected) amino; R<2> represents esterified carboxyl; R<10> represents lower alkyl; n is 0 or 1] or salt thereof. EXAMPLE:Pivaloyloxymethyl 7-[(Z)-2-(2-formylamino-4-thiazolyl)-2-(methoxyimino) acetamide]-3-[(3-methyl-1,2,4-thiadiazol-5-yl)thiomethyl]-3-cephem-4-c arboxylate. USE:An orally absorbable preventive and remedy for microbisms. PREPARATION:A 7-amino-3-(3-alkyl-substituted-1,2,4-thiadiazol-5-yl)thiomethyl-3- cephem-4-carboxylic acid derivative expressed by formula II [R<6> represents R<2> or (protected) carboxyl] is acylated with a compound expressed by formula III, followed by deprotection and esterification of carboxyl group as required to obtain the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Field of Application> The present invention relates to an orally absorbable cephalosporin derivative useful as a prophylactic and therapeutic drug for mycobacteria.

<Prior Art> In recent years, the development of cephem antibiotics as therapeutic agents for infectious diseases has been remarkable, and compounds with strong antibacterial activity and a wide range of antibacterial spectrum are now commercially available. However, most of these compounds are poorly absorbed when administered orally and are only effective when injected.

On the other hand, among penicillin compounds, compounds whose carboxylic acids are esterified and have improved oral absorption as so-called prodrugs are in clinical use. That is, it was esterified. It is believed that after the compound is absorbed into the body, it is hydrolyzed by enzymes present in blood, serum, and body tissues, and becomes a sharp compound of the original carboxylic acid, which exerts its effects. Similar attempts have been made with cephalosporin compounds, but so far only cefuroxime axetil and cefteram bipoxil have been put into clinical use, i.e. penicillin compounds. Certain ester groups that were effective in enhancing oral absorption in cephalosporin compounds may not be equally effective in cephalosporin compounds.

<This invention attempts to solve! ! ! Title: The object of the present invention is to provide a cephem antibacterial agent that is highly absorbable upon oral administration and has a long-lasting effect.

<Method for solving L1 problem> The present invention relates to cephem derivatives, and more specifically, -
Catalytic formula (I) CRs (wherein R1 represents an amine group or a protected amino group,
The present invention relates to a cephem derivative or a salt thereof, represented by R''G represents an esterified carboxyl group, R10 represents a lower alkyl group, and n represents 0 or 1.

The present inventors have repeatedly conducted research on improving oral absorption using prodrugs of cephalosporin compounds, but oral absorption was completely unpredictable, and the structure and properties of the selected acute compound and ester moiety I found that it depends a lot.

As a result of examining compounds with various structures based on this knowledge, we found that ester compounds with certain structures have higher oral absorption and persistence than could be expected from known compounds with similar structures, This led to the present invention.

The compound represented by Ichihime is a useful compound that has strong antibacterial activity against Durham-positive bacteria and Durham-negative bacteria, as well as strong antibacterial activity against beta-lactamase-producing resistant bacteria. The above compound in which R'' is a methyl group is described in JP-A-53-108996.

After the ester compound of the present invention is orally absorbed, it is thought that it becomes a sharp compound with a carboxyl group at the 4-position and exerts its effect, and it can be used as a prophylactic and therapeutic drug for bacterial infections.
It is an extremely valuable compound.

-a In Formula (1), the esterified carboxyl group represented by R1 is
” υ can be done.

Here, R3 is a hydrogen atom, an alkyl group or a cycloalkyl group, and l? 4 is an alkyl group, a cycloalkyl group or a 1-substituted cycloalkyl group. The alkyl group of R3゜R4 is a linear or branched alkyl group having, for example, 1 to 2 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl. , n-pentyl, n-hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and the like. R',
The cycloalkyl group for R' is a cycloalkyl group having 3 to 12 carbon atoms, and examples thereof include cyclopropyl, cyclohexyl, cyclohebutyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. Furthermore, the 1-substituted cycloalkyl group of R4 has the general formula R5 (wherein, R5 is a lower alkyl group, m is 3.4 or 5
). The lower alkyl group of Rs is a linear or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl group, etc. .

