JPS6034975A - Production of cephalosporin - Google Patents

Abstract

PURPOSE:To produce the titled compound useful as a remedy for bacteriosis for oral administration, in high efficiency, by reacting D-O-(L-alanyl)-mandel or its reactive derivative with a specific compound. CONSTITUTION:The objective compound of formula IV is produced either by reacting the free carboxylic acid of formula I (R2 is H or hydroxy) or its alkali metal salt or its reactive derivative with the compound of formula II in a solvent such as acetone at -20-+35 deg.C, or by removing the R<1> group from the compound of formula III (R<1> is formyl, t-butoxycarbonyl, trityl, etc.). When the compound of formula I is used in the form of free carboxylic acid, it is preferable to use a condensation agent such as N,N'-dicyclohexylcarbodiimide, etc. EFFECT:High blood concentration of a non-ester compound having excellent antibacterial activity can be achieved by oral administration.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing novel cephalosporin derivatives and salts thereof.

The present inventors previously developed a novel cephalosporin derivative (1) represented by the general formula (in the formula, R2 represents hydrogen or hydroxyl) and salts thereof (Patent Application No. 197458). The cephalosporin derivative (1) and its salts have poor absorbability from the gastrointestinal tract, and after absorption, they are immediately combined with the carboxylic acid ester moiety at position 4 of the cephem ring by enzymes in the body.
The amino acid ester moiety at the α-position of the side chain is hydrolyzed and converted into a non-ester form represented by the general formula (wherein R2 has the same meaning as above) corresponding to the cephalosporin derivative CI). That is, each intravenous administration of the cephalosporin derivative (1) results in a high blood concentration of non-coastal derivatives having excellent antibacterial activity. This is extremely helpful.

The present inventors have discovered that the novel cephalosporin r'+fi
About the improved manufacturing method of '+1 body (+) and its salt Gods 1
As a result of repeated research, the present invention was completed by discovering that the cephalosporin derivative (1) and its salts can be efficiently removed by the following method.

The cephalosporin derivative (1) and its salt of the present invention are produced as follows.

(Manufacturing method 1) general formula (In the formula, R2 has the same meaning as above) Compound and general formula represented by A method of reacting with a compound represented by

Compound (Ill) is used in this reaction as a free carboxylic acid, or as a salt thereof such as a mineral acid salt, an organic acid salt, an alkali metal salt, or a reactive derivative thereof. That is,
Acid halides (acid chlorides, acid bromides, etc.) as free acids or as salts of hydrochloric acid, sulfuric acid, sodium toluenesulfonate, potassium, calcium, triethylamine, pyridine, etc., or as their reactive derivatives.
, acids; nail solutions, mixed acid anhydrides [substituted phosphoric acids (dialkyl phosphoric acids, etc.), alkyl carbonates (monoethyl carbonates, etc.)], activated amides (amides with imidazole, etc.), esters (cyanomethyl esters, 4- nitrophenyl ester, etc.) in the acylation reaction.

When compound (Ill) is used as a free acid or in the form of a mineral acid salt or an organic acid salt, it is preferable to use an appropriate condensing agent. Examples of the condensing agent include N, N''-
N,N''-disubstituted carbodiimides, such as dicyclohexylcarbodiimide, N.

Dehydrating agents such as azolyte compounds such as N'-carbonyldiimidazole and N,N'-thionyldiimidazole are used. When these 11 combination agents are used, it is thought that the reaction proceeds through the inverse derivative of the carboxylic acid and the 1-component derivative.

This reaction is usually carried out in an inert solvent. /8 ν specifically includes water, acetone, dioxin, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, and N.
- Dimethylbormamide, organic solvents such as pyridine, and mixtures thereof.

This reaction is preferably carried out at room temperature or under cooling (-20°C to 0°C).
(°C).

(iu method 2) General formula (wherein, R1 is polmyl, t-butoxycarbonyl, 1
-Methyl-2-methoxycarbonylvinyl, 1-methyl-2-ethoxycarbonylvinyl, benzyloxycarbonyl, p-methoxyhensyloxycarbonyl, chloroacetyltrityl, silyl, 2.2.2-)lichloroethoxycarbonyl , R2 has the same meaning as above) A method for producing a compound by subjecting the compound represented by the following to an elimination reaction of an amino group-protecting group.

Silyl for R1 refers to trialkylsilyl, dialkylalkoxysilyl, etc., and alkyl is preferably lower alkyl having 1 to 4 carbon atoms such as methyl, ethyl, propyl, etc.

Examples of the elimination reaction include conventional methods such as hydrolysis and reduction.

(11 hydrolysis: Hydrolysis is preferably carried out in the presence of an acid.

Examples of acids include inorganic acids (e.g. hydrochloric acid, hydrobromic acid,
sulfuric acid, etc.), organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, mechnesulfonic acid, Hensensulfonic acid, p-toluenesulfonic acid, etc.), acidic ion exchange resins, and the like.

When using an organic acid such as trifluoroacetic acid, p-trienesulfonic acid, etc. in this reaction, reaction 1. , j is preferably carried out in the presence of a cation scavenger (for example, anisole, etc.). Hydrolysis is generally carried out using conventional solvents that do not adversely affect the reaction, such as water, methanol, ethanol,
propatool, tertiary butyl alcohol, tetrahydrofuran, N,N-dimethylbormamide, dioxane, acetone, methyl ethyl ketone, ethyl acetate, or mixtures thereof, and additionally as a solvent when the acid is a liquid. You can also use

The reaction temperature of this hydrolysis) W is not particularly limited, and the reaction is generally carried out under cooling or heating.

(2) Reduction: Reduction is carried out by conventional methods such as chemical reduction and catalytic reduction. Suitable reducing agents used in chemical reduction include gold B (e.g. tin, zinc, iron, etc.) or metal compounds (e.g. chromium chloride, chromium acetate, etc.) and organic or inorganic acids (e.g. formic acid, acetic acid, propionic acid, etc.). Examples include combinations with acids, 1 to lifluoroacetic acid, P) luenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).

Suitable catalysts used for catalytic reduction include conventional catalysts,
For example, platinum catalysts (e.g. platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g. palladium sponge, palladium black, palladium oxide, palladium, carbon, colloidal palladium, palladium/barium acetate) , palladium, barium carbonate, etc.),
Nickel catalysts (e.g. reduced nickel, oxidized ninogel, boro-nisokel, etc.), cobalt catalysts (e.g. ternary cobalt, Raney cobalt, etc.), iron catalysts (e.g. iV elemental iron 3)
Raney iron, etc.), copper catalysts (eg, reduced tha+, ferrous copper, Ullmann copper, etc.), and the like.

Reduction can be carried out using conventional solvents that do not adversely affect the reaction, such as water, methanol, ethanol, propatool, N.I.
It is carried out in N-dimethylborumamide 1 or mixtures thereof. Furthermore, when the acid used for chemical reduction is a liquid, it can also be used with a solvent. Further, suitable solvents used in the catalytic reduction include the above-mentioned solvents, but also diethyl ether, di-F
4J', tetrahydrofuran, or their compounds can also be used.