Specific examples of the above esters include -a formula % formula % ci) propyl ester, l-acetoxypropyl ester, ]-methylcyclohexanecarbonyloxymethyl ester, 1-ethylcyclohexanecarbonyloxymethyl ester, etc. , methoxycarbonyloxymethyl ester, l-methoxycarbonyloxyethyl ester, 1-methoxycarbonyloxypropyl ester, ethoxycarbonyloxymethyl ester, propyloxycarbonyloxymethyl ester, 1-ethoxycarbonyloxyethyl ester, 1-propyloxycarbonyl Examples include oxyethyl ester.

-i In formula (1), the lower alkyl group represented by 1710 is a linear or branched chain having 1 to 4 carbon atoms.
~4 alkyl groups, such as methyl, ethyl, n
Examples include -propyl, isopropyl, n-butyl groups, and methyl group is particularly preferred.

The compound of formula (1) above can form a salt with an acid.

Among the compounds of the present invention, sulfoxide compounds in which n is 1 are useful as intermediates for producing compounds in which n is O, as described below.

Next, a method for producing the cephem compound of the present invention will be explained.

The compound of the present invention can be produced according to a method known per se. For example, the method (a) below.

(bl, (can be produced by the method of C1.

(al-spelling allowance (■) [In the formula, n and R+6 are the same as above, R- has the same meaning as the above-mentioned R'', or represents a carboxyl group, a salt thereof, or a protected carboxyl group] 7-amino-3-(3-alkyl group substituted-1,2,4)
-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid derivative is acylated with a compound represented by the formula (n) 0CR3(n), and if necessary, the retaining rl group is removed and the carboxyl Method of carrying out esterification of groups.

(bl-ship type (rV) (in the formula, R6 and n are the same as above, X is 10C0CH
z or a halogen atom), the 3-alkyl group is substituted at the 3-position X of the compound represented by -1,
A method of substituting with 2,4-thiadiazole-5-thiol.

(01 Method for deriving the acyl group at the 7-position of the present invention compound (1) from another acyl group.

Below, the above-mentioned methods (al, (bl and (C1) will be explained in more detail.

fa+ -11 A compound represented by the general formula or its reactive derivative is reacted with a carboxylic acid represented by the formula (I[) and a compound represented by the -m formula (III) or a salt thereof. You can get salt. Furthermore, l
When the group represented by i& is a carboxyl group or a salt thereof, the compound of the present invention represented by the above-mentioned -tsusuriyo (1) can be obtained by esterifying the compound. Further, when the group represented by R6 is a protected carboxyl group, the retaining group of the compound is removed and then esterified.

- The reactive derivative of the compound represented by Tsuzuriyo (n) is -
It refers to a reactive derivative of a carboxyl group that can form an amide bond with a compound represented by the formula (l [ It will be done. More specifically, dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, dialkyl phosphorous acid, methanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, alkyl carbonic acid, aliphatic carboxylic acid (for example, pivalic acid, mixed or symmetrical acid anhydrides with acids such as pentanoic acid, isopentanoic acid, 2-ethylbutanoic acid), aromatic carboxylic acids; acid azolides with imidazoles, substituted imidazoles, dimethylpyrazoles, triazoles, tetrazoles, etc.; cyano Methyl ester, methoxymethyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorphenyl ester, methanesulfonylphenyl ester, phenylthiophenyl ester, p-nitrophenylthioester, paracresyl thioester , carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, or N,N'-dimethylhydroxylamine,
Active esters such as esters with 1-hydroxy-2(IH)-pyridone, N-hydroxyphthalimide, N-hydroxyphthalimide, or hydroxybenztriazole may be mentioned.