The reaction temperature for this reduction is not particularly limited, and the reaction is usually carried out under cooling or heating.

The elimination method explained above is based on the species IJ′i of the protecting group to be eliminated.
be selected as appropriate.

The cephalosporin derivative (1) can be prepared as a pharmaceutically acceptable acid addition salt, such as a mineral salt (e.g., hydrochloride), by conventional means.
etc.

Cephalosporin derivative (I) and its salts can be isolated and purified according to conventional methods.

The cephalosporin derivative (I) thus produced can be diluted with a pharmaceutical excipient according to a method known per se to produce an orally administered bacterial infection therapeutic agent. Dilution is carried out by means known per se, such as mixing. Specific examples of excipients include starch, anhydrous lactose, sugar, calcium carbonate, calcium phosphate, and the like.

The oral bacterial infection therapeutic agent may further contain other additives as desired, such as binders (e.g., starch, gum arabic, carboxymethylcellulose, etc.).
hydroxypropyl cellulose, crystalline cellulose, etc.)
Preferred additives include lubricants (eg, magnesium stearate, talc, etc.), and disintegrants (eg, calcium carboxymethyl cellulose, talc, etc.). After mixing the various ingredients, the mixture can be formulated into a dosage form suitable for oral administration, such as capsules, tablets, thin capsules, granules, and dry syrup, by means known per se.

The dosage of the cephalosporin derivative (1) and its salts varies depending on the subject of administration, symptoms, etc. For example, for purulent diseases in adults, convert to a non-ester corresponding to cephalosporin derivative (1), For example, about 1 to 40
It is orally administered at a dose of 7 kg body weight, 1 to 4 times a day.

The present invention will be explained in more detail with reference to Examples below.
These do not limit the invention.

In addition, in the examples, Boc means t-butycarbonyl.

Example 1 (5-methyl-1,3-dioxo-2-one-4-
yl)methyl 7=CD-0-(L-alanyl)mandelamide)-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-
Synthesis of carboxylate hydrochloride fil method (5-methyl-1,3-dioxo-2-
Dissolve 1.5 g of methyl 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate in 45 ml of methylene chloride. .

0.92 g of D-0-(L-alanyl)mandelic acid chloride hydrochloride was added over 30 minutes at 0°C, then at room temperature.
Stir at night. The solid was collected by filtration and washed with methylene chloride to obtain 2.1 gt of the crude title compound. This was recrystallized from ethanol to obtain 1.7 g of the title compound.

(2) Method (5-methyl-1,3-dioxo-2-
on-4-yl)methyl 7- (D70- (N-B
oc-1,-alanyl)mandelamide]-3-(5-
72 g of methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate was dissolved in 700 ml of ethyl acetate, 7 g of hydrogen chloride gas was blown in at -5°C, and then 0°C. Stir for 30 minutes. The solid was collected by filtration and washed with isopropyl ether to obtain 66 g of the crude title compound. This was recrystallized from ethanol to obtain 56 g of the title compound.

(3) Method (5-methyl-1,3-dioxo-2-
on-4-yl)methyl 7-CD-0-(N-pormyl-■,-alanyl)mandelami1] -3-(5
-Methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate (2 g in 50 ml of methanol), IJ, concentrated hydrochloric acid 1.32
Add m1 and stir at room temperature overnight. The reaction solution was poured into isopropyl ether, and the precipitated solid was collected by filtration and purified with frF with isopropyl ether to obtain the title compound 1 manufactured by 111.
．． Obtain 7g. This was recrystallized from ethanol to obtain 1.2 g of the title compound.

(4) Method (5-methyl-1,3-dioxo-2-
on-4-yl)methyl 7-[D-(J-CN-(
1-Methyl-2-ethoxycarbonylvinyl)-L-alanyl]mandelamide l -1-(5-methyl-1,
3,4-thiadiazol-2-yl)thiomethyl-3-
5 g of cephem-4-carboxylate and 30 g of methanol
20 ml of 4N hydrogen chloride/ethanol solution was added at 0°C, and then stirred at room temperature for 30 minutes. Add diethyl ether to the reaction solution, filter the precipitated solids,
Wash with diethyl ether to obtain 3.8 g of the crude title compound.
get. This was recrystallized from ethanol to obtain the title compound 2.
．． Obtain 9g. Melting point: 158°C (decomposition) l R (nu
jol, cm-'); 1815.1760.169
ONMR ((CD3)2 So, δ value); 1.48 (
d, 311. J-711z, -Cll-(43)2
．． 18 (s, 311. Dioxo-ru CI+3)
2.66 (s, 311. Thiadiazole-C11
3) 3.62 (br, s, 211.2nd place - 112
)4.2 (m, IH, -CIl-CIl3)4.
07.4.65 (d, d, 211. J=1411
z, 3rd position -Cl12S-)5.05 (d, Ill,
J = 5Hz, 6th-II) 5.15 (s,
211. Dioxo-ru CI+2- )5.72 (
d x d, ill, J=5 and 9112. 7th place - 11) 6.13 (s, 1tL -Cjj-CONI
I-)7.4 (m, 511. phenyl)8.73
(br, 311. -Nl+3'')9.46 (
d, Ill, J=911z, -CONII-) Example 2 (5-methyl-1,3-dioxol-2-one-4-
yl)methyl 7-[D-α-(L-alanyloxy)
Synthesis of -p-hydroxyphenylacetamide)-3-(5-methyl-L 3.4-thiadiazol-2-yl)thiomethyl-3-cefef 1-4-carboxylate hydrochloride (5-methyl-1, 3-dioxo-2-one-4-
yl) methyl 7-[D-α-(+3oC-L-alanyloxy)-p-hydroxyphenylacetamide)-3
-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylene 1
-0.8 g was dissolved in 3.9 ml of technical acid, and the concentration was 4.0 at 0°C.
Add 1.26 ml of 8N hydrogen chloride/rice propatool solution, and then stir at room temperature for 10 minutes. Diethyl ether is added to the reaction solution, and the precipitated solid is collected by filtration, washed with diethyl ether, and dried to obtain 586 mg of the title compound.

I R (nujol, cm'); 1B30.179
0.1760.1695NMR((CD3)2So
, δ value); 1.45 (d, 311. J=711°
z, -CIl-CH3)2.1B, (s, 3H, dioxol-C113)2, [i6 (S, 3+1.
Thiadiazole-CIl3) 3.64 (br, s
, 211.2nd-II2) 4.08.4.66 (d
, d, J=14+1z, 3rd position -CH2S-)4-4.
3 (m, 1tL-CIl-C113)5.12
(d, III, J=511z, 6th position-H) 5.1
4 (s, 211. dioxol-C112-)5
．． 69 (d x d, IIL J-5 and 911z
, 7th place-II) 6.0 (s, IIL-Cdan-CON
ll-)6.78.7.31 (d, d, 411.
J=811z, ), lul) 8.7 (br, 41
1. −0ff, −Nth” )9.3 (d, I
IL J=911z, -CONII-) Reference Example 1 Production of D-0-(L-alanyl)mandelic acid 1-hydrochloride 7 g of D-0-(L-alanyl)mandelic acid hydrochloride was dissolved in methylene chloride. 140 ml of 8% phosphorus pentachloride in methylene chloride solution was added under cooling, stirred overnight, and the solid was collected by filtration, washed with methylene chloride, dried, and 7.5 g (yield 94%) of the title product was obtained. Obtain the compound.

[α) 28-56.28°C (C = 1. dioxane) I
R(nujol, cm'); 3020. 17
90. 17511NMR (CF3 GOOD); 1.83 (d, 311. J-711z, -C1l
-CIl3)4.65 (q, Ill, J-711z
, -Cll-C,lh)6.32 (s, III,
-Cll-CONII-)7.51 (s, 511
．． Phenyl) Preparation Example 1 Tablets having the following composition are manufactured by a counterfeit method.

Compound of Example 1 125n+r; Nozuki 111! Polyvinylpyrrolidone 20mg Starch 20mg Magnesium stearate 20mg Preparation Example 2 Tablets having the following composition are manufactured by applying electricity.

Compound 250B titer of Example 1 Citric acid 50mH Starch 20m5 Magnesium stearate 3.0mg formulation example 3 Tablets having the following composition are manufactured in a conventional manner.

Compound of Example 1 500 mg Strength starch 20 m length Hydroxypropyl cellulose 3B Magnesium stearate 5 mg Preparation Example 4 The compound of Example 1 and tartaric acid are added and mixed, and capsules are manufactured according to a conventional capsule filling method.

Compound of Example 1 125 mg + l [i tartaric acid 2
5 mB magnesium stearate 1 ml Add starch to make a total amount of 3011 mg Preparation Example 5 According to the method of Preparation Example 4, capsules having the following composition are manufactured.

Compound of Example 1 125 m8 (illill mystearinnesium 2 mB) Anhydrous lactose was added to make a total of 2 (10 m (H)) Formulation Example 6 A dry syrup was prepared according to the following composition.

Compound of Example 1 62.5 mg Power 1 + IIi Citric acid 25 mg Sugar 70 m8 CMC-Na 20 m6 Acute toxicity experiment The results of acute toxicity when the cephalosporin Hfi 4 of the present invention was orally administered to mice are as follows. .

Administration target: Male mouse (ICR5 service) n-3 Administration method: The cephalosporin derivative obtained in the above example was dissolved in tame water to form an aqueous solution, and the solution was orally administered.

Oral Administration Experiment The results of the blood concentration and urinary recovery rate of the non-ester form when the cephalosporin derivative of the present invention was orally administered to humans (n-3) are as follows.

Administration method: A 125 mg capsule was administered orally as a non-ester.

Quantification method: Quantitated using H. subtilis.

Result: Compound procedure amendment of Example 1 August 23, 1980 Patent Application No. 62950 of 1982 2, Name of invention Method for producing cephalosporin 3, Relationship with the person making the amendment Case Patent applicant Name: Kyoto Yakuhin Kogyo Co., Ltd. 4, Agent ■541 Address: 406 New Life Hirano-cho, 4-53-3 Hirano-cho, Higashi-ku, Osaka Telephone: (06) 227-1156 July 31, 1980 (Shipping date) ) 6. The entire text of the specification to be amended and the document certifying the power of attorney 7. Contents of the amendment (11) We will first correct the entire text of the specification as per the attached amended specification.

(2) I will submit a power of attorney as shown in the attached document. 2. Claims C=0 CHN H2 H3 (in the formula, R2 represents hydrogen or a hydroxyl group) or a reactive derivative thereof is reacted with a compound represented by the general formula, or the compound represented by the general formula ( In the formula, R1 is polmyl, t-butoxycarbonyl, 1
-Methyl-2-methoxycarbonylvinyl, 1-methyl-2-ethoxycarbonylvinyl, benzyloxycarbonyl, p-methoxyhensyloxycarbonyl, chloroacedel, trityl, silyl, 2.2.2-trichloroethoxycarbonyl, R2 A method for producing a cephalosporin derivative represented by the general formula (wherein R2 has the same meaning as above), which comprises subjecting a compound represented by the following formula to an elimination reaction of R1 (wherein R2 has the same meaning as above).

3. Detailed Description of the Invention' [Technical Field] The present invention relates to a method for producing a novel cephalosporin derivative and a salt thereof.

[Background of the invention/prior art]

The present inventors previously developed a novel cephalosporin derivative (1) represented by the general formula (in the formula, R2 represents hydrogen or a hydroxyl group) and a salt thereof (see Japanese Patent Application No. 197458/1983).

The cephalosporin derivative N) and its salts have poor absorbability from the gastrointestinal tract, and after absorption, the carboxylic acid ester moiety at the 4-position of the cephem ring and the side chain at the 7-position are continuously activated by enzymes in the body. The amino acid ester moiety at the α-position is hydrolyzed and converted to a non-ester form represented by the general formula (wherein R2 has the same meaning as above) corresponding to the cephalosporin derivative (1). That is, by orally administering the cephalosporin derivative (1),
It is a cephalosporin derivative (1) that provides a high blood concentration of a non-ester with excellent antibacterial activity.
and its salts are of excellent quality.

The present inventors have discovered that the novel cephalosporin derivative (1)
As a result of various studies on improved production methods for cephalosporin derivatives (1) and salts thereof, the present invention was completed by discovering that cephalosporin derivatives (1) and salts thereof can be efficiently obtained by the following method.

[Purpose of invention/disclosure]

The present invention provides a method for producing a cephalosporin derivative (I) and a salt thereof.

The present invention also provides intermediates for producing cephalosporin derivatives (1) and salts thereof [i.e., compound (V) described below].
] and its manufacturing method.

The cephalosporin derivative (1) and its salt of the present invention are produced as follows.

(Production method 1) C=　O(III　) ■ CH-N H2 H3 (In the formula, R2 has the same meaning as above) Compound and general formula represented by A method of reacting with a compound represented by

Compound (III) is used in this reaction as a free carboxylic acid, or as its alkali metal salt, or its reactive derivative. That is, free lIII acid as it is, or sodium, potassium, calcium, triethylamine,
as a salt of pyridine or its reactive derivatives, such as acid halides (rf! chloride, acid bromide, etc.)
, acid anhydrides, mixed acid anhydrides [substituted phosphoric acids (dialkyl phosphoric acids, etc.), alkyl carbonates (monoethyl carbonates, etc.)], activated amides (amides with imidazole, etc.), esters (cyanomethyl ester, 4-nitrophenyl) ester, etc.) in the acylation reaction.

When compound (1) is used as a free carboxylic acid, it is preferable to use a suitable condensing agent.
For example, N,N'-disubstituted carbodiimides such as N,N'-dicyclohexylcarbodiimide, N,N'-
Dehydrating agents such as azolide compounds such as carbonyldiimidazole and N,N'-thionyldiimidazole are used. When these condensing agents are used, the reaction is believed to proceed via reactive derivatives of carboxylic acids.