Furthermore, when the compound represented by (II) is used in the form of a free acid (or a salt thereof), the amidation reaction can be carried out in the presence of a binder. Examples of binders include N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N''-morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4-
diethylaminocy)yohexyl)carbodiimide, N
, N'-dimethylformamide, N,N'-diisopropylcarbodiimide, N-ethyl-N'-
(3-dimethylaminopropyl)carbodiimide, N,
N'-carbonylbis(2-methylimidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, alkoxyacetylene, 1-alkoxy-1chloroethylene, phosphite trialkyl ester, ethyl polyphosphate ester, polyphosphoric acid isopropyl ester, phosphorus oxychloride,
Phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine, 2-ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5-(m-sulfonyl)isoxazolium hydroxide inner salt, (
Vilsmeier reagents such as compounds prepared from dimethylammonium chloride (chloromethylene), phosphorous oxychloride and dimethylformamide, etc. can be mentioned.

Thus, amidation methods used in -a in peptide chemistry, penicillin, cephalosporin chemistry, or other fields are used in the present invention.

During amidation, it is preferable that the amino group of -suji (II) be protected depending on the amidation method. As the amino group protecting group, known amino group protecting groups such as formyl group, t-butoxycarbonyl group, trityl group,
Chloracetyl group, trichloroethoxycarbonyl group,
A benzyloxycarbonyl group or the like is used.

- Salts of the carboxyl group of formula (I[[) include, for example, salts with alkali metals or alkaline earth metals such as sodium, potassium, and calcium; salts with organic bases such as trimethylamine, triethylamine, quinoline, and collidine salts; can be given.

In the general formula (III), R6 is represented by the above-mentioned general formula (
In addition to the esters listed above, examples include carboxyl groups protected by esterification or amidation. The protected carboxyl group is easily decomposed after the acylation reaction, for example by hydrolysis or alcoholysis in an acidic or slightly alkaline medium, hydrogenolysis, reduction, oxidation, a-nuclear substitution, photoreaction, or enzymatic reaction. Groups that give free carboxylic acid are preferable, and examples of such protected carboxyl group derivatives include silyl esters, organotin esters, toluenesulfonyl ethyl esters,
Known carboxylic acid protecting groups include paranitrobenzyl ester, diphenylmethyl ester, trityl ester, trichloroethyl ester, phthalimidomethyl ester, 2-nitrobenzyl ester, and 2,2°-dinitrobenzyl ester. In the case of a silyl ester, a site that can be silylated, ie, an amino group, may be silylated. The amino group may also form a salt with an organic sulfonic acid such as toluenesulfonic acid, naphthalenesulfonic acid, or tetralinsulfonic acid, or with an inorganic acid such as hydrochloric acid, sulfuric acid, or nitric acid.

More specifically, examples of the inert solvent used in the reaction between the compound represented by the general formula (II) and the compound represented by the general formula (III) include dichloromethane, chloroform,
Polar solvents such as acetone, tetrahydrofuran, dioxane, acetonitrile, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, hexanemethylphosphoric triamide, sulfolane, or nonpolar solvents such as benzene, toluene, petroleum ether, n-hexane, Alternatively, depending on the e# in which a mixed solvent thereof is used, a water-containing temperature mixed solvent thereof may also be used.

- A carboxylic acid represented by II or a reactive derivative thereof and a compound represented by the general formula (■) or a salt thereof,
The reaction temperature with the compound or its derivative can be set to any desired temperature, but is usually 50° C. or lower.

In the manner described above, the compound represented by the above-mentioned -tsuji margin (■°) can be produced. Here, the group represented by R1 is
When the compound is a carboxyl group or a salt thereof, the compound of the present invention can be produced by reacting the compound with an esterifying agent.

The esterification reaction can be carried out by a method known per se. For example, a compound in which the group represented by R1 in the - binding margin (■') is an alkali metal salt of a carboxyl group, and a halogen compound (preferably iodine, bromine or chloride) corresponding to the alcohol moiety that forms the ester. Ester compounds can be produced by reaction in an inert solvent.

At this time, known methods such as a method of carrying out esterification in the presence of a crown ether or in the presence of a phase transfer catalyst can be used. Further, it is advantageous to carry out this esterification reaction in the presence of a base, and as the base, an organic base such as triethylamine or an inorganic base such as sodium carbonate or potassium carbonate is advantageously used.

When an alcohol is used as the esterifying agent, the reaction is preferably carried out in the presence of a condensing agent; examples of such condensing agents include, for example, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide, .

N'-diethylcarbodiimide, N-cyclohexyl-
Carbodiimide compounds such as N”-(4-diethylaminocyclohexyl)carbodiimide, e.g.
Sulfonic acid esters of N-hydroxybenzotriazole derivatives such as N-hydroxybenzotriazole such as (4-chlorobenzenesulfonyloxy)-6-chloro-IH-benzotriazole, benzenesulfonic acid chloride, dimethylformamide and thionyl chloride, oxy Examples include the so-called Vilsmeier reagent, which is produced by a reaction with a halogen compound such as phosphorus chloride.

Although the reaction temperature is not particularly limited, it is usually carried out at 50°C or lower. Inert solvents used for esterification include:
The inert solvents used in the amidation reactions are similarly used.

When the product obtained by the above-mentioned esterification reaction is a sulfide compound where n is 0, 2-
May contain cephem bodies.

In this case, the 2-cephem compound can be removed by subjecting the product to operations such as recrystallization, reprecipitation, and column purification. Alternatively, the product containing the 2-cephem is oxidized with metachloroperbenzoic acid, peracetic acid, periodic acid, etc. to form the 3-cephem-1-oxide, and then it is converted into a 3-cephem-1-oxide, such as phosphorus oxychloride, dichloride, etc. By reducing with a combination of tin and acetyl chloride, a practically pure 3-cephem ester can be obtained. Oxidation of the sulfur atom of the cephem ring can be carried out according to conventional methods. Depending on the oxidizing agent used at that time, S and R-oxides are generated, both of which are included in the present invention. Oxidation of the sulfur atom of the cephem ring and its reduction have been described, for example, in E. Flynnli rc.
ephalosporins and penicil
lins.

Chesistry and BiologyJ (A
cade+gic Press 1972) Chapter 4 13
It is described on page 5.

- The raw material compound indicated by Tsuzuriyo (U) is, for example, as described in Journal of the Chemical Society of Japan 1981. +51.785. Che+m,
Pharm.

Bull, 25.3115 (1977), The
Journal of Antibiottcs 3
4.171 (1981), JP-A-51-149296
It is manufactured by the method described in the publication.

In addition, the raw material compound represented by -Tsuriyo (II+) can be obtained by a known method (for example, using 7-aminoceph-10-suboranic acid and a 3-alkyl group-substituted-1,2,4-thiadiazole-5-thiol compound). U.S. Patent No. 3,979,3
Specification No. 83, JP-A No. 53-98987, 55-90
No. 48, No. 55-049383, and No. 57-82392).

3-alkyl group substituted at the 3-position
By nucleophilic substitution with 1,2,4-thiadiazole-5-thiol, the compound represented by the above-mentioned -tsujizole (■°) can be obtained. As for the nucleophilic substitution method itself, known methods can be used in series. [For example, E, Flynn[r
cephalosporins and penici
llins.

Chemistry and Biology J (
Academic Press 1972) Chapter 4, Chapter 1
58 pages, Japanese Patent Application Laid-Open No. 53-130689, J, E
lks & I collectionRecent Advances i
n the Chemistry of β-Lacta
m Antibiotics, Cambridge,
England+ 28-30 Juns, 197
6 J (The Chemical 5ociety
I Burlfgton House, London
WIV 0BN) page 109, Tetrahedr
on Letters 22.3915 (1981)
It is described in. ] General binding allowance IV) Ihi hardware is -
The carboxylic acid of Tsuzuriyo (■) and the compound represented by the general formula (V) (in the formula, L R', n are the same as above), and the compound represented by - Tsuzuriyo (■゛) It can be produced by reacting in the same manner as the method used to obtain it. Furthermore, among the compounds represented by -resistance (rV), compounds in which X is a halogen atom are described in, for example, J, Elks & I Collection rRecen
tAdvances in the ChemtsL
ry of β-Lactars Antibioti
cs Cambridge.

England+ 28-30 June, 1976
J (the Chea+1calSociety+
Burlington House+ London
HIV 0BN) page 106, Tetrahedro
It can also be produced by the method described in Letters 22.3915 (1981). The halogen atom refers to an iodine atom, a bromine atom, and a chlorine atom.