This reaction is usually carried out in an inert solvent. Examples of the solvent include organic solvents such as water, acetone, dioxin, acetonitrile, chloroborm, Hensen, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylbormamide, pyridine, and mixtures thereof. can give.

This reaction is preferably carried out at -20°C to 35°C.

(Production method 2) General formula (wherein, R1 is polmyl, t-butoxycarbonyl,
-Methyl-2-methoxycarbonylvinyl, 1-methyl-2-ethoxycarbonylvinyl, henzyloxycarbonyl, p-methoxy, ndyloxycarbonyl, chloroacetyl, trityl, silyl, 2.2.2-)lichloroethoxycarbonyl (R2 is the same as defined above) A method for producing a compound represented by the following formula (where R2 is the same as defined above) by subjecting it to an amino group-protecting group elimination reaction.

Silyl for R1 refers to trialkylsilyl, dialkylalkoxysilyl, trialkoxysilyl, etc., and alkyl refers to a carbon number of 1 such as methyl, ethyl, propyl, etc.
-4 lower alkyl is preferred.

Examples of the Jm separation reaction include conventional methods such as hydrolysis and reduction.

(1) Hydrolysis: Hydrolysis is preferably carried out in the presence of an acid.

Examples of acids include inorganic acids (e.g. hydrochloric acid, hydrobromic acid,
sulfuric acid, etc.), organic acids (for example, formic acid, acetic acid, trifluoroacetic acid, propionic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) - acidic ion exchange resins, and the like.

When an organic acid such as trifluoroacetic acid, p-trienesulfonic acid, etc. is used in this reaction, it is preferable that the reaction is carried out in the presence of a LJ cation scavenger (eg, anisole, etc.). The hydrated +89T is usually a conventional solvent that does not adversely affect the reaction, such as water, methanol, ethanol,
propatool, tertiary butyl alcohol, tetrahydrofuran, N,N-dimethylborumamide, dioxane,
It is carried out in acetone, methyl ethyl ketone, ethyl acetate, or mixtures thereof, but can also be used as a solvent if the acid is liquid.

The reaction temperature for this hydrolysis is not particularly limited.

(2) Reduction: Reduction is chemical reduction, catalytic reduction, etc. ; done by law. Suitable reducing agents used in chemical reduction include metals (
tin, zinc, iron, etc.) or metal compounds (e.g. chromium chloride, chromium acetate, etc.) and organic acids or inorganic acids (e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p
-) luenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).

Suitable catalysts used for catalytic reduction include conventional catalysts,
For example, platinum catalysts (e.g. platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g. palladium sponge, palladium black, palladium oxide, palladium/carbon, colloidal palladium, palladium/barium acetate, etc.) palladium, barium carbonate, etc.), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g. reduced cobalt, ferrous cobalt, etc.), iron catalysts (e.g. reduced iron, ferrous cobalt, etc.)
iron, etc.), copper catalysts (for example, reduced copper, Raney copper, Ullmann copper, etc.), and the like.

Reduction is usually carried out using conventional solvents that do not adversely affect the reaction, such as water, methanol, ethanol, propatool, N,
It is carried out in N-dimethylformamide or mixtures thereof. Moreover, when the acid used for chemical reduction is a liquid, these can also be used as a solvent. Furthermore, as a suitable solvent used for catalytic reduction, the above-mentioned /8
In addition, solvents such as diethyl ether, dioxane, and tetrahydrofuran, or their tM
Compounds can also be used.

The reaction temperature for this reduction is not particularly limited.

The detachment method explained above is appropriately selected depending on the type of protected bird to be detached.

Compound (V) is a new compound, and is produced, for example, as follows.

(Law 1) C=　O(Vl　) CH-N H-R.

A method of reacting a compound represented by H3 (wherein R1 and R2 have the same meanings as above) or a reactive derivative thereof with the general formula.

Compound (Vl) is used in this reaction as a free carboxylic acid or as a reactive derivative thereof. Therefore, JIi acid dispersion is a salt of sodium, potassium, calcium, 1-ethylamine, pyridine, etc., or its acid halide (ffi, chloride, acid bromide, etc.), acid anhydride, mixed acid anhydride [substituted phosphorus]. Acids (dialkyl phosphoric acids, etc.)
, alkyl carbonates (monoethyl carbonate, etc.)], active amides (amides with imidazole, etc.), esters (cyanomethyl ester, 4-nitrophenyl ester, etc.), and the like are used in the acylation reaction.

When compound (Vl) is used in a discrete state, it is preferable to use a suitable condensing agent, such as N,N'-disubstituted carbodiimide such as N,N'-dicyclohexylcarbodiimide. Dehydrating agents such as azolide compounds such as N, N''-carbonyldiimidazole, N, N'-thionyldiimidazole, etc. are used. When these condensing agents are used, the reaction is a reaction of carboxylic acid. It is thought that the reaction proceeds via a sexual derivative.
Usually carried out in an inert solvent. Examples of solvents include organic solvents such as water, acetone, dioxane, acetochloride, chloroborm, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, acetic acid Kogel, N,N-dimethylbormamide, and pyridine. Mixtures of these are possible.

This reaction is usually carried out from -30°C to 50°C, preferably -20°C.
The temperature is between 20'C and 20'C.

Compound (■) is, for example, a compound represented by the general formula (in the formula, R3 represents hydrogen or an amino group protecting group) and a general formula (wherein, It is produced by reacting the compound represented by

Regarding R3 in the general formula (3), examples of amino group-protecting groups include known amino group-protecting groups such as hensyl carbonyl, 2-chenylacetyl, 2-furylacetyl,
D-5-amino-5-carboxyvaleryl, trityl,
Phthalimide, formyl, t-butoxycarbonyl, ■
-Methyl-2-methoxycarbonylvinyl, 1-methyl-2-methoxycarponylvinyl, and the like.

Regarding the general formula (IX), examples of "a group reactive with a carboxyl group (its reactive group)" represented by X include halogen (bromo, chloro, iodo, etc.), alkylsulfonyloxy (methanesulfonyloxy, etc.), Examples include arylsulfonyloxy (p-toluenesulfonyloxy, etc.) and hydroxy.

Compound (■) is used in this reaction as a free carboxylic acid or as its reactive derivative.

That is, it is subjected to the '1 sylation reaction as a reactive derivative similar to the reactive derivative related to M discrete or compound (Vl).

When X in compound (IX) is used in a hydroxy form, a suitable condensing agent can also be used. As the condensing agent in this case, the same ones as mentioned above are used.

When these condensing agents are used, the reaction is believed to proceed via reactive derivatives of carboxylic acids.

This reaction is carried out preferably from Tsutomu -30°C to 50'C1, 1-
It is carried out at 20°C to 20°C.

The protecting group (R3) can be removed by a method known per se.