As a method for chemically deriving the 7-position acyl group of the compound represented by (C1-Tsuzuriyo (!')) from another acyl group, there is, for example, the following method.

(wherein R1 is the same as above) A carboxylic acid represented by the formula (III) or a reactive derivative thereof is reacted with a compound represented by the -catalytic formula (III), a salt thereof, or a derivative thereof, and the general formula ( ■) (in the formula, n, R'g
A method of obtaining a compound represented by R"* R' is the same as above, and then reacting with methoxyamine to obtain a compound represented by the formula (I).

Alternatively, -catalytic (■) (wherein R', R', X and n are the same as above)
The 3-alkyl group at position X of the compound represented by -1,
By nucleophilic substitution with the 2,4-Kima 8''pGe-9-T-Ge-Ge-R body, the -catalytic formula (IX) (wherein R1, R111, ip and n are the same as above,
) is obtained, and then reacted with methoxyamine to obtain the compound represented by -Tsuriyo (I゛).

Alternatively, a compound represented by the formula (X) (where 1lleJ& and n are the same as above, and Xo represents a chlorine atom or a bromine atom) is reacted with thiourea to form the -catalytic formula (
There is a method to obtain the compound shown in b).

The carboxylic acid represented by the catalytic formula (Vl) is a known compound, for example, as disclosed in JP-A-53-112895, ? l
+a j6urnal of A IIItlb
j otica 5G, 846 (ヱ983
It is stated in the

-II Compound represented by formula (Vl) and general formula (III)
The method for obtaining the compound represented by the general formula (■) by reacting the compound represented by the above-mentioned general formula (II) with the compound represented by the general formula CIII) is as follows: This can be carried out in the same manner as in the method for obtaining the compound represented by the general formula (■゛).

-a The reaction between the compound represented by the formula (■) and methoxyamine can be carried out according to a known method (for example, JP-A-54-52096).

Further, the 3-position purification 1-stirring reaction of the compound represented by the -catalytic formula (■) can be carried out in the same manner as in the method explained above.

The compound represented by the general formula (X) can also be produced according to known methods (for example, JP-A-53-13599
Publication No. 6).

A method of reacting a compound represented by general formula (X) with thiourea to obtain a compound represented by -catalytic formula (I') can also be carried out according to known reaction conditions.

As mentioned above, the compound of the present invention has excellent oral absorbability and is therefore useful as an orally administrable antibacterial agent. When administering the compound of the present invention orally, capsules, powders, granules, tablets, etc. can be prepared and administered according to conventional formulations for oral administration. It can also contain conventional excipients, binders, lubricants, disintegrants, and the like.

The compounds of formula (I) of the present invention can also be formulated as rectal compositions (eg, suppositories or retention enemas) or as injections.

The dosage varies depending on age, body weight, symptoms, etc. (Usually, for adults, 0.2 g to Zg per day can be administered in one or several doses.

Next, Shuttle Technique 1 reveals the excellent properties of the compound of the present invention.
[Aim U] Next, the method for producing the compound of the present invention will be specifically explained with reference to Examples, but the present invention is not limited thereto.

Reference example 1? -((Z)-2-(2-formylamino-4-thiazolyl')-2-(methoxyimino)acetamide)-3
-(3-Methyl-1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid dimethylformamide 1.67 g in ethyl acetate 27
+al solution was cooled to -5°C, and phosphorus oxychloride 2
．． Add 17 g and stir at -5 to 0°C for 2 hours. Next (Z
)-2-(2-formylamino-4-thiazolyl)-2
Add 3.27 g of -(methoxyimino)acetic acid and stir at the same temperature for 2 hours.

On the other hand, 7-amino-3-(3-methyl-1,2゜4-thiadiazol-5-yl)thiomethyl-3-cephem-
4.34 g of 4-carboxylic acid is suspended in 86-1 ethyl acetate, 7.92 g of bis(trimethylsilyl)acetamide is added to this suspension, and the mixture is stirred at room temperature for 1.5 hours.

This solution is cooled to -5°C, and the reaction solution is added while keeping the temperature below 0°C, followed by reaction at the same temperature for 1.5 hours.

Add 26 g of water and 5.2 g of methanol to this reaction solution,
After stirring for 0 minutes, the precipitated crystals were collected by filtration, washed with ethyl acetate, and dried under reduced pressure to obtain the title compound. Obtain 13.49 g.

'H-NMR (DMSO-d') δ value: 2.52 (3H
, s), 3.54.3.76 (2H, ABq J=1
8Hz), 3.89 (3H, s), 4.23.4.
62 (2H, ABq J-13, 5Hz), 5.15
(IH, d.

J-5)1z), 5.8H11(,dd, J-5,
8Hz), 7.40 (IH, s), 8.50 (IH,
s), 9.69 (IH, d, J-8Hz), 12
．． 62(LH,s) Reference Example 2 7- ((Z)-2-(2-formylamino-4-thiazolyl)-2-(methoxyimino)acetamide)-
3-(3-methyl-1,2,4-thiadiazole-5-
((Z)-2-(2-formylamino-4-thiazolyl)-2-(methoxyimino)acetamide)-
3-(3-methyl-1,2,4-thiadiazole-5-
yl)thiomethyl-3-cephem-4-carboxylic acid 0.
59 g was dissolved in a solution consisting of 94 mg of sodium bicarbonate and 17 s+1 of water, and then freeze-dried to obtain 0.62 g of the title compound.

Example 1 Pivaloyloxymethyl 7- ((Z)-2-(2-
formylamino-4-thiazolyl)-2-(methoxyimino)acetamide)-3-((3-methyl-1,2
,4-thiadiazol-5-yl)thiomethyl)-3-
Cephem-4-carboxylate 7- ((Z)-2-(2-formylamino-4-thiazolyl)-2-(methoxyimino)acetamide)-3
0.61 g of sodium '-((3-methyl-,;1,2.4-thiadiazol-5-yl)thiomethyl]-3-cephemu-4-carboxylate was dissolved in dimethylformamide 3
ml and cooled to 5°C.

While stirring, add 0.41 g of iodomethyl pivalate,
The reaction solution, which was stirred for 1 hour at 0.degree. C., was poured into a mixture of ethyl acetate (30-1) and water (10-111), and the organic layer was separated. The machine layer was washed twice with 10111 l of water and 10 ml of brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.4 g of the title compound.

'H-NMR (D gate 5O-d'') δ value: 1.14 (9B
, s), 2.52 (3Ls), 3.61.3.81
(21(, ABq, J-18Hz), 3.88(3
H,s), 4.23.4.59(2H,ABq, J
-13°5Hz), 5.20 (IH, d, J-51
(Z), 5.88 (LH, dd, J-5,8Hz)
.

7.42 (IH, s), 8.51 (IH, s), 9
．． 70(1)1. J-8Hz).

12.62(IH,s) Example 2 Pivaloyloxymethyl 7- ((Z)-2-(2-
Amino-4-thiazolyl)-2-(methoxyimino)acetamide)-3-((3-methyl-1,2,4-thiadiazol-5-yl)thiomethyl]-3-cephem-
4-Carboxylate pivaloyloxymethyl? −(
(Z)-2-(2-formylamino-4-thiazolyl)
-2-(methoxyimino)acetamide)-3-((3
-Methyl-1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylate 1.
14g with 5ml of methanol and 5ml of tetrahydrofuran
Dissolve in a mixture of and cool to 5°C.

Add 1.5 ml of concentrated hydrochloric acid while stirring and stir at 0 to 5°C for 8 hours. Add 30-1 of water to the reaction solution and dilute with saturated sodium bicarbonate solution.
After adjusting to 2.5, the organic solvent was distilled off under reduced pressure, the precipitated crystals were collected by filtration, the filtered material was washed with water, and then dried under reduced pressure to obtain the compound 1. Obtain Of g.

' H-NMR (CDCI s>δ value: 1.22 (9H
1s) + 2.60 (3H, s), 3.62.3.7
5 (211, ABq, JdBHz), 4.10 (3
H,s), 4.20.4.68(21(,^Bq,
J=1311z).

5.07 (IH, d, J-5Hz), 5.88~5
．． 99(3)1. m), 6.6 to 7.1 (2H, br
oads>, 7.00(l)1. s), 7.80(
IH, d, J=9Hz) Example 3 1-Methyl-1-cyclohexanecarbonyloxymethyl? -((Z)-2-(2-formylamino-4-thiazolyl)-2-(methoxyimino)acetamide)-
3-((3-methyl-1゜2.4-thiadiazole-5
-yl)thiomethyl2-3-cephem-4-carboxylate 7-((Z)-2-(2-formylaminol 4
-thiazolyl)-2-(methoxyimino)acetamide)-3-((3-methyl-1,2,4-thiadiazol-5-yl)thiomethyl]-3-cephemu-4-carboxylate (0.58 g) in dimethyl Formamide 3
The mixture was dissolved in solute and cooled to 5°C.

Add 0.58 g of iodomethyl (1-methyl-1-cyclohexanecarboxylate) under stirring, and heat at 0 to 5°C for 1.
The six reaction solutions stirred for 5 hours were treated in the same manner as in Example 1 to obtain crude crystals. The obtained crude crystals were subjected to reverse phase liquid chromatography [Column: LiChroprep RP-8,
Size B (manufactured by Merck & Co.): Mobile phase: 2.5% aqueous acetic acid-acetonitrile (40-60, V/V) Necessary fractions of Nika At were taken, concentrated under reduced pressure, and then extracted with ethyl acetate. did. The ethyl acetate layer is washed with brine, dried over magnesium sulfate, and then ethyl acetate is distilled off under reduced pressure to obtain 0.27 g of the title compound.

'H-NMR (CDCIs) δ value: 1.19 (3H, s), 1.23-2.05 (IOH
, m), 2.60 (3H, s).

3.61.3.78 (2H, ABq, J-19Hz)
, 4.07(3H,a), 4.22°4.66(2
H,ABQ, J-13,5H2), 5.09(LH
, d, J-5Hz).

5.80 ~ 6.04 (3H, m), 7.37 (I
H,s), 7.54 (III, broads).

8.59 (18,s) Example 4 1-Methyl-1-cyclohexanecarbonyloxymethyl 7- ((Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamide)-3 −(
(3-Methyl-1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylate 1-methyl-1-cyclohexanecarbonyloxymethyl? -((Z)-2-(2-formylamino-4-thiazolyl")-2-(methoxyimino)acetamide)
-3-((3-methyl-1゜2.4-thiadiazole-
0.2''! g of 5-yl)thiono(mon))-3-cephem-4-carboxylate was dissolved in a mixture of 1 ml of methanol and 1 ml of tetrahydrofuran and cooled to 5°C. While stirring, 0.5 ml of concentrated hydrochloric acid was added. and stirred at 15° C. for 2.3 hours. The reaction solution was treated in the same manner as in Example 2 to obtain 0.23 g of the target compound.

'H-NAR (CDC13) δ value: 1.18 (3H, s), 1.24-2.01 (1ON
, a+), 2.60 (3Ls).

3.60.3.75(2)1. ABq, J=18Hz
), 4.05(38,s), 4.20°4.68(
211,ABQ, J-13,5H2), 5.08(
LH, d, J-582).

5.7 (2H, broads), 5.81-6.05
(3M, m), 6.84 (II, s).

7.66 (IH, d, J-8H2)

Claims (3)

[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 an esterified carboxyl group, R^1
^0 represents a lower alkyl group, and n represents 0 or 1. A cephem derivative or a salt thereof. (2) The cephem derivative or a salt thereof according to claim 1, which is a syn isomer. (3) The esterified carboxyl group has the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^3 is a hydrogen atom, an alkyl group, or a cycloalkyl group. The cephem derivative or salt thereof according to claim 1 or 2, wherein R^4 represents an alkyl group, a cycloalkyl group, or a 1-substituted cycloalkyl group.