Compound (VI) is, for example, a compound represented by the general formula 0H (wherein R2 has the same meaning as above) or a reactive derivative thereof and the general formula % (wherein R1 has the same meaning as above). It is produced by reacting with the indicated compound.

(Second Law) general formula (In the formula, R2 is the same class as above) The compound represented by or its reactive derivative and the general formula %formula%() (In the formula, R1 has the same meaning as above) How to react.

Compound (χ■) is subjected to this reaction as a free carboxylic acid or as a derivative similar to that in compound (Vl).

When compound (XI) is used in the form of a free acid, it is preferable to use a suitable condensing agent, and as the tiij mixture, the same ones as mentioned above are used. When these condensing agents are used, the reaction is believed to proceed via reactive derivatives of carboxylic acids. In this reaction, it is preferable to use a base such as 4-dimethylaminopyridine as a catalyst. This reaction (J) is usually carried out in an inert solvent.Solvents include water, acetone, dioxane, acetylene chloride, chloroporum, Hensen, methylene chloride, ethylene chloride, Examples include organic solvents such as 1-rahidofuran, ethyl acetate, N,N-dimethylpolamide, pyridine, and mixtures thereof.

Compound (X) is produced by reacting compound (It) and compound (IX), or by reacting compound (■) with a compound represented by the general formula (wherein R2 has the same meaning as above). be done.

For this reaction, compound (II) is a reactive derivative thereof (
For example, it is preferable to use the reaction as an alkali metal salt such as a sodium salt or a potassium salt, an alkaline earth metal salt such as a calcium salt, an organic amine salt such as a triethylamine salt or a pyridine salt, etc.).

This reaction is preferably carried out under cooling to avoid the by-product of the Δ2-isomer, and a solvent that does not inhibit the reaction (e.g., N,N-dimethylpolamide, N,N-dimethylacetamide, hexamethyl phosphoramide, acetone, acetonitrile, dimethyl sulfoxide, chloroporum, methylene chloride).

(Third method) A method of reacting a compound represented by the general formula (wherein R1 and R2 have the same meanings as above) or a reactive derivative thereof with compound (IX).

Regarding this reaction, compound (X Ill ) is subjected to this reaction as a free acid, or as a reactive derivative similar to that for compound (Vl).

When X in compound (IX) is used in a hydroxy form, it is preferable to use the same condensing agent as described above. When a condensing agent is used, it is believed that the reaction proceeds via a reactive derivative of the J carboxylic acid. In this reaction, it is preferable to use a salt such as 4-dimethylaminopyridine as a catalyst.

Compound (XIII) is 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (7-A CT D
) and compound (Vl).

Compound (Vl) is preferably subjected to the unarylation reaction as a reactive derivative similar to the above.

The cephalosporin derivative (1) can be prepared as a pharmaceutically acceptable acid addition salt, such as a mineral salt (e.g., hydrochloride), by conventional means.
etc.

The cephalosporin derivative (1) and its salt can be manufactured according to Toyama.

The cephalosporin derivative (I) thus produced can be diluted with a pharmaceutical excipient according to a method known per se to produce an orally administered bacterial infection therapeutic agent. Dilution is carried out by means known per se, such as mixing. Specific examples of excipients include starch, anhydrous lactose, sugar, calcium carbonate, calcium phosphate, and the like.

The bacterial infection therapeutic agent for oral administration may further contain other additives as desired, such as binders (e.g., starch, gum arabic, carboxydimethyl cellulose, etc.).
Preferred additives include hydroxypropylcellulose, crystalline cellulose, etc.), lubricants (eg, magnesium stearate, talc, etc.), and disintegrants (eg, carboxymethyl cellulose, calcilano, talc, etc.). After mixing the various ingredients, the mixture is prepared into capsules, tablets, fine granules, etc. by means known per se.
It can be formulated into a dosage form suitable for oral administration, such as dry syrup.

Administration of cephalosporin derivatives (1) and its salts varies depending on the subject, symptoms, etc. For example, for purulent diseases in adults, cephalosporin derivatives (1)
For example, about 1 to 1 equivalent amount is substituted with the corresponding non-ester.
4 (1 mg/kg body weight is administered orally about 1 to 4 times a day.

The present invention will be explained in more detail with reference to Examples below.
These do not limit the invention.

In the Examples, BOC represents t-butoxycarbonyl.

Example 1 (5-methyl-1,3-dioxo-2-one-4-
yl)methyl 7-CD-0-(L-alanyl)mandelamide)-1-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-
Synthesis (1) of carboxylate hydrochloride (5-methyl-1,3-dioxol-2-
1.5 g of on-4-inolimethyl 7-amino-3-(5-methyl-1,3,4-thiacyp-2-yl)thiomethyl-3-cephem-4-carboxylate are dissolved in 45 ml of methylene chloride.

At 0°C, 0.92 g of D-0-=(L-alanyl)mandelic acid chloride hydrochloride is added over 30 minutes and then stirred overnight at room temperature. The solid substance was filtered off and washed with methylene chloride to obtain 2.1 g of the crude title compound. This was recrystallized from ethanol to obtain 1.7 g of the title compound.

(2) Method (5-methyl-1,3-dioxo-2-
on-4-yl)methyl 7- [1)-0-(N-B
oc-L-alanyl)mandelamyl")-3-(5-
72 g of methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate was dissolved in 700 ml of ethyl acetate, and 7 g of hydrogen chloride gas was blown in at -5°C. Then stir for 30 minutes at 0° C. The solids are collected by filtration, washed with isopropyl ether,
66 g of the title compound manufactured by 11n are obtained. This was recrystallized from ethanol to obtain 56 g of the title compound.

(3) Method (5-methyl-1,3-dioxole-2-
on-4-yl)methyl 7- (D-0-(N-pormyl-alanyl)mandelamyl") -=3-(
5-methyl-1,3,4-thiadiazol-2-yl)
2g thiomethyl-3-cephem-4-carboxylate
was dissolved in 50 ml of methanol, and 1.32 ml of concentrated hydrochloric acid was added.
and stirred for 1 liter overnight at room temperature. The reaction solution is pressurized into isopropyl ether, and the precipitated solid is collected by filtration and washed with isopropyl ether to obtain 1.7 g of the crude title compound. This was recrystallized from ethanol to obtain the title compound 1.
Obtain 2g.

(4) Method (5-methyl-1,3-dioxo-2-
on-4-yl)methyl 7- (D-0-(N-(1
-Methyl-2-ethoxycarbonylvinyl)-L-alanyl lamandelamide l-3-(5-methyl-1,3,
5 g of 4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate was added to 30 ml of methanol.
f6M, 4N hydrogen chloride/ethanol/at 0°C.
Add 20 ml of liquid 8 and stir at room temperature for 30 minutes.

Diethyl ether was added to the reaction solution, the precipitated solid was collected, washed with diethyl ether, and the crude title compound 3 was obtained.
．． Obtain 8g. This was recrystallized from ethanol to obtain 2.9 g of the title compound. Melting point: 158°C (decomposition) I R
(nujol, cm J; 1B15.1760.1
69ONMR ((CD3)2SO, δ value); 1.4
8 (d, 311. J-711z, -CJI-Cl
h) 2.18 (s, 311. Dioxol-C
113) 2.66 (s, 311. Thiadiazole-CI+313.62 (br, s, 211.2 position-II2) 4.2 (m, Ill, -CIl-CIl3
)4.07. 4.65 (d, d, 2H, J=1411z, 3rd place - CIl, 5
-)5.05 (d, III, J=511z, 6
-11) 5.15 (s, 211. dioxol CI+2-) 5.72 (d x d, III,
J=5 and 911z, 7th place - 11) 6.13 (s,
IIL-C1l-CONII-)7.4 (m, 5
11. phenyl) 8.73 (br, 311. -N
II3”)9.46 (d,ill,J=9112
．． -CONII-) Example 2 (5-Methyl-1,3-dioxo-2-'No4-
yl)methyl 7-[D-α-(1,,-i'ranyloxy)-p-hydroxyphenylacetamide)-3-
Synthesis of (5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate hydrochloride (5-methyl-1,3-dioxol-2-one-4-
yl)methyl 7-CD-α-(Boc-L-alanyloxy)-p-hydroxyphenylacetamide)-3
-(5-Methyl-1,3,4-thiadiazol-2-yl)thiomethy'-3-cephemu-4-carboxylate (0.8 g) was dissolved in 3.9 ml of phosphoric acid, and 4.
08N-Hydrogen chloride/isopropanol solution 1.26ml
and then stirred at room temperature for 10 minutes. Diethyl ether is added to the reaction solution, and the precipitated solid is collected by filtration, washed with diethyl ether, and dried to obtain the title compound 586B.

I R (nujol, cm-'); 1830.17
90.1760.1695NMR((CD3)2S
o, δ value); 1.45 (d, 311. J=711
z, -CIl-CIl3)2.18 (s, 311
．． Dioxole CI+3) 2.66 (s, 31
1. Thiadiazole-CIl3) 3.64 (br,
s, 211.2nd - 112) 4.08.4.66
(d, d, J-14, Ilz, 3rd position-C)hs-)4
~4.3 (m, IIL-CIl-C113)5.
14 (s, 211. Dioxol-CI+2-
)5.69 (d x d, III, J=5 and 9
+11. 7th place-11) 6.0 (s+ 11!, -heel-CONll-) 6.7B, 7.31 (d, d, 4+1
．． J-poor t112. -/-y, 2゛,)1ノ)8.7
(br, 411.-011.-N113'')9.
3 (d, III, J=911z, -CONII
-) Example 3 (5-methyl-1,3-dioxol-2-meno4)
-yl)methyl 7- +D-0-CN -(l-methyl-2-ethoxycarbonyl vinyl 1,-alanyl lamandelamide l-3-(5-methyl-1.3.4-thiazol-2-ino 1))'J-:tMethyl-3-cephemu-4-cuff1nonl (Kinru 1, Example 1 (4)
Example 1 and 1. IL: The target compound was obtained.

Example 4 (5-methyl-1,3-dioxono1-2-2-4-yl)methyl 7-CI)-0-(N-1.
IJ methyl L-alanyl) mandelami l-゛〕-r(
(5-methyl-l,3.4-thiazol-2-yl)
Thiomethyl-3-cephem-4-carboxylate,
The same target compound as in Example 1 was obtained by treatment in the same manner as in Example 2.

Example 5 (5-methyl-1,3-dioxol-2-one-4-
yl)methyl 7-CD-0-(N-p-methquinhensyloxycarbonyl-L-alanyl)mandelamide)-3-(5-methyl-1°3.4-thiazole-2
Example 1
The same target compound was obtained.

Example 6 (5-methyl-1,3-sooxol-2-one-4-
yl)methyl 7-CD-0-(N-trimethylsilyl-monoalanyl)mandelamide]-3-(5-methyl-1,3,4-thiazol-2-yl)thiomethyl-
3-cephem-4-carboxylate in Example 1 (3
) The same target compound as in Example 1 was obtained by treatment in the same manner as in Method 1.

Example 7 (5-methyl-1,3-dioxo-2-one-4-
yl)methyl 7-[1:L-0-(N-hensyloxycarbonyl-L--, F-7yl)mandelamide)-3-(5-methyl-1,3,II-thiazole-2- yl)thiomethyl-3-sesodine-J-=4-carboxylate in acetic acid-hydrogen bromide 11.4. ) i Koyori dehensylation, pressurizing ether, 11 no.'11
After converting the diluted hydrobromide to a free base, 111f of the same compound as in Example 1 was prepared by adding -4 chloride to the hydrochloride.

Example 8 (5-Methyl-1,3-dioxo-2-"No4-
yl) methyl 7- (r)-0-(N-2゜2.2-
11) Dissolved in 10ml of acid at 20°C
So active &! i2t? Add and stir for 1 hour. Add methylene chloride, remove 4 insoluble substances by filtration, add cold sodium bicarbonate solution,
Wash quickly with cold brine, dry with sodium sulfate, remove the solvent under reduced pressure, and add 5N hydrogen chloride in methanol solution.
Add 2ml, then add 1ml of methanol and 10ml of acetone.
By adding m1, the compound of Example 1 is obtained.

Reference Example I Production of D-0-(L-alanyl)mandelic acid chloride hydrochloride 7 g of D-0-(L-alanyl)mandelic acid chloride hydrochloride
was suspended in 140 ml of methylene chloride, and mixed with 8% phosphorus pentachloride in methylene chloride/8? while cooling. & 140ml, stirred overnight, filtered the solid matter, washed with methylene chloride, dried,
7.5 g (94% yield) of the title compound are obtained.

[α]? =-56.28°C (C=1. dioxane)
I R (nujol, cm-1); 3020. 17
90. 175ONMR (CF3 GOOD, δ value); 1.83 (d, 311. J=IHz, -CIl-
CIl3)4.65 (q, Ill, J=711
2. -CIl-CIl3)6.32 (s, II
I, -Cji-CONII-)7.51 (s, 5
11. Synthesis of D-0-(Boc-L-7 ranyl) mandelic acid; 2 g of Boc-L-alanine was dissolved in 30 ml of anhydrous tetrapi-11-furan, and 1.1 g of 1-lycomonylamine was dissolved. Add ethyl chloroformate at -20'C! (Water Tee I・
Add 11/81 1' to 10m1 of lahydrofuran.
Stir for 30 minutes at the same temperature. I for this]
- Add 1.61 g of mandelic acid and 5 Fl m of 4-dimethylaminopyridine; at 0°C for 30 minutes, then at room temperature for 2 hours.
De-stir. Distill the ld medium under reduced pressure, add ethyl acetate to dissolve, wash with water and brine, and dry over anhydrous sodium sulfate.
■ By distilling off the soybean paste under reduced pressure and adding hexane, 830 mg of the IHH title compound (same compound as in Example 2) was obtained.
8 (Yield 24%) I R (nujol, cm″1); 3500+ 3
425.1725.16! l[lNMR(CDCρ3.
δ value); 1.38 (s, 911. -C (CIl3 > 3)
1.40 (d, 311. J-711z, C113
-C1l-)4.40 (m, III, C1l3-C
River-)6.00 (s, III, φ-C1l-)7.
2 ~ 7.5 (m, 611.φ, -COOI+)
9.27 (br, s, IIl, -Nll-) Reference Example 3 D-0-(N-Boc-L-alanyl) obtained in Reference Example 2
49.7 g of mandelic acid, (5-methyl-1,3-dioxol-2-one-4-yl)methyl 7-amino-3-
(5-methyl~1.3.4-thiadiazole-2-
yl)thiomethyl-3-cephem-4-calhokitre-
Dissolve 2g of Toro in methylene chloride (iooml).-
At 5°C, 80ml of 2N-N,N'-dicyclohexolluponimide methylene chloride/8 solution was added dropwise, and the mixture was stirred at the same temperature for 1 hour. Insoluble matter was removed by σF, the lees and liquid were distilled off under reduced pressure, ethyl acetate was added to the residue and the mixture was evaporated again, the filtrate was distilled off under reduced pressure, methanol was added to the residue, and the precipitated crystals were collected by filtration.2) Drying and (5-methyl-1,3-dioxol-2-one-4-yl)methyl 7-[D-0-(N-
Boc-L-alanyl)mandelamide]-3-(5-
12 g of methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate
get. Melting point: I5G'CL decomposition) I R (nujol, c+n'); 3340, 1820.1780.1750.1138O
NMR (CDC7!3. δ value); 1.40 (d, 311. J-7112, -CIl
-C113) 1.41 (s, 91L -C(CIl
3) 3) 2.22 (s, 31L Dioxo-Cl 113) 2.73 (s, 311. Thiadiazole-CI+3) 3.42.3.82 (d, d, 21
1. , I=1711z, 2nd place - 112) 3.89.4
．． 91 (d, d, 211. J=1411z, 3rd place - CIl
25-)4.1~4.55 (m, IIl, -Cjj
-C1h)5.0 (br, IIL -Nll-)
5.03 (d, III, J=511z, 6th place -
11) 5.05 (s, 211. Dioxol-C
11,,-)5.69 (d x d, Ill J=
5 and 911z, 71 11) 6, 19 (s, Il
l, -C1l-CONII-)7.4 (s, 51
1. phenyl) 7.68 (d, ill, J-9
11z, -CONII-) Reference Example 4 (5-methyl-1,3-dioxol-2-one-4-
yl)methyl 7-amino-3-(5-methyl-1,3
, 4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate (1-45.6 g) was dissolved in 500 ml of methylene chloride, and anhydro-0
17.8 g of carboxymandelic acid are added over 15 minutes and then stirred for 2 hours at the same temperature. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate (8/8), washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure, addition of isopropyl ether, and the precipitated solid was collected at 21δ, crystallized from methanol,
49 g of 7-D-mandelamido-3-(5-methyl-1,3,4-thiacyazol-2-yl)thiomethyl-3-cephem-4-carboxylate are obtained.

Melting point, 151°C (decomposition) I R (nujol, am'); 3350, 1820.1780.1730.168ON
MR ((CD3)2 So, δ value) 2.22 (s,
311. Dioxo-ru CI+3)2-10 (s
, 311. Thiadiazole-CIl3) 3.59.
3.97 (d, d, 211. J-1711z, 2
-112) 4.07, 4.87 (d, d, 2iL
J=1411z, 3i standing heat (2) 5.12 (d,
ill, J-511z, 6th-11) 5.15 (
s, 211. Dioxo-ru C1h-)5.21
(d, IIL J-611z, -Cll-011)5.
41 (d, Ill, J=611ha-011)5.
81 (d x d, Ill, J=5 and 9112
．． 7th position-11) 7.42 (m, 511. phenyl) 7.99 (d, III, J=911z, -CON
II-) Reference Example 5 (1) 7-[D-0-(L-alanyl)mandelamide)-3-(5-methyl-C3,4-thianoazole-
Add 20 ml of methanol to 1.7 g of 2-yl)thiomethyl-3-cephe J, -4-carboxylic acid, and 0.4 g of acetate/ethyl acetate, stir with an eyebrow, and dissolve 0.2 g of potassium hydroxide in methanol at room temperature. 15m1? Add S solution and stir for 4 hours. Add 350+nl of diethyl ether to the reaction solution, collect the precipitated solid by filtration and dry it to give 7--CD-
0-(N-1-methyl-2-ethoxycarbonylvinyl)-L-alanyl)-underamido)-3-(5-methyl-1,3°4-thiadiazol-2-yl)thiomethyl-3-cephem-4 -carboxylic acid potassium salt],
Obtain 92 g.

NMR ((CD3)2SO, δ value) 1.15 (t
, 311. J=711z, -CO2-C112-
CIl3) 1.41 (d, 3H, J=711z,
-CIl-CIl3 ) 1.92 (s, 31L C
Il3-C=)2.66 (s, 31L Thiadiazole-C113>3.4 (br, s, 21L 2
-112) 3.9 to 4.8 (m, 311.3 -
C112S-, -Cll-C113) 3.98 (q,
211. J=711z, -CO2-C112-C
113) 4.43 (s, III, -C=CII-)
4.94 (d, Ill, J = 511z, 6
position-11) 5.50 (d x d, ill, J-
5 and 911z, 7th place heat 1) 6.01 (s, Ill
, -CIl-CONII-)7.36 (s, 51
1. phenyl) 8.67 (d, Ill, J-911
z, -CONII-)9.25 (d, IIL J-9
11z, -Nll-) (2) Compound 1 obtained in (1) above
g in 20 ml of N,N-dimerformamide.
4-bromomethyl-5-methyl-L at -10'C
A solution of 0.37 g of 3-dioxol-2-one and 2 ml/8 of N,N-dimethylborumamide was added dropwise, and the mixture was heated at the same temperature.
IS'L l'lnJ for 0 minutes. 100ml of water to the reaction solution
and extracted twice with 5 [1 ml portions] of ethyl acetate. Combine the ethyl acetate layers 1! , washed with water and saturated saline, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure for 1 hour, diethyl ether was added to the residue, and 4 Jl of solid matter was collected by filtration and dried.
5-methyl-1゜3-dioxol-2-one-yl)
Methyl 7-CD-0-[N-1-methyl-2-conitonitoncarbonylvinyl)-L-alanyl)mandelamide)-3-(5-methyl-1,3,4-thianoazol-2-yl) Thiomethyl-3-7ph, r, A-4
- Carboxylate 0.6g fj? Ru.

NMR ((CD3)2SO, δ value) 1.16 (t
, 311. J=711z, -CO2-C112-
CIl3) 1.41 (d, 311. J=7Hz,
-C8-CL)1.92 (s, 311.C113
-C=)2.18 (s, 31L dioxo-C
th) 2.65 (s, 311. Thiadiazole-
C1la) 3.65 (br, s, 211.2nd place-
112) 4.0 (q, 211. J=711z, -
CO2-C112-CIl3)4.0~4.8 (m
, 311.3-CH2S-, -(Jj-Clh)
4.42 (s, Ill, -C=CH-)5.10
(d, ltl, J=5+1z, 6th position-I+)5.
13 (s, 211. dioxo-CH2-)5
．． 72 (d x d, IH, J=5 and 911z,
7th place-11) 5.98 (s, Ill, -Cll-CO
NII-) 7.38 (s, 5H, phenyl) 8.70 (d, IIL J-911z, -CONII
-)9.35 (d, ill, J=9+1z, -Nll
-) Reference Example 6 D-α-(N-Boc-L-alanyloxy)-p-hydroxyphenylacetic acid 0.88 g, (5-methyl-1,
3-dioxol-2-one-4-yl)methyl 7-
Amino-3-(5-methyl-1゜3.4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate 1H, methylene chloride 30ml and ethyl acetate 1
Add 5ml.

IN-N, N'-disic 1,2 at -5°C under suspension stirring.
Hexylcarbodiimide methylene chloride/8 liquid 2.11
ml was added dropwise and then kept at the same temperature for 1 hour. Not t'a 1. l'1 was filtered off, the filtrate was distilled off under reduced pressure,
Cortyl acetate was added to the residue, the insoluble matter was filtered off again, isobutylene ether was added to the filtrate, the precipitated solid was collected by filtration and dried, and (5-methyl-1,3-dioxol-2
-oni/-4-yl)mekyl 7- CD-α-(N-
IJoc-L-alanyloxy)-p-hydroxyphenylacemide)-3-(5-methyl-1,3,/1-
11.45 g of thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate (11 filters).

NMR (CDC13, δ value); 1.39 (s, 9H, -C(CIl3)3)1.
40 (d, 311. J-711z, -Cll-C
Li) 2.19 (s, 311. Dioxol-C
1b>2.70 (s, 311. Thiadiazole-
CIl3) 3.3B, 3.80 (d, d, 21+
, J=1711z, 2nd place -82) 3.89. 4.9
0 (d, d, 21L J=1411z, 3rd position -CH2S
-)4.0~4.4 (m, III, -C++-C11
3) 4.95 (d, LH, J=511z, 6th place -
11) 5.05 to 5.25 (m, 3H, -Nll-, dioxy7-Jlz-Cl
l2-)5.70 (d x d, III, J=
5 and 911z, 7th position-11) 6.06 (s+ Hl
, -Cll-CONII-)6.75.7.23 (d
, d, 411. J = 811z,)y-nyl)
7.25 (br, IIL-011) 7.75 (d
, ill, J-911z -CONII-) Reference Example 7 (5-methyl-1,3-dioxol-2-one-4-
yl)methyl 7-amino-3-((5-methyl-1,
3,4-thiadiazol-2-yl)thiomethyl)-3
-=Synthesis of cephemu 4-carboxylate Potassium 7-amino-3-[(5-methyl-1°3.4
-thiadiazol-2-yl)thiomethyl]-3-cephemu-4-carboxylene-1-12,4g in a mixture of dimethyl sulfoxide and dimethylpor J\amide in 250ml
In addition to 4-butyl-5-methyl-1 at 0
．． Add 7.51 g of 3-dioxol-2-one and stir at the same temperature for 30 minutes. Dissolve the reaction solution in ethyl acetate, add water and then saline in order 7! After the X a value, it was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified with a silica gel column (solvent: Hensen: r!it acid, 7:3) and crystallized with petroleum ether. Title compound 6.
3g was obtained.

I R (nujol, cm'); 3400, 3350.1810.1780.173ON
MR (CD (13, δ value); 1.83 (s, 311.-Nll2) 2.22
(s, 311. Dioxol CI+3) 2.71
(s, 311. Thiadiazole-Cll3)3.
33.3.86 (d, d, 211. J=1811
2.2-Cl12) 3.91.4.88 (d, d,
211. J=1411z, -Cll23-)4.7
8-4.95 (m, 211.6-C11,7-Cl
1) 4.90.5.19 (d, d, 211. J=1511z, dioxo-
Lu C112-) Preparation Example 1 Tablets having the following composition are manufactured by a conventional method.

Compound of Example 1 125mg potency Polyvinylpyrrolidone 20mg Starch 20mH Magnesium stearate 20mg ! ! D agent prescription example 2 Tablets having the following composition are manufactured in a conventional manner.

Compound of Example 1 250mg potency Citric acid 50mg Starch 20mg Magnesium stearate 3.0m8 occlusive formulation example 3 Tablets having the following composition are manufactured in a conventional manner.

Compound of Example 1 500mg Potency Starch 20mg Hydroxypropylcellulose 3mg Magnesium Stearate 5m[! Formulation Example 4 The compound of the example and tartaric acid are added and mixed, and capsules are prepared according to a conventional capsule filling method.

Compound of Example 1 125 ml + titer, 2 tl mg of white acid, 1 mg of magnesium stearate, starch added to give a total of 30 Qmp. Manufacture the agent.

Compound of Example 1 125mB Nozuki ini Magnesium Stearate '1m (Total amount by adding 2 anhydrous lactose 20
0m8 and 7. )''J Formulation Prescription Example 6 A dry syrup formulation is manufactured according to the following composition.

Compound of Example 1 62.5 mg + l [Citric acid 25 mg Sugar 70 mg CMC-Na 20 mli Acute maternal experiment The results of acute toxicity when the cephalosporin derivative of the present invention was orally administered to mice were as follows. be.

Administration subject: Male mouse (lcR 5 weeks old) n-3 Administration method: The cephalosporin derivative fη obtained in the above example was dissolved in distilled water to make a water/8 solution and orally administered.

Oral Administration Experiment The results of the blood concentration and urinary recovery rate of the non-ester form when the cephalosporin derivative of the present invention was orally administered to humans (n-3) are as follows.

Administration method: A 1.25 mPX capsule was administered orally as a non-ester.

Quantification method: Quantification was performed using Bacillus subtilis.

Results: Compound of Example 1

Claims (1)

[Claims] (11 A compound represented by the general formula % formula % (wherein R2 represents hydrogen or a hydroxyl group) or a reactive derivative thereof is reacted with a compound represented by the general formula, or ( 2) General formula (in the formula, R1 is polmyl, L-butoxycarbonyl,
- Methyl-2-methoxycarbonylvinyl, methyl-2-ethoxycarbonylvinyl, hensyloxycarbonyl, p-methoxyhensyloxycarbonyl, chloroacetyltrityl, nril, 2.2.2-1-lichloroethoxycarbonyl, R2 has the same meaning as above) The compound represented by R1 is subjected to the Fi11 removal reaction (t
A method for producing a cephalosporin derivative or its Jp represented by the general formula (wherein R2 has the same meaning as above) characterized by the following: