KR790001023B1 - Acyl derivatives and their preparation - Google Patents

Abstract

Acyl cephalosporin derivs. (I, X = acetoxycephalosporinyl; Y = N-substituted 6-membered heterocyclic group) were manufd. by reacting II (X' = deactoxy-cephalosporinyl group contg. protected 4-carboxyl group; W' = free atom or group) with III, or by reacting IV (X'' = deacetoxy-cephalosporinyl group contg. protected 4-carboxyl group) with acids or their reactive derivs. of V (Z = acyl group being thought as substituent of amino acid in cephalosporin), and followed by isolating the protecting group to give I.

Description

Method for preparing acyl derivative

The present invention relates to acyl derivatives of formula (I) and pharmaceutically possible salts thereof and to methods of hydrates thereof.

X-S-Y (I)

In the structural formula, X is a deacetoxy-cephalosporinyl group

Y contains 1,2 or 3 nitrogen atoms but is not aromatic and does not enolate with an aromatic group, i.e., a nitrogen optionally substituted hexagonal heterocyclic group (where at least one of the nitrogens described above is substituted and at least one nitrogen atom is Forms an amide with adjacent carbonyl groups)

Examples of salts of the compounds of formula (I) include alkali metal salts such as sodium salts and potassium salts, alkali metal salts such as ammonium salts and calcium salts, amines such as N-ethyl-pyrriridine, furokine, dibenzylamine, N, N ' -Salts with organic bases such as dibenzylethyl-ethylenediamine, alkylamines or dialkylamines, and salts with amino acids (ie arginine or lysine).

Structural formula (I) compounds containing free bases (ie amino groups) form addition salts with organic and inorganic acids. Examples of such salts include hydrohalides (ie hydrochlorides, hydrochlorides and hydrochlorides), other inorganic salts (ie sulfates, nitrates, phosphates, etc.), alkylsulfonates and monoarylsulfonates (ie ethanesulfonates). , Toluenesulfonate, benzenesulfonate, etc.) and other organic acid salts (ie, acetate, tartarate, maleate, citrate, benzoate, salicylate, ascorbate, etc.).

The salt of the compounds of formula (I) may be a hydrate. Hydrates may be formed slowly due to the hygroscopic properties of the anhydrous salts of formula (I), which are produced or initially produced during the manufacturing process.

Preferred compounds of formula (I) are those in which X is of general formula (X ₁ ).

Where R ₁ is a hydrogen atom or a methoxy group

R ₂ is cyano, pyridyloxy or aliphatic, alicyclic, aromatic or heterocyclic group

R ₃ represents a hydrogen atom or hydroxy hydroxymethyl, amino, azido, carboxy or sulfo group,

Optionally substituted with hydroxy, halogen, lower alkyl or lower alkoxy when R ₂ is a non-cyano group and R ₃ is a hydrogen atom when R ₂ is a pyridylthio group.

Halogen here is chlorine, fluorine or cancellation and chlorine is preferred. Aliphatic groups are straight-chain or branched alkyl and alkenyl groups having up to 6 carbon atoms, for example methyl, ethyl, furophyll, isofurophyll, n-butyl, isobutyl, pentyl, hexyl, and the like, vinyl, furophenyl, butenyl, Pentenyl, hexenyl, and the like and C ₄ alkyl, in particular n-butyl and isobutyl. Alicyclic groups are C ₃ -C ₆ saturated or unsaturated non-aromatic groups such as cyclofurophyll, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and the like and contain six carbon atoms, in particular cyclohexyl and Cyclohexadienyl groups are preferred. Aromatic groups refer to phenyl, phenyl-C _1-3 -3-alkyl and phenoxy-C _1-3 -alkyl, wherein the phenyl and / or alkyl moiety is substituted with one or several hydroxy halo, lower alkyl or lower alkoxy Phenyl and P-hydroxyphenyl may be preferred. Heteroaromatic groups include cydnonyl, tetrazolyl, triazolyl, furyl, chienyl, pyrazolyl, pyrroyl, chiazolyl, isothiazolyl, oxazolyl, isoxazolyl and the like, pyridyl, pyrimidinyl, pyrazinyl, pyri Refers to a 5-6 hexa aromatic group containing 1-4 nitrogen atoms and / or one oxygen or sulfur atom, such as dazinyl, triazinyl, etc., pentagonal ring, especially chienyl, huryl, tetrazolyl, triazolyl, pyrazolyl And sidnoyl are preferred.

Most preferred compounds of formula (I) are those wherein R ₂ is 2-chienyl, 2-furyl, 1-tetrazolyl, 1-triazolyl, 1-pyrazolyl, 3-sidonyl, phenyl, cyclohexyl, 4-pyridyl R ₃ is a hydrogen atom when the compound is a cation or cyano group and R ₂ is 1-tetrazolyl, 1-triazolyl, 1-pyrazolyl, 3-sidonyl or 4-pyridylthio group.

Furthermore, preferred compounds of formula (I) are non-aromatic, N-substituted pyridonyl groups in which Y is optionally substituted on one or more carbon atoms or on at least one nitrogen atom and optionally substituted on one or more carbon atoms. It refers to a compound which is a non-aromatic pyrimidonyl, pyrazonyl, pyridazonyl or triazonyl group.

Such compounds are for example compounds in which Y is the following group.

2-oxopyridin-4-yl

1-amino, 1-ethyl or 1-butoxy-1, 2-dihydro-2-oxopyrimidin-4-yl,

Or 2-oxopyrimidin-4-yl, such as 1-butoxy-1, 2-dihydro-5-methyl-2-oxopyrimidin-4-yl,

1-ethyl-1, 4-dihydro-6-methyl-4-oxopyrimidin-2-yl or 1,4-dimethyl-1, 6-dihydro-6-oxopyrimidin-2-yl 4-oxopyrimidin-2-yl group,

2,6-dioxopyrimidin-4-yl group,

2-oxopyrazine-3-yl group

2,3,5-trioxopyrazinyl-6-yl group,

3-oxopyridazine-6-diary,

4-ethyl-, 4-methyl-, 4-allyl-, 4-butyl-, 4- (2-methoxyethyl)-, 1, 4-dimethyl- or 1, 4-diethyl-1,4,5 , 6-tetrahydro-5,6-dioxo-as-triazin-3-yl or 1,2,5,6-tetrahydro-1-ethyl 5,6-dioxo-as-triazine-3- Diary 5,6-dioxo-as-triazine-3-diary,

2-oxotriazine-4-yl group or 2,4-dioxotriazine-6-yl group.

Substituents on cyclic nitrogen atoms include lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, hydroxy lower alkoxy, amino, mono (lower alkyl) amino, di (lower alkyl) amino, formyl, lower alkanoyl, lower alka Noylamino, carbamoyl, mono (loweralkyl) aminocarbonyl and di (loweralkyl) aminocarbonyl groups.

Substituents for cyclic carbon atoms include lower alkyl, lower alkoxyamino, mono (lower alkyl) amino, di (lower alkyl) amino, lower alkanoylamino, carboxy, lower alkoxycarbonyl, carbamoyl, mono (lower alkyl) aminocarbonyl, The lower alkyl groups which are di (lower alkyl) aminocarbonyl, cyano and halogen and are bonded to carbon or nitrogen atoms are hydroxy, lower alkoxy, amino, mono (lower alkyl) amino, di (lower alkyl) amino, formyl, Lower alkanoyl, lower alkanoylamino, carboxy, lower alkoxycarbonyl, carbamoyl, mono (lower alkyl) aminocarbonyl, di (lower alkyl) aminocarbonyl, cyano, halogen or epoxy groups.

The lower alkyl, lower alkenyl, lower alkynyl and lower alkoxy groups described above contain up to 6 carbon atoms and the lower alkanoyl groups contain up to 7 carbon atoms. Examples of such lower alkyl groups are methyl, ethyl and the like. Examples of such lower alkenyl groups are vinyl and allyl. Lower alkynyl groups are ethynyl, furopynyl and the like. Lower alkoxy is methoxy, ethoxy and the like. Lower alkanoylyl groups are acetyl, propionyl and the like. Cycloalkyl group refers to a cyclic hydrocarbon group containing 3-7 carbon atoms, such as cyclofurophyll, cyclohexyl, and the like.

Particularly preferred acyl derivatives in the present invention are the following structural formula (I) compounds and their salts.

(7R) -3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7- [2 -(2-chienyl) -acetamido] -3-cef-4-carboxylic acid,

(7R) -3-[[(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7- [2 -(2-chienyl) -acetamido] -3-cef-4-carboxylic acid,

(7R) -3-[[(1,4,5,6-tetrahydro-4-allyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7- [2 -(2-chienyl) -acetamido] -3-cef-4-carboxylic acid,

(7R) -3-[[(1,4,5,6-tetrahydro-4-butyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7- [2 -(2-chienyl) -acetamido] -3-cef-4-carboxylic acid,

(7R) -3-[[(1,4,5,6-tetrahydro-4- (2-methoxyethyl) -5,6-dioxo-as-triazin-3-yl) -thio] methyl ] -7- [2- (2-chienyl) -acetamido] -3-cepem-4-carboxylic acid,

(7R) -3-[[(1,4,5,6-tetrahydro-1,4-dimethyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7- [2- (2-Cheniyl) -acetamido] -3-cefe-4-carboxylic acid,

(7R) -3-[[(1,4,5,6-tetrahydro-1,4-dimethyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7- [2- (2-Cheniyl) -acetamido] -3-cefe-4-carboxylic acid,

(7R) -3-[[(1,2,5,6-tetrahydro-1-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7- [2 -(2-chienyl) -acetamido] -3-cef-4-carboxylic acid,

(7S) -7-methoxy-3-[[(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7- [2-chienyl) -acetamido] -3-cef-4-carboxylic acid,

(7R) -3-[[(1-amino-1, 2-dihydro-2-oxo-4-pyrimidinyl) -thio] -methyl] -7- [2- (2-chienyl)- Acetamido] -3-cepem-4-carboxylic acid,

(7R) -3-[[(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) -thio] -methyl] -7- [2- (2-chienyl)- Acetamido] -3-cepem-4-carboxylic acid,

(7R) -3-[[(1-butoxy-1,2-dihydro-2-oxo-4-pyrimidinyl) -thio] -methyl] -7- [2- (2-chienyl) Acetamido] -3-cepem-4-carboxylic acid,

(7R) -3-[[(1-butoxy-1,2-dihydro-5-methyl-2-oxo-4-pyrimidinyl) -thio] methyl] -7- [2- (2-value Enyl) -acetamido] -3-cef-4-carboxylic acid,

(7R) -3-[[(1,4-dimethyl-1,6-dihydro-6-oxo-2-pyrimidinyl) -thio] methyl] -7- [2- (2-chienyl) Acetamido] -3-cepem-4-carboxylic acid,

(7R) -3-[[(1-ethyl-1,4-dihydro-6-methyl-4-oxo-2-pyrimidinyl) -thio] methyl] -7- [2- (2-chi Yl) -acetamido] -3-cepem-4-carboxylic acid,

(7R) -7- (2-cyanoacetamido) -3 [[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl ) -Thio] methyl] -3-cepem-4-carboxylic acid,

(7R) -3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7-[( R) -mandelamido] -3-cepem-4-carboxylic acid,

(7R) -7-[(R) -2-amino-2-phenylacetamido-3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as) -Triazin-3-yl) -thio] methyl] -3-cef-4-carboxylic acid,

(7R) -3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7- [2 -5-oxo1,2,3-oxadiazolidin-3-yl) -acetamido] -3-cef-4-carboxylic acid,

(7R) -3-[[(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) -thio] -methyl-7- [2- (5-oxo-1,2, 3-oxadiazolidin-3-yl) -acetamido] -3-cef-4-carboxylic acid,

(7R) -3-[[(1-amino-1, 2-dihydro-2-oxo-4-pyrimidinyl) -thio] -methyl] -7- [2- (3-sidonyl) -acet Amido] -3-cepem-4-carboxylic acid,

(7R) -3-[[(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl) -thio] methyl] -7- [2- (1-tetrazolyl) -acetami -3--3-fem-4-carboxylic acid,

(7R) -3-[[(1,4,5,6-terahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7-2 -(1-H-tetrazol-1-yl) -acetamido-3-cefe-4-carboxylic acid,

(7R) -3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7- (R ) -2-hydroxyhexaneamido-3-cepem-4-carboxylic acid,

(7R) -3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7- (R ) -2-hydroxy-4-methyl-valetamido-3-cepem-4-carboxylic acid,

(7R) -3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7- (R ) -2-hydroxy-2- (cyclohexyl-acetamido-3-cefe-4-carboxylic acid,

(7R) -3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) thio] methyl] -7- [2- (2-furyl) acetamido] -3-cef-4-carboxylic acid,

The compounds of formula (I) may exist as optically pure isomers and isomer mixtures.

According to the manufacturing method of the present invention

A) reacting a compound of general formula (II) with a compound of general structure (III) and then

B) reacting a compound of general formula (IV) with an acid or a reaction derivative of general structure (V), separating a protecting group, and converting the resulting material into a salt, if desired, to prepare a compound of formula (I) and salts thereof.

X'-W ₁ (II)

H-S-Y (III)

X "-S-Y (IV)

Z-OH (V)

X 'is present in a protected form of a deacetoxy-cephalosporinyl group or a 4-position carboxyl group corresponding to the X group,

W ₁ is a glass atom or free radical

X ″ is a deacetoxy-cephalosporanyl group corresponding to the X group or a 4-position carboxyl group in a protected form.

Z is an acyl group considered as a substituent on the amino group at the 7-position of cephalosporin.

The carboxyl groups of X 'or X "in the compounds of formula (II) or (IV) are converted to silyl esters such as ester benzyl esters or trimethylsilyl esters which are easily separated, or with tertiary organic or inorganic bases such as leriethylamine. It can be protected by salt formation.

As the free atom or free group represented by W ₁ in the compound of formula (II), halogen atom (chlorine, cancel or oxo) acyloxy (lower alkanoyloxy such as acetoxy), lower alkylsulfonyloxy group such as methyloxy, and arylsulfur such as tosyloxy Phonyloxy and azido groups.

A) When the compound of formula (II) is reacted with the compound of formula (III) according to the method, a polar solvent such as dimethylformamide, dimethylsulfoxide or lower alkoxy at 40 ° C-80 ° C, preferably about 60 ° C. Alcohols such as knol (ethanol, furanpanol, etc.), preferably water, or about 3-8 hours, preferably 6 hours in a buffer solution of pH 6-7, preferably 6.5.

Examples of reactive derivatives of the acid of formula (V) include, for example, halides (chlorides, bromides, fluorides), azides, anhydrides, especially mixed anhydrides with strong acids, reactive esters (N-hydroxysuccinimide esters) And amides (imidazolides).

B) According to the method, it may be carried out by a known method when the compound of formula (IV) is reacted with an acid of formula (V) or a reactive derivative thereof. For example, the free acid of formula (V) is a compound of formula (IV) in an inert solvent such as ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, benzene or dimethylformamide in the presence of a carbodiimide such as dicyclohexylcarbodiimide. The ester group can be reacted with one of the aforementioned esters and subsequently separated. The reaction can be carried out in the presence of oxazol salt (N-ethyl-5-phenyl-isooxazolium-3'-sulfonate) instead of carbodiimide.

Alternatively, the salt of the acid of formula (IV) (trialkylammonium salt) may be reacted with the reactive derivative of the acid of formula (V) in an inert solvent (one of the solvents described above).

The reaction of the compound of formula (IV) with the acid of structure (V) or their reactive derivatives can be carried out at about + 5 ° C to -40 ° C, for example at about 0 ° C.

The protecting group is separated after reacting a compound of formula (II) with a compound of formula (III) or a compound of formula (IV) with an acid of formula (V) or a reactive derivative thereof. When the protecting group is a benzyl group (benzyl ester), it can be separated by catalytic hydrogenation in the presence of a noble metal catalyst such as palladium / carbon. When the protecting group is a silyl (silyl ester) group, the winning reaction product can be easily separated by treatment with water.

If the carboxyl group of the acid of formula IV is protected due to salt formation (salts with triethyl amine) it can be carried out by treatment with acid at some low temperature (about 0 ° C. to about 10 ° C.). Acids that can be used are hydrochloric acid, sulfuric acid, phosphoric acid and citric acid.

The compounds of formula (II) are conventional and can be prepared from the corresponding cephalosporins, ie compounds of the general structure XO-CO-CH ₃ (X: as described above).

-메톡시-세팔로틴, 세파세트릴, (7R)-만델아미도-세팔로스포라닌산 및 7-(3-시드논아세트아미도)-세팔로스포라닌산 및 양이온 세팔로글라이신이 있다.Alkali metal salts of sodium cephalodine (sodium salt), 7-

-Methoxy-cephalotin, cephacetyl, (7R) -mandelamido-cephalosporanoic acid and 7- (3-sidnonacetamido) -cephalosporanoic acid and cationic cephalolysine .

Some of the compounds of formula III are new and some are existing. New compounds of formula (III) can be prepared by methods analogous to the preparation of existing compounds.

1-Substituted 2-oxo-4-merfatopyridine is prepared from correspondingly substituted 4-chloro-2-oxopyridine by nucleophilic substitution (ie with alkaline hydrogen sulfide).

[Chem. Ber. 99, 255 (1966)]

In the same manner, 1,3-disubstituted-2,6-dioxo-1,2,3,6-tetrahydro-4-mulpaytopyridine is substituted with the corresponding 4-chloro-2,6-dioxo-1, It can be prepared from 2,3,6-tetrahydropyrimidine.

Synthesis of 5,6-dioxo-3-mercapto-as-triazine from 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine It can be prepared from correspondingly substituted thiosemicazide in a similar manner.

[K.H. Organia et al. (Insbruck 1672)] The thiol of formula (III) having a double bond between a carbon atom substituted with a mercapto group and an adjacent nitrogen atom may exist as a tautomeric chioketone.

Compounds of formula (IV) may be prepared by reacting a compound of general formula X ″ -W ₁ with a compound of formula (III). The reaction is carried out when the compound of formula (II) is reacted with a compound of formula (III). It can be carried out under the reaction conditions such as.

Acids of structural formula (V) and their reactive derivatives are known and can be prepared by known methods.

Acids of the formula (V) containing subtitle carbon atoms exist in the form of racemic mixtures. Such racemates can be separated into optically active isomers by known methods.

,

-(1-나프틸)-에틸아민이나

-메틸벤질아민같은 광학적으로 활성인 분리제를 사용하여 라세믹 혼합물로 부터 생성될 수 있다. 생성된 투공이성체는 선택결정법으로 분리하고 대응하는 광학이성체로 전환시킨다.For example, the isomer may react with an optically active base such as a carboxyl group.

,

-(1-naphthyl) -ethylamine

It can be produced from racemic mixtures using optically active separating agents such as methylbenzylamine. The resulting porous isomers are separated by the selective crystallization method and converted into the corresponding optical isomers.

The D-chain structural formula (I) compound is separated from the D-form to be obtained by separating a compound of the structural formula (I) present in the form of an isomeric mixture by known methods (i.e., by crystallizing salts such as calcium salts) or It may be prepared by reacting the compound of (III) with the D-compound of the formula (II) or by reacting the compound of the formula (IV) with the D-acid of the formula (V) or a reactive derivative thereof. The latter method is preferred.

Structural formula (I) compounds, their salts, and the hydrates of their salts have antimicrobial wear, in particular bactericidal wear. For their Gram-positive bacteria and Gram-negative bacteria, penicillinase-positive stars as well as various cephalosporinase-positive gram-negative bacteria such as Escherichia coli, Puroteus, Klipsiela, Arobacter and Serratia types It has a wide range of active wear against phycocacas.

Structural formula (I) compounds, their pharmaceutically possible salts and hydrates of the foregoing salts are used for the treatment and prevention of infectious diseases and as disinfectants. The daily dose of an adult is about 1-4 g. Parenteral administration is particularly suitable.

Acyl derivatives prepared according to the process of the invention

(7R) -3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) thio] methyl] -7- [2- Sodium salt of (5-oxo-1,2,3-oxadiazolidin-3-yl) -acetamido] -3-cef-4-carboxylic acid (A substance) and (7R) -3-[[( 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7- [2- (1-H-tetrazol- 1-yl) -acetamido] The antibiotic wear of the sodium salt (B substance) of 3-cepem-4-carboxylic acid can be seen from the CD ₅₀ value. (Mg / kg subcutaneous administration to mice)

[table]

Intravenous injections in mice (CD ₅₀ ) are 2,000-4,000 mg / kg for A and 1,000-2,000 mg / kg for B.

Pharmaceutical formulations, preferably anhydrous ampoules, may contain the formula (I) compounds, pharmaceutically acceptable salts or hydrates of those salts along with other therapeutically valuable substances.

The following examples illustrate the method of the present invention.

Example 1

(7R) -3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) thio] methyl] -7- [2- Preparation of the sodium salt of (2-chienyl) -acetamido] -3-cef-4-carboxylic acid

〕

=+130°4.4 g of cephalotin sodium salt [[

]

= + 130 °

(C = 1, water-soluble)] 2.25 g of 1,4,5,6-tetrahydro-4-epe-5,6-dioxo-3-mercapto-as-triazine in nitrogen stream in 100 ml of water. And 1.05 g sodium bicarbonate at 60 ° C., pH about 6.5 for 6 hours. The mixture is then cooled to 10 ° C. and adjusted to pH 2 with 2N hydrochloric acid. The precipitated material is filtered off with suction and washed with 25 ml of ice water. It is then dissolved in acetone and the solution is evaporated in vacuo. The remaining residue is taken up in dimethylformamide and the solution is treated with 7.5 ml of 2N-ethyl acetate solution of 2-ethyl caprophosphate sodium salt. Dilution with ethyl acetate crystallizes the product to be obtained. Suction filtered, washed with ethyl acetate, ether and petroleum ether continuously and dehydrated in vacuo.

Yield: 4.5 g (80%)

Melting Point:〉 170 ℃ (Decomposition)

〕

=+13.1°(C=0.800, 수용액)[

]

= + 13.1 ° (C = 0.800, aqueous solution)

1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine used as starting material can be prepared as follows.

120 g of 4-ethyl thiosemicarbazide is reacted with 116 g of dimethyl hydroxy ester in the presence of 23 g of sodium in 1 liter of methanol, at the boiling point of the mixture for 4 hours.

Triazine is separated from the mixture in the form of sodium salts and the aqueous solution is acidified.

Melting Point: 189 ° -190 ℃

Example 2

(7R) -3-[[(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7- [2 Preparation of the sodium salt of-(2-chienyl) -acetamido] -3-cef-4-carboxylic acid

This salt was prepared in a similar manner to Example 1, using 4.18 g of cephalotin sodium salt and 1-91 g of 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-3-mercapto- Prepared from As-triazine.

Yield: 2.8 g (54.1%)

Melting Point: 200 ° -205 ° C (Decomposition)

〕

=2.7(C=0.592, 수용액)[

]

= 2.7 (C = 0.592, aqueous solution)

Triazines used as starting materials are prepared from 176 g of 4-methyl- thiosemicarbazide and 198 g of hydroxyester dimethyl ester in a similar manner as in Example 1.

Melting Point: 218 ° -220 ° C (Decomposition)

Example 3

(7R) -3-[[(1,4,5,6-tetrahydro-4-allyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7- [2 Preparation of the sodium salt of-(2-chienyl) -acetamido] -3-cef-4-carboxylic acid

This salt was prepared in a manner similar to that of Example 1, following 6.27 g of cephalotin sodium salt and 3.33 g of 1,4,5,6-tetrahydro-4-allyl-5,6-dioxo-3-mercapto- Prepared from astriazine.

Yield: 3.0 g (36.8%)

Melting Point:> 180 ℃ (Decomposition)

〕

=+19.7°(C=0.376, 수용액)[

]

= + 19.7 ° (C = 0.376, aqueous solution)

Triazines used as starting materials are prepared from 26.2 g of 4-allyl-thiocemiccarbazide and 23.6 g of hydroxyester dimethyl ester in a similar manner as in Example 1.

Melting Point: 138-140 ℃

Example 4

(7R) -3-[[(1,4,5,6-tetrahydro-4-butyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7- [2 Preparation of the sodium salt of-(2-chienyl) -acetamino] -3-cef-4-carboxylic acid

This salt was prepared in a similar manner to Example 1 by 6.27 g of cephalotin sodium salt and 3.62 g of 1,4,5,6-tetrahydro-4-butyl-5,6-dioxo-3-mercapto-as Manufactured from triazine.

Yield: 3.0 g (35.7%)

Melting Point:> 160 ℃ (Decomposition)

〕

=+17.6°(C=0.640 수용액)[

]

= + 17.6 ° (C = 0.640 aqueous solution)

Triazines used as starting materials are prepared from 14.7 g of 4-butyl- thiosemicarbazide and 11.8 g of hydroxyl dimethyl ester in a similar manner as in Example 1.

Melting Point: 180-181 ℃

Example 5

(7R) -3-[[(1,4,5,6-tetrahydro-4- (2-methoxyethyl) -5,6-dioxo-as-triazin-3-yl) -thio] methyl ] -7- [Production of sodium salt of [2- (2-chienyl) -acetamido] -3-cepem-4-carboxylic acid

This salt was prepared using 6.27 g of cephalotin sodium salt and 3.65 g of 1,4,5,6-tetrahydro-4- (2-methoxyethyl) -5,6-dioxo according to a similar method as in Example 1. Prepare from 3-mercapto-as-triazine.

Yield: 2.0 g (23.8%)

〕

=+10°(C=0.280, 수용액중에서)[

]

= + 10 ° (C = 0.280 in aqueous solution)

Triazine used as starting material is obtained from 14.9 g of 4- (2-methoxyethyl) -thiosemicarbazide and 11.8 g of hydroxyl dimethyl ester in a similar manner as in Example 1.

Melting Point: 158 ° -160 ℃

Example 6

(7R) -3-[[(1,4,5,6-tetrahydro-1,4-dimethyl-5,6-dioxo-as-triazin-3-yl) -thio] -methyl] -7 Preparation of the sodium salt of [2- (2-chienyl) -acetamido] -3-cef-4-carboxylic acid

This salt was prepared in a similar manner to Example 1 with 6.27 g of cephalotin sodium salt and 2.6 g of 1,4,5,6-tetrahydro-1,4-dimethyl-5,6-dioxo-3-mercapto It is made from astriazine.

Yield: 4.6 g (58.0%)

〕

=-9.55°(C=0.461, 수용액중에서)[

]

= -9.55 ° (C = 0.461 in aqueous solution)

Triazines used as starting materials are prepared from 11.9 g of 1,4-dimethyl-thiosemicarbazide and 11.8 g of hydroxyl dimethyl ester in a similar manner as in Example 1.

Melting Point: 231-233 ° C (Decomposition)

Example 7

(7R) -3-[[(1,4,5,6-tetrahydro-1,4-diethyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7 Preparation of the sodium salt of [2- (2-chienyl) -acetamido] -3-cef-4-carboxylic acid

This salt was prepared in a similar manner to Example 1 by 6.27 g of cephalotin sodium salt and 2.01 g of 1,4,5,6-tetrahydro-1,4-diethyl-5,6-dioxo-3-mer Prepared from Capto-as-triazine.

Yield: 5.5 g (65.7%)

Melting Point:> 175 ℃ (Decomposition)

〕

=+10.2°(C=0.547, 수용액중에서)[

]

= + 10.2 ° (C = 0.547 in aqueous solution)

Triazine used as starting material is obtained from 14.7 g of 1,4-diethyl-thiosemicarbazide and 11.8 g of hydroxy dimethyl ester according to the method of Example 1.

Melting Point: 177 ° -179 ℃

Example 8

(7R) -3-[[(1,2,5,6-tetrahydro-1-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7- [2 Preparation of the sodium salt of-(2-chienyl) -acetamido] -3-cef-4-carboxylic acid

This salt was prepared in the same manner as in Example 1 with 10.45 g of cephalotin sodium salt and 4.8 g of 1,2,5,6-tetrahydro-1-ethyl-5,6-dioxo-3-mercapto- Obtained from astriazine.

Yield: 7.0 g (52.6%)

Melting Point:> 210-215 ℃ (Decomposition)

〕

=+8.85°(C=0.181, 수용액중에서)[

]

= + 8.85 ° (C = 0.181 in aqueous solution)

Triazines used as starting materials are prepared as follows. 46.5 g of 1-ethyl-thiocemicarbazide are reacted with 48 g of monomethyl ester chloride in 40 ml of acetone. 34.3 g of the resulting product are treated with 9.2 g sodium methylate in 300 ml of methanol. Triazine is obtained from the mixture in the form of sodium salts and by acidifying the aqueous solution.

Melting Point: 213 ° -214 ° C (Decomposition)

Example 9

(7S) -7-methoxy-3-[[(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] Preparation of the sodium salt of -7- [2- (2-chienyl) -acetamido] -3-cepm-4-carboxylic acid

-메톡시-세팔로틴 나트륨염 [〔

〕

=+194.5°(C=0.308, 수용액중에서)] 및 1.82g 의 1,4,5,6-테트라하이드로-4-메틸-5,6-디옥소-3-멀캅토-아스-트리아진으로 부터 수득한다.This salt was prepared in a similar manner to Example 1 by 5.16 g of 7-

-Methoxy-cephalotin sodium salt [[

]

= + 194.5 ° (C = 0.308 in aqueous solution) and 1.82 g of 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-3-mercapto-as-triazine To obtain.

Yield: 1.0 g (15.9%)

〕

=+54.6°(C=0.308, 수용액중에서)[

]

= + 54.6 ° (C = 0.308 in aqueous solution)

Example 10

(7R) -3-[[(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) -thio] methyl] -7- [2- (2-chienyl) -acet Amido] Production of Sodium Salt of 3-Cefem-4-carboxylic Acid

This salt is prepared from 4.18 g of cephalotin sodium salt and 1.8 g of 1-ethyl-1,2-dihydro-4-mercapto-2-oxo-pyrimidine according to the method of Example 1.

Yield: 3.2 g (65.3%)

Melting Point:〉 190 ℃ (Decomposition)

〕

=-58°(C=0.570, 수용액중에서)[

]

= -58 ° (C = 0.570 in aqueous solution)

Example 11

(7R) -3-[[(1-butoxy-1,2-dihydro-2-oxo-4-pyrimidinyl) -thio] methyl] -7- [2- (2-chienyl)- Acetamido] -3-production of sodium salt of cefem-4-carboxylic acid

This salt is prepared from 4.18 g of cephalotin sodium salt and 2.2 g of 1-butoxy-1,2-dihydro-4-mercapto-2-oxo-pyrimidine in a similar manner to Example 1.

Yield: 3.8 g (70%)

〕

=-83.6°(C=0.850, 수용액중에서)[

]

= -83.6 ° (C = 0.850 in aqueous solution)

Pyrimidine used as starting material is prepared from 2 g of 1-butoxy uracil and 4 g of phosphorus pentasulfide.

Melting Point: 99-100 ℃

Example 12

(7R) -3-[[(1-butoxy-1,2-dihydro-5-methyl-2-oxo-4-pyrimidinyl) -thio] methyl] -7- [2- (2-value Enyl) -acetamido] -3-sodium salt of cefem-4-carboxylic acid

This salt was converted into 6.0 g of cephalotin sodium salt and 3.36 g of 1-butoxy-1,2-dihydro-4-mercapto-5-methyl-2-oxo-pyrimidine in a similar manner to Example 1. Manufacture from.

Yield: 0.8 g (9.7%)

Melting Point:〉 170 ℃ (Decomposition)

Pyrimidine used as starting material is prepared by reacting 25 g of 1-butoxy-5-methyl-uracil with 50 g of phosphorus pentasulfide in a similar manner to Example 1.

,

-디에톡시-

-메틸푸로피온산 에스테르와 반응시켜 제조한다.1-butoxy-5-methyl-uracil contains 110g butoxyurea and 184g

,

Diethoxy

Prepared by reacting with methylpropionic acid ester.

Example 13

(7R) -3-[[(1,4-dimethyl-1,6-dihydro-6-oxo-2-pyrimidinyl) -thio] methyl] -7- [2- (2-chienyl) Acetamido] -3-Cefe-4-carboxylic acid sodium salt

This salt was prepared from 4.18 g of cephalotin sodium salt and 1.8 g of 1,4-dimethyl-1,6-dihydro-2-mercapto-6-oxo-pyrimidine according to a similar method as in Example 1. do

Yield: 1.35 g (26.3%)

Melting Point: 200-210 ℃ (Decomposition)

〕

=+9.5°(C=0.348, 수용액중에서)[

]

= + 9.5 ° (C = 0.348 in aqueous solution)

Example 14

(7R) -3-[[(1-ethyl-1,4-dihydro-6-methyl-4-oxo-2-pyrimidinyl) -thio] methyl] -7- [2- (2-chi Yl) -acetamido] -3-preparation of sodium salt of cefe-4-carboxylic acid

This salt was prepared in a similar manner to Example 1 from 6.27 g of cephalotin sodium salt and 2.98 g of 1-ethyl-1,4-dihydro-2-mercapto-6-methyl-4-oxo-pyrimidine. Manufacture

Yield: 3.2 g (40.4%)

Melting Point:〉 170 ℃ (Decomposition)

〕

=-14.4°(C=0.333, 메타놀중에서)[

]

= -14.4 ° (C = 0.333 in methanol)

Pyrimidine used as starting material is prepared as follows. 18 g of N-ethyl-thiourea is dissolved in 50 ml of glacial acetic acid, refluxed and boiled, and then treated with dropwise addition of 17.2 g of dikerene. The mixture is then boiled under reflux for 20 minutes and then evaporated to 50 ml. Cool, stir and treat the residue with 50 ml of water. The yellow crystals dropped into the precipitate are filtered off with suction and recrystallized with tetrahydrofuran.

Melting Point: 190 ℃

Example 15

(7R) -7- (2-cyanoacetamido) -3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl Preparation of Sodium Salt of) -Cio] methyl] -3-cepem-4-carboxylic Acid

This salt was prepared according to the method of Example 1 with 9.5 g of cephacetyl sodium salt and 5.46 g of 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as Manufactured from triazine.

Yield: 3.3 g (26.8%)

〕

=+7.85(C=0.1785, 수용액중에서)[

]

= + 7.85 (C = 0.1785 in aqueous solution)

Example 16

(7R) -3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7-[( R) -mandelamido] -3-Sodium salt of cefem-4-carboxylic acid

This salt was prepared in a similar manner to Example 1 by 8.0 g of sodium salt of (7R) -mandelamido-cephalosporanic acid and 3.72 g of 1,4,5,6-tetrahydro-4-ethyl-5, Prepared from 6-dioxo-3- mercapto-as-triazine.

Yield: 1.7 g (16.8%)

〕

=-19.6°(C=0.500, 수용액중에서)[

]

= -19.6 ° (C = 0.500 in aqueous solution)

Example 17

(7R) -7-[(R) -2-amino-2-phenylacetamido] -3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo- Preparation of As-triazin-3-yl) -thio] methyl] -3-cepem-4-carboxylic acid

This compound was prepared in a similar manner to Example 1 by 8.1 g of cephalolysine and 3.78 g of 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-tri Prepared from azine and separated as zwitterion.

Yield: 4.19 g (40.5%)

Melting Point:> 180 ℃ (Decomposition)

〕

=-86.3°(C=0.276, 디메틸포름아마이드중에서)[

]

= -86.3 ° (C = 0.276 in dimethylformamide)

Example 18

(7R) -3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7- [2 Preparation of the sodium salt of-(5-oxo-1,2,3-oxadiazolidin-3-yl) -acetamido] -3-cef-4-carboxylic acid

This salt was prepared in a similar manner to Example 1 by 7.7 g of 7- (3-sidnonacetamido) -cephalosporinic acid sodium salt and 3.46 g of 1,4,5,6-tetrahydro-4- Prepare from ethyl-5,6-dioxo-3-mercapto-as-triazine.

Yield: 3.3 g (31%)

Melting Point:> 210 ℃ (Decomposition)

〕

=+17.9°(C=0.380, 수용액중에서)[

]

= + 17.9 ° (C = 0.380 in aqueous solution)

Example 19

(7R) -3-[[(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) -thio] methyl] -7- [2- (5-oxo-1,2, Preparation of Sodium Salt of 3-Oxadiazolidin-3-yl) -acetamido] -3-cepem-4-carboxylic acid

This salt was prepared in a similar manner to Example 1 in 11.6 g of 7- (3-sidnonacetamido) -cephalosporanoic acid sodium salt and 4.7 g of 1-ethyl-1,2-dihydro-4- Prepared from mercapto-2-oxo-pyrimidine.

Yield: 3.6 g (23.2%)

〕

=-43.7°(C=0.600, 수용액중에서)[

]

= -43.7 ° (C = 0.600 in aqueous solution)

Example 20

(7R) -3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7- [2 Preparation of the sodium salt of-(1-H-tetrazol-1-yl) -acetamido] -3-cef-4-carboxylic acid

1.28 g of tetrazol-1-acetinic acid is dissolved in 50 ml of a mixture of tetrahydrofuran and dimethylformamide. The solution is subsequently treated with 1.18 ml of N-methyl-morpholine and 1.4 ml of chloroformic isobutyl ester at -20 ° C and then stirred at -10 ° C to -20 ° C for 20 minutes. 3.85 g of 7-amino-3-deacetoxy-3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -Cio]-Ice-cold solution is added to 50 ml of an aqueous solution of cephalosporanic acid and a salt obtained from 1.4 ml of triethylamine. The mixture is stirred at 0 ° C. for 30 minutes and at 20 ° C. for 1 hour. The mixture is then concentrated in vacuo and the aqueous layer is acidified with 5 ml of 2N hydrochloric acid to drop the desired product to precipitate. This was filtered by suction, washed with a large amount of ethyl acetate, and dissolved in dimethylformamide. The solution is treated with a 2-N-ethyl acetate solution of 2-ethyl-cafurophosphate salt and then diluted with ethanol and ether to drop the desired crude sodium salt (3.3 g) into the precipitate. For purification, the crude sodium salt is dissolved in 20 ml of water, treated with 60 ml of ethanol and the dark resin is removed by precipitation. The filtrate is evaporated in vacuo and the residue is treated with ethanol and ether to give the desired pure sodium salt as a pale beige powder.

Yield: 2.3 g (44.5%)

Melting Point: 210 ℃ (Decomposition)

〕

=+23°(C=0.824, 수용액중에서)[

]

= + 23 ° (C = 0.824 in aqueous solution)

7-amino-3-deacetoxy-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) used as starting material -Cio] -Cefalosporanoic acid is prepared as follows.

2.72 g of 7-amino-cephalosporanic acid are suspended in 100 ml of water with 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-3-mercapto-as-triazine. Let's do it. The suspension is treated with 1.85 g of sodium bicarbonate to give a solution of pH 6.4, then stirred at 60 ° C. for 3 hours in nitrogen stream, cooled to 20 ° C., and further stirred for 1 hour by addition of 1 g of activated carbon in nitrogen stream. After filtration, the filtrate was adjusted to pH 3.8 with 2N hydrochloric acid, cooled to 0 ° C. and stirred for 1 hour. The separated crystals are suction filtered and subsequently washed with a small amount of water, acetone, ether and petroleum ether and dried in vacuo at 50 ° C.

Yield: beige powder 2.3g (60%)

Melting Point: 230 ° -235 ° C (Decomposition)

7-amino-3-deacetoxy-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] -ce Palosporanic acid is prepared as follows.

5.16 g of 1,4,5,6-tetrahydro-4-ethyl-5,6-di in 5.1 g of 7-amino-3-amido-3-deacetoxy-cephalosporanic acid in a nitrogen stream Stir for 6 hours at 60 ° C. in 200 ml of pH 7.0 buffer with oxo-3-mercapto-as-triazine and 4.2 g sodium bicarbonate. The solution is cooled to 25 ° C. and adjusted to pH 3.5 with 2N hydrochloric acid. The separated crystals are suction filtered (2.2 g). The mother liquor is concentrated to give 1.7 g more.

Total yield: 3.9g (50%)

Example 21

(7R) -3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7-[( R) -2-hydroxyhexaneamido] Preparation of Sodium Salt of 3-Cefem-4-carboxylic Acid

4.4 g of 7-amino-3-deacetoxy-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio -Cephalosporanic acid is dissolved in 44 ml of water and 44 ml of acetone at 0 ° C. and stirred with 2.5 g of sodium bicarbonate. Next, a solution of 3 g of (R) -2-dichloroacetoxy-n-capurophosphate chloride (boiling point: 0.5 = 75-76 ° C.) in 30 ml of acetone was added dropwise while stirring at 0 ° C. The mixture is stirred at 0 ° C. for 2 hours and then at 20 ° C. for 1 hour. Acetone is distilled off from the filtrate at 30 ° C. under reduced pressure. The aqueous solution was added with sodium bicarbonate, stirred for 45 minutes at pH 9.5, extracted twice with ethyl acetate and adjusted to pH 1.5-2.0 with 3N-sulfuric acid. Dimethylformamide is added, followed by extraction with ethyl acetate. The ethyl acetate solution is washed several times with 10% sodium chloride solution and evaporated with magnesium sulfate to 25 deg. The residue is taken up in 100 ml of asofuropanol and treated with 12 ml of a 2N-isopropanol solution of 2-ethyl caprophosphate sodium salt. The desired crude sodium salt is filtered off with suction, reprecipitated with water / isofuropanol and dried under reduced pressure. Crude sodium salt is obtained as a beige powder.

Yield: 56%

Melting Point: 183 ° C (Decomposition)

〕

=+8.2°(C=1.00, 수용액중에서)[

]

= + 8.2 ° (C = 1.00 in aqueous solution)

Example 22

(7R) -3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7-[( R) -2-hydroxy-4-methyl valeramido] Preparation of Sodium Salt of 3-Cefem-4-carboxylic Acid

This salt was prepared in a similar manner to Example 21 by 3.5 g of 7-amino-3-deacetoxy-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as) -Triazin-3-yl) -thio] -cephalosporanic acid and 2.4 g of (R) -2-dichloroacetoxy-isocapurophosphate chloride (boiling point 0.2 = 63-64 ° C.).

Yield: 51%

Melting Point: 180 ℃ (Decomposition)

〕

=+6.0°(C=0.00, 수용액중에서)[

]

= + 6.0 ° (C = 0.00 in aqueous solution)

Example 23

(7R) -3-] [(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7-[( R) -2-hydroxy-2-cyclohexyl acetamido] -3-preparation of the sodium salt of carboxylic acid

This salt was prepared in accordance with the method of Example 21 with 3.9 g of 7-amino-3-deacetoxy-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as) -Triazin-3-yl) -thio] -cephalosporanic acid and from 2.9 g of (R) -2-dichloroacetoxy-2-cyclohexyl-acetyl chloride (boiling point 0.5 = 105-107 ° C.) do.

Yield: 37%

Melting Point: 190 ℃ (Decomposition)

〕

=+2.8°(C=1.50, 수용액중에서)[

]

= + 2.8 ° (C = 1.50 in aqueous solution)

Example 24

(7R) -3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] -methyl] -7- [ Preparation of sodium salt of 2- (2-furyl) -acetamido] -3-cef-4-carboxylic acid

3.85 g of 7-amino-3-deacetoxy-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio -Cephalosporanic acid is dissolved in 2.4 g of sodium bicarbonate and stirred at 0 ° C. in a mixture of 40 ml of water and 40 ml of acetone. To this solution, a solution of 1.45 g of 2- (2-furyl) -acetyl chloride in 15 ml of acetone is added at -5 ° C, and the mixture is stirred at -5 ° C for 3 hours and 1.5 hours. The solution is extracted twice with ethyl acetate and the aqueous layer is acidified to pH 2 with 3N-sulfuric acid at 0 ° C. Dimethylformamide was added and extracted with ethyl acetate. The ethyl acetate solution was washed three times with 10% sodium chloride solution, dehydrated with magnesium sulfate, and evaporated at 25 ° C under reduced pressure. The residue is taken up in methanol and treated with 8 ml of 2N-isofuropanol solution of the sodium salt of 2-ethyl-caprophosphate. The desired crude sodium salt is precipitated with diethyl ether, filtered off with suction, washed with acetone with diethyl ether and recrystallized from water. Beige powder is obtained.

Yield: 43%

Melting Point: 180 ℃ (Decomposition)

〕

=+18.4°(C=10, 수용액중에서)[

]

= + 18.4 ° (C = 10 in aqueous solution)

Example 25

(7R) -3-[[(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl-thio] methyl] -7- [2- (2-chienyl) -acetami Manufacture of Sodium Salt of 3-Cefem-4-carboxylic Acid

This salt is prepared from 8.36 g of cephalotin sodium salt and 3.0 g of 1-amino-1,2-dihydro-4-mercapto-2-oxo-pyrimidine in a similar manner to Example 1.

Yield: 4.1 g (40.2%)

Melting Point:> 185 ℃ (Decomposition)

〕

=-78.5°(C=0.439, 수용액중에서)[

]

= -78.5 ° (C = 0.439 in aqueous solution)

The pyrimidine used as starting material is prepared from 8.6 g of 1-benzylideneamino-uracil (melting point 220 ° -223 ° C. monacheft tewiakemi 96, 1735 (1965)) and 12 g of phosphorus pentasulphide in pyridine and hydrochloric acid. To hydrolysis.

Example 26

(7R) -3-[[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7- [2 Preparation of the sodium salt of-(2-chienyl) -acetamido] -3-cef-4-carboxylic acid

This salt was prepared according to the method of Example 1 by 8.36 g of cephalotin sodium salt and 3.34 g of 1,2,5,6-tetrahydro-5,6-dioxo--3-mercapto-2-methyl- Obtained from astriazine.

Yield: 5.8 g (56%)

Melting Point: 185 ℃ (Decomposition)

〕

=-49.3(C=0.450, 수용액중에서)[

]

= -49.3 (C = 0.450 in aqueous solution)

Triazines used as starting materials are prepared from 31.5 g of 2-methyl- thiosemicarbazide and 35.4 g of hydroxyl dimethyl ester in a similar manner as in Example 1.

Melting Point: 260 ℃

Example 27

(7R) -3-[[(1,2-dihydro-1-methyl-2-oxo-4-pyrimidinyl) -thio] methyl] -7- [2- (2-chienyl) -acet Amido] Preparation of Sodium Salt of 3-Cefem-4-carboxylic Acid

This salt is prepared from 8.36 g of cephalotin sodium salt and 2.98 g of 1,2-dihydro-mercapto-1-methyl-2-oxo-pyrimidine according to the method of Example 1.

Yield: 6.3 g (62.4%)

Melting Point: 180 ℃ (Decomposition)

〕

=-67.7°(C=0.604, 수용액중에서)[

]

= -67.7 ° (C = 0.604 in aqueous solution)

Example 28

(7R) -3-[[(1,2-dihydro-1-methoxy-2-oxo-4-pyrimidinyl) -thio] -methyl] -7- [2- (2-chienyl) -Acetamido] -3-Production of Sodium Salt of Cefem-4-carboxylic Acid

This salt is prepared from 8.36 g of cephalotin sodium salt and 3.32 g of 1,2-dihydro-4-mercapto-1-methoxy-2-oxo-pyrimidine in a similar manner to Example 1.

Yield: 6.3 g (61.2%)

Melting Point: 175-180 ℃ (Decomposition)

〕

=-90.6°(C=0.338, 수용액중에서)[

]

= -90.6 ° (C = 0.338 in aqueous solution)

Pyrimidine used as starting material is prepared from 6 g of 1-methoxyuracil and 18 g of phosphorus pentasulfide according to the method of Example 11.

Melting Point: 177 ℃

Example 29

(7R) -3-[[(1-ethoxy-1,2-dihydro-2-oxo-4-pyrimidinyl) -thio] dithyl] -7- [2- (2-chienyl)- Acetamido] -3-production of sodium salt of cefem-4-carboxylic acid

This salt is prepared from 6.27 g of cephalotin sodium salt and 2.75 g of 1-ethoxy-1,2-dihydro-4-mercapto-2-oxo-pyrimidine according to the method of Example 1.

Yield: 3.5 g (44%)

Melting Point:> 180 ℃ (Decomposition)

〕

=-74.2°(C=0.525, 수용액중에서)[

]

= -74.2 ° (C = 0.525 in aqueous solution)

Pyrimidine used as starting material is prepared from 6.4 g of 1-ethoxyuracil and 18 g of phosphorus pentasulphide in a similar manner as in Example 11.

Melting Point: 119-120 ℃

Example 30

(7R) -3-[[(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl) -thio] methyl] -7- [2- (2-chienyl) -acet Amido] Production of Sodium Salt of 3-Cefem-4-carboxylic Acid

This salt is prepared from 1.25 g of cephalotin sodium salt and 0.470 g of 1,6-dihydro-3-mercapto-1-methyl-6-oxo-pyridazine according to the method of Example 1.

Yield: 1.0 g (66.7%)

Melting Point:> 215 ℃ (Decomposition)

〕

=-49.7°(C=0.332, 수용액중에서)[

]

= -49.7 ° (C = 0.332 in aqueous solution)

The pyridazine used as starting material was 2.88 g of 3-chloro-1,6-dihydro-1-methyl-6-oxo-pyridazine at 130 ° C. and 5-7 atm pressure [melting point 91-92 ° C., monazepte Hua Chemie 99, 33 (1968)] and 5.88 g of sodium ethanol sulfide ethanol solution.

Melting Point: 115 ℃

Example 31

(7R) -3-[[(1-amino-1,2-dihydro-2-oxo-4-pyridazinyl) -thio] methyl] -7- [2- (3-sidonyl) -acetami Manufacture of Sodium Salt of 3-Cefem-4-carboxylic Acid

This salt was prepared according to the method of Example 20 with 9.5 g of cynono-3-acetinic acid and 21.4 g of 7-amino-3-deacetoxy-3-[(1-amino-1,2-dihydro- 2-oxo-pyrimidin-4-yne) -thio] cephalosporanic acid.

Yield: 9.7 g (32%)

Melting Point: 200 ° C (Decomposition)

〕

=-61.3(C=0.5, 수용액)[

]

= -61.3 (C = 0.5, aqueous solution)

Example 32

(7R) -7-[[(R) -2-amino-2- (P-hydroxyphenyl) -acetamido-3-[[(4-ethyl-1,4,5,6-tetrahydro- Preparation of 5,6-dioxo-as-triazin-3-yl) -thio] methyl] -3-cepem-4-carboxylic acid

This compound was prepared in accordance with the method of Example 1 with 24.5 g of DP-hydroxy-N-tertbutyl-oxycarbonyl-cephaloglycine and 8.66 g of 1,4,5,6-tetrahydro-4-ethyl- Obtained by reaction with 5,6-dioxo-3-mercapto-as-triazine and removal of the tertiary butyl oxycarbonylprotecting group with formic acid.

Yield: 5.7 g (23%)

Melting Point: 200 ° C (Decomposition)

〕

=-79.8°(C=0.3, 디메틸포름아마이드중에서)[

]

= -79.8 ° (C = 0.3 in dimethylformamide)

Example 33

(7R) -3-[[(4-ethyl-1,4,5,6-tetrahydro-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7- [2 Preparation of the sodium salt of-(4-pyridyl-thio) -acetamido] -3-cef-4-carboxylic acid

This salt was prepared in a similar manner to Example 1 by 6.0 g of cepapirine and 2.56 g of 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine Manufacture from.

Yield: 1.9 g (26%)

Melting Point: 205 ° C (Decomposition)

〕

=+36.2°(C=0.5, 수용액중에서)[

]

= + 36.2 ° (C = 0.5, in aqueous solution)

Example 34

(7R) -3-[[(4-ethyl-1,4,5,6-tetrahydro-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7- (2 Preparation of Sodium Salt of Pyrazol-1-yl-Acetamido] -3-cepem-4-carboxylic Acid

This salt was prepared in a similar manner to Example 1 by 6 g of (pyrazol-1-yl-methyl) -cephalosporin sodium salt and 3.12 g of 1,4,5,6-tetrahydro-4-ethyl-5,6 Prepared from dioxo-3-mercapto-as-triazine.

Yield: 4.0 g (51%)

Melting Point: 190 ℃ (Decomposition)

Example 35

(7R) -3-[[(1,2,3,6-tetrahydro-2,6-dioxo-1-methyl-S-triazin-4-yl) -thio] methyl] -7- [2 Preparation of the sodium salt of-(2-chienyl) -acetamido] -3-cef-4-carboxylic acid

This salt was prepared in a similar manner to Example 1 with 8.36 g of cephalotin sodium salt and 3.34 g of 1,2,3,6-tetrahydro-2,6-dioxo-4-mercapto-1-methyl-S Manufactured from triazine.

Yield: 5.5 g (53%)

Melting Point: 200 ° C (Decomposition)

〕

=-43°(C=0.1, 수용액중에서)[

]

= -43 ° (C = 0.1 in aqueous solution)

1,2,3,6-tetrahydro-2,6-dioxo-4-mercapto-1-methyl-S-triazine used as starting material is prepared as follows.

14.8 g of sodium solution dissolved in 1,000 ml of methanol were treated with 39.9 g of 5-methyl-2-thio-buret and 72 g of diethyl carbonate and heated to reflux for 24 hours. The solution is concentrated in vacuo to 200 ml. The crystallization material is suction filtered, dissolved in 200 ml of water and acidified with 2N hydrochloric acid. The precipitate is suction filtered and recrystallized with 350 ml of ethanol.

Yield: 11.2 g (23%) (colorless material)

Melting Point: 275 ℃

5-Methyl-2-thio-burette can be prepared as follows. 76 g of thiourea solution dissolved in 1,000 ml of dimethylformamide was treated with 65.4 ml of methyl isocyanate and stirred at 50-55 ° C. for 72 hours. The solution is then evaporated in vacuo and the residue is recrystallized from water.

Yield: 79.4 g (60%, colorless material)

Melting Point: 209-210 ℃

Example 36

(7R) -3-[[(1-ethyl-5-chloro-1,2-dihydro-2-oxo-4-pyrimidinyl) -thio] methyl] 7- [2- (2-chienyl ) -Acetamido] -3-Production of Sodium Salt of Cefme-4-carboxylic Acid

This salt was prepared from 6.27 g of cephalotin sodium salt and 3.04 g of 1-ethyl-5-chloro-1,2-dihydro-4-mercapto-2-oxo-pyrimidine according to the method of Example 1. Manufacture.

Yield: 3.5 g (42%)

Melting Point: 185 ℃ (Decomposition)

〕

=95.2°(C=0.394, 수용액중에서)[

]

= 95.2 ° (C = 0.394 in aqueous solution)

1-ethyl-5-chloro-1,2-dihydro-4-mercapto-2-oxo-pyrimidine used as starting material was prepared as follows.

1.74 g of 1-ethyl-5-chlorouracil is mixed with 4.44 g of phosphorus pentasulfide and 0.1 ml of water, then treated with 30 ml of pyridine and heated to reflux for 3.75 hours. The mixture is evaporated in vacuo at 40 ° C. and the residue suspended in 30 ml of water and treated with 30 ml of 2N hydrochloric acid. The resulting crystals are suction filtered, washed with water and then recrystallized with ethanol.

Yield: 1.3 g (68%, yellow material)

Melting Point: 217-220 ℃

1-ethyl-5-chlorouracil used in the above method can be prepared as follows.

9.9 g of 1-ethyl-5-uracil solution dissolved in 150 ml of glacial acetic acid reacted positively with iodine-potassium starch paper until chlorine was no longer detected by thin layer chromatography (approximately 0.5 hours). Introduce. The mixture is evaporated in vacuo at 40 ° C. and the crystal phase residue is recrystallized from 300 ml of ethanol.

Yield: 10.0 g (81%, colorless, fine needle)

Melting Point: 244-247 ℃

,

-디에톡시푸로피온산 에틸 에스테르를 가한다.The 1-ethyl-uracil used in the above method can be prepared as follows. In 15.0 g of sodium solution dissolved in ethanol in 700 ml, 44 g of N-ethylurea and 105 g of

,

Diethoxyfuropionic acid ethyl ester is added.

The yellow solution is then heated at 25 ° C. for 3 hours and then heated to reflux for 15 hours. The mixture is evaporated in vacuo and the residue is taken up in 300 ml of water, cooled to 0 ° C. and acidified with 100 ml of concentrated hydrochloric acid. The crystalline intermediate falls into precipitation (43 g), which is filtered under vacuum, washed with 100 ml of ice water and subsequently placed in 250 ml of water and heated to 80 ° -100 ° C. to complete conversion to the desired water-soluble 1-ethyl-uracil. The solution is evaporated in vacuo at 40 ° C. and the remaining residue is recrystallized from ethanol ether.

Yield: 14.0 g (20%, colorless substance)

Melting Point: 150 ℃

Example 37

(7R) -3-[[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7- [2 Preparation of-(1-H-tetrazol-1-yl) -acetamido] -3-cephem-4-carboxylic acid sodium salt

This salt was prepared according to the method of Example 20 with 2.95 g of tetrazol-1-acetic acid and 8.55 g of 7-amino-3-[(1,2,5,6-tetrahydro-2-methyl-5, 6-dioxo-as-triazin-3-yl) -thio] -cephalosporanic acid.

Yield: 4.65 g (40%)

Melting Point: 220-230 ℃ (Decomposition)

〕

=53.6°(C=0.321, 수용액중에서)[

]

= 53.6 ° (C = 0.321 in aqueous solution)

Example 38

(7R) -7- (R) -Mandelamido-3-[[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl) -Cio] methyl] -3-cepem-4-carboxylic acid sodium salt

This salt was prepared according to the method of Example 21 with 9.25 g of D-0-dichloroacetyl-mandelic acid chloride and 11.1 g of 7-amino-3-deacetoxy-3-[(1,2,5,6-tetra Hydro-2-methyl-5,6-dioxo-as-triazin-3-yl) -thio] -cephalosporanic acid.

Yield: 4.3 g (27%)

Melting Point: 200-210 ℃ (Decomposition)

〕

=66.8°(C=0.296, 수용액중에서)[

]

= 66.8 ° (C = 0.296 in aqueous solution)

Example 39

(7R) -7- [2- (3-sidnonyl) -acetamido] -3-[[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as- Preparation of Sodium Salt of Triazine-3-yl) -Cio] methyl] -3-cepem-4-carboxylic Acid

This salt was prepared according to the method of Example 20 with 5.76 g of cydnono-3-acetinic acid and 14.95 g of 7-amino-3-deacetoxy-3-[(1,2,5,6-tetrahydro- 2-methyl-5,6-dioxo-as-triazin-3-yl) -thio] -cephalosporanic acid.

Yield: 7.0 g (33%)

Melting Point: 200 ° C (Decomposition)

〕

=-25.5°(C=0.227%)[

]

= -25.5 ° (C = 0.227%)

Example 40

(7R) -3-[[(1-dimethylamino-1,2-dihydro-2-oxo-4-pyrimidinyl) -thio] methyl] -7- [2- (2-chienyl)- Acetamido] -3-production of sodium salt of cefem-4-carboxylic acid

This salt is prepared from 3.34 g of cephalotin sodium salt and 1.42 g of 1,2-dihydro-1-dimethylamino-4-mercapto-2-oxo-pyrimidine according to the method of Example 1.

Yield: 2.4 g (57%)

Melting Point: 165 ℃ (Decomposition)

〕

=-65.2°(C=0.557, 수용액중에서)[

]

= -65.2 ° (C = 0.557, in aqueous solution)

Example 41

(7R) -3-[[(3-chloro-1,6-dihydro-1-methyl-6-oxo-4-pyridazinyl) -thio] methyl] -7- [2- (2-chi Yl) -acetamido] -3-preparation of sodium salt of cefe-4-carboxylic acid

This salt was prepared from 8.36 g of cephalotin sodium salt and 3.7 g of 3-chloro-1,6-dihydro-4-mercapto-1-methyl-6-oxo-pyridazine according to the method of Example 1. Manufacture.

Yield: 4.7 g (44%)

Melting Point: 225-230 ℃ (Decomposition)

〕

=+5.35°(C=0.522, 수용액중에서)[

]

= + 5.35 ° (C = 0.522 in aqueous solution)

3-Chloro-1,6-dihydro-4-mercapto-1-methyl-6-oxo pyridazine used as starting material can be prepared as follows.

17.9 g of 3,4-dichloro-1,6-dihydro-1-methyl-6-oxo-pyridazine solution dissolved in 200 ml of methanol is treated with a solution of 14.8 g of sodium hydrosulfide monohydrate dissolved in 200 ml of methanol. . The mixture was then stirred for 1.5 hours at 25 ° C. in a nitrogen stream. The undissolved material is filtered off and the filtrate is concentrated in vacuo. The residue is suspended in 150 ml of water, acidified with 1N hydrochloric acid and extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed with water, dehydrated with sodium sulfate and evaporated in vacuo. The resulting residue is recrystallized from ethanol.

Yield: 9 g (yellow tack)

Melting Point: 163 ℃

The 3,4-dichloro-1,6-dihydro-1-methyl-6-oxo-pyridazine used in the above method is prepared as follows.

67.75 g of 3,4-dichloro-6-hydroxy-pyridazine is dissolved in 205 ml of 2N-sodium hydroxide solution and treated with dropwise addition of 36 ml of dimethylsulfate. The mixture is heated at 70 ° C. for 0.5 h, then cooled and extracted twice with chloroform. The combined chloroform extracts are washed with water and evaporated on dehydration vacuum over sodium sulfate. The residue is recrystallized from petroleum ether with high boiling point.

Yield: 54 g (73%)

Melting Point: 97 ℃

Example 42

(7R) -3-[[(1,2-dihydro-1,6-dimethyl-2-oxo-4-pyridyl) -thio] methyl] -7- [2- (2-chienyl) acet Amido] Production of Sodium Salt of 3-Cefem-4-carboxylic Acid

This salt is prepared from 7.55 g of cephalotin sodium salt and 2.95 g of 1,2-dihydro-1,6-dimethyl-4-mercapto-2-oxo-pyridine according to the method of Example 1.

Yield: 3.0 g (31%)

Melting Point: -185 ℃ (Decomposition)

〕

=46.2 °(C=0.353, 수용액중에서)[

]

= 46.2 ° (C = 0.353 in aqueous solution)

Example 43

(7R) -3-[[(4-ethyl-1,4,5,6-tetrahydro-5,6-dioxo-as-traria-3-yl) -thio] methyl] -7- (2 -Phenylacetamido] Preparation of Sodium Salt of 3-Cefem-4-carboxylic Acid

This salt was prepared according to the method of Example 1 with 8.24 g of cephaloram sodium salt and 3.63 g of 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as Manufactured from triazine.

Yield: g (21%)

Melting Point: -200 ° C (Decomposition)

〕

=19.8°(C=0.339, 수용액중에서)[

]

= 19.8 ° (C = 0.339, in aqueous solution)

Example 44

(7R) -7-[(RS) -2-sulfo-2-phenylacetamido] -3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo- Preparation of Sodium Salt of As-triazin-3-yl) -thio] methyl] -3-cepem-4-carboxylic acid

9.07 g of (7R) -7-[(RS) -2-bromo-2-phenylacetamido] -3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6 -Dioxo-as-triazin-3-yl) -thio] methyl] -3-cepem-4-carboxylic acid sodium salt is dissolved in 100 ml of water and treated with 2.8 g of sodium sulfite. The solution is stirred at 25 ° C. for 4.5 hours and then acidified to pH 2 with 2N hydrochloric acid. Filter and discard the sediment. Subsequently, the filtrate is extracted several times with 100 ml of ethyl acetate. Discard ethyl acetate extract. The aqueous layer containing the desired product is concentrated to about 30 ml in a vacuum at 40 ° C. and chromatographed on a column of 400 g of Amberide XAD-2 (particle size 300-1,000 μ).

Yield: 1.0 g (10.6%)

Melting Point: 230 ℃ (Decomposition)

〕

=5.0°(C=0.1, 수용액중에서)[

]

= 5.0 ° (C = 0.1 in aqueous solution)

(7R) -7-[(RS) -2-bromo-2-phenylacetamido] -3-[[1,4,5,6-tetrahydro-4-ethyl-5 used as starting material , 6-dioxo-as-triazin-3-yl) -thio] methyl] -3-cef-4-carboxylic acid sodium salt was prepared according to the method of Example 21 according to the method of 7-amino-3-deacetoxy-3- [(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] -cephalosporanic acid and 14.0 g of DL-α- Prepared from bromophenylacetinic acid chloride.

Yield: 10 g (28%)

Melting Point: 190 ℃ (Decomposition)

Example 45

(7R) -3-[[(1-ethyl-1,2-dihydro-2-oxo-3-pyrazinyl) -thio] methyl] -7- [2- (2-chienyl) -acetami Manufacture of Sodium Salt of 3-Cefem-4-carboxylic Acid

This salt is prepared from 6.27 g of cephalotin sodium salt and 2.50 g of 1-ethyl-1,2-dihydro-3-merlo-2-oxo-pyrazine in a similar manner to Example 1.

Yield: 5.0 g (65%)

Melting Point: 175 ℃ (Decomposition)

〕

=+12.2°(C=0.5, 수용액중에서)[

]

= + 12.2 ° (C = 0.5, in aqueous solution)

1-ethyl-1,2-dihydro-3-mercapto-2-oxo-pyrazine used as starting material was prepared as follows.

23.7 g of 1-ethyl-3-chloro-1,2-dihydro-2-oxo-pyrazine was added to 22.2 g of sodium hydrosulfide monohydrate solution dissolved in 1,000 ml of methanol, and the mixture was stirred at 25 ° C. for 3 hours. do. Precipitated sodium chloride is filtered off and the yellow filtrate is evaporated in vacuo at 40 ° C. The residue is recrystallized from ethanol.

Yield: 8.0 g (34%, crude yellow color)

For purification, 5.0 g of the crude product obtained above are suspended in 50 ml of 0.5 N hydrochloric acid and 10 ml of 2 N hydrochloric acid is added to make it strongly acidic. The mixture is stirred at 25 ° C. for 10 minutes and then stored overnight in the refrigerator. The resulting orange crystals (3.65 g) are filtered off in vacuo and washed with a small amount of ice water and dehydrated in vacuo at 50 ° C.

Melting Point: 204-206 ° C (Decomposition)

Example 46

(7R) -3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-trijin-3-yl) -thio] methyl] -7- [2 Preparation of the sodium salt of-(2-chienyl) -acetamido] -3-cef-4-carboxylic acid

(Variation of Example 1 Method)

4.0 g of (7R) -3-azidomethyl-7- [2- (2-chienyl) -acetamido] -3-cefe-4-carboxylic acid sodium salt

Melting Point: 170 ℃ (Decomposition)

〕

=+134.4°, (C=0.5, 수용액중에서)을 pH7.0인 완충액 100ml에 넣고 질소기류하, 50-55℃에서 2.07g의 1,4,5,6-테트라하이드로-4-에틸-5,6-디옥소-3-멀캅토-아스-트리아진 및 1.01g의 중탄산나트륨과 함께 24시간 교반한다. 혼합물을 25℃로 냉각하고 2N-염산으로 pH2로 맞춘다.[

]

= + 134.4 ° C. (C = 0.5, in aqueous solution) was added to 100 ml of buffer at pH 7.0 and 2.07 g of 1,4,5,6-tetrahydro-4-ethyl-5 at 50-55 ° C. under nitrogen stream. Stir for 24 h with, 6-dioxo-3-mercapto-as-triazine and 1.01 g sodium bicarbonate. The mixture is cooled to 25 ° C. and adjusted to pH 2 with 2N hydrochloric acid.

The precipitated crude acid is filtered off with suction, washed with water and stirred in 100 ml of ethyl acetate for 10 minutes. Pure acid was suction filtered (1.3 g), suspended in 25 ml of methanol and treated with 2.5 ml of a solution of 2N 2-ethyl-capurophosphate sodium salt dissolved in ethyl acetate to obtain a solution. Dilute with 100 ml of ethyl acetate to drop the desired sodium salt into the precipitate.

Yield: 1.25 g (24%)

Same as the properties of the product prepared in Example 1.

Example 47

(7R) -3-[[(1-amino-1, 2-dihydro-2-oxo-4-pyrimidinyl) -thio] -methyl] -7- [2- (1-tetrazolyl) -acet Amido] Production of Sodium Salt of 3-Cefem-4-carboxylic Acid

This salt was prepared in a similar manner to Example 20 by 6.4 g of (1-tetrazolyl) -acetinic acid and 17.75 g of 7-amino-3-deacetoxy-3-[(1-amino-1,2-di Hydro-2-oxopyrimidin-4-yl) -thio] -cephalosporanic acid.

Yield: 8.0 g (33%)

Melting Point: 190 ℃ (Decomposition)

The following relates to the preparation of a formulation comprising the compound of formula (I) prepared according to the method of the present invention as an active ingredient.

[Example 1]

Preparation of anhydrous ampoules for intramuscular administration

1 g of (7R) -3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7- A lyophilisate of [2- (1-H-tetrazol-1-yl) -acetamido] -3-cepem-4-carboxylic acid is prepared by conventional methods and filled in ampoules. Prior to use it is treated with 2.5 ml of 2% lidocaine hydrochloride solution.

[Example 2]

Preparation of anhydrous ampoules for intramuscular administration

1 g of (7R) -3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] methyl] -7- A lyophilized product of [2- (5-oxo-1,2,3-oxodiazolidin-3-yl) -acetamido] -3-cefe-4-carboxylic acid was prepared as in Preparation Example 1 and filled in an ampoule. Let's do it.

The present invention as described above is summarized as follows.

1) The preparation method of the present invention reacts a compound of general formula (II) with a compound of general formula (III) or reacts a compound of general formula (IV) with an acid of general structure (V) or a reactive derivative thereof Isolation and, if desired, the conversion of the product to a salt to prepare acyl derivatives of general formula (I).

X-S-Y (I)

X'-W '(II)

H-S-Y (III)

X "-S-Y (IV)

Z-OH (V)

X is deacetoxy-cephalosporinyl group

Y is an optionally substituted six-membered heterocyclic group containing 1,2 or 3 nitrogen atoms but not aromatic and not enolated with an aromatic group (Cabo recognized by at least one of the nitrogen atoms described above and substituted by at least one nitrogen atom) To form an amide group with the niyl group)

X 'is a deacetoxy-cephalosporinyl group corresponding to X in the structural formula (I) but in which a carboxyl group in 4-position exists in a protected form,

W ₁ is a glass atom or a free radical

X "is a deacetoxy-cephalosporinyl group corresponding to X in the formula (I) but in which the carboxyl group at the 4 position exists in a protected form.

Z is an acyl group considered as a substituent on the amino group at position 7 of cephalosporin

2) X ', the following formula (X _1' using the starting material of formula (II), such as a), or

A process for preparing an acyl derivative of general formula (I) by reacting a compound of formula (IV), wherein X ″ is the following formula (X ₁ ″), with an acid of formula (V) wherein Z is a general formula (Z ₁ ).

R is the protected carboxyl group

R ₁ represents a hydrogen atom or a methoxy group

R ₂ is cyano or pyridyl group, or aliphatic, alicyclic, aromatic, heterocyclic group

R ₃ is a hydrogen atom or a hydroxy, hydroxymethyl, amino, azido, carboxy or sulfo group (other groups other than cyano in R ₂ are optionally substituted with hydroxy, halogen, lower alkyl or lower alkoxy and R ₂ R3 is hydrogen atom when is pyridylthio group.

3) X 'or Z is a manufacturing method using a starting material of the formula (II) or (V) having a structural formula of X ₁ ' or Z ₁ , respectively, wherein R ₂ is 2-chienyl, 2-furyl, 1 -Tetrazolyl, 1-triazolyl, 1-pyrazolyl, 3-sidnonyl, phenyl, cyclohexyl, 4-pyridylthio or cyano group and R ₂ is 1-tetrazolyl, 1-triazolyl, 1-pyrazolyl R ₃ is a hydrogen atom when the 3-sidonyl or -pyridyl group is used.

4) a non-aromatic, N-substituted pyridonyl group optionally substituted on one or more carbon atoms, or a non-aromatic pyrimidonyl, pyrazonyl, pyridazonyl or triazonyl having a substituent on one or more carbon atoms Production process using the starting material of the structural formula (III) or (IV).

5) Non-aromatic, N-substituted 2-oxopyridin-4-yl groups, or non-aromatic 2-oxopyrimidin-4-yl, 4-oxopyrimi, wherein Y optionally has substituents on one or more carbon atoms Din-2-yl, 2,6-dioxopyrimidin-4-yl, 2-oxopyrazin-3-yl, 2,3,5-trioxopyrazin-6-yl, 3-oxopyridazine-6- 1, 3-oxopyridazin-4-yl, 5,6-dioxo-as-triazin-3-yl, 2-oxotriazin-4-yl, or 2,4-dioxotriazine-6- A process using the starting materials of formula (III) or (IV), which is a diary (having a substituent on at least one nitrogen atom and optionally a substituent on one or more carbon atoms). Wherein the substituent on the cyclic nitrogen atom is lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, hydroxy, lower alkoxy, amino, mono (lower alkyl) amino, di (lower alkyl) amino, formyl, lower alkanoyl , Lower alkanoylamino, carbamoyl, mono (lower alkyl) aminocarbonyl or di (lower alkyl) aminocarbonyl group, and the substituent on the cyclic carbon atom is lower alkyl, lower alkoxy, amino, mono (lower alkyl) amino, di (Lower alkyl) amino, lower alkanoylamino, carboxy, lower alkoxycarbonyl, carbamoyl, mono (lower alkyl) aminocarbonyl, di (lower alkyl) aminocarbonyl, cyano or halogen and are cyclic nitrogen or cyclic carbon atoms Lower alkyl groups bound to hydroxy, lower alkoxy, amino, mono (lower alkyl) amino, di (lower alkyl) amino, formyl, lower alkanoyl, lower alkanoylamino, carboxy, lower alkoxycarbonyl, carbamo , Mono (lower alkyl) aminocarbonyl, di (lower alkyl) aminocarbonyl, cyano, a halogen or an epoxy group.

6) cephalotin, 7-α-methoxy-cephalotin, cephacetyl, (7R) -mandelamido-cephalosporanic acid, cephalolysine or 7- (3-sidnonacetamido) -Using the structural formula (II) starting material of one of the cephalosporanic acid.

7) 4-ethyl-, 4-methyl-, 4-allyl-, 4- (2-methoxyethyl)-, 1,4-dimethyl-, or 1,4-diethyl as starting material of formula (III) Process for using -1,4,5,6-tetrahydro-5,6-dioxo-3-mercapto-as-triazine.

8) A process for using 1,2,5,6-tetrahydro-1-ethyl-5,6-dioxo-3-mercapto-as-triazine as starting material of formula (III).

9) A process using 1-amino, 1-ethyl- or 1-butoxy-1,2-dihydro-4-mercapto-2-oxopyrimidine as starting material of formula (III).

10) A process for using 1-butoxy-1,2-dihydro-4-mercapto-5-methyl-2-oxopyrimidine as starting material of formula (III).

11) A process for using 1,4-dimethyl-1,6-dihydro-2-mercapto-6-oxopyrimidine as starting material of formula (III).

12) A process for using 1-ethyl-1,4-dihydro-2-mercapto-6-methyl-4-oxopyrimidine as starting material of formula (III).

13) 7-amino-3-deacetoxy-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazine as starting material of formula (IV) -3-yl) -thio]. A process for using a compound derived from cephalosporanic acid.

14) 7-amino-3-deacetoxy-3-[(1-amino-1,2-dihydro-2-oxopyrimidin-4-yl) -thio] as starting material of formula (IV) A process for using a compound derived from palosporanic acid.

15) Tetrazol-1-acetinic acid, α-hydroxycapurophosphoric acid, α-hydroxyisocapurophosphoric acid, cyclohexyl-α-hydroxyacetinic acid, cydnonyl- as starting materials of formula (V) A manufacturing method using 3-acetinic acid or furyl-2-acetinic acid or their reactive groups.

16) Preparation of Reaction of Compound of Formula (II) Derived from Cephalotin with 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine Way.

17) Preparation of Reaction of Compound of Formula II Derived from Cephalotin with 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-3-mercapto-as-triazine Way.

18) Reaction of Compound of Formula II Derived from Cephalotin with 1,4,5,6-tetrahydro-4-allyl-5,6-dioxo-3-mercapto-as-triazine Way.

19) Preparation of Reaction of Compound of Formula II Derived from Cephalotin with 1,4,5,6-tetrahydro-4-butyl-5,6-dioxo-3-mercapto-as-triazine Way.

20) A compound of formula (II) derived from cephalotin is prepared as 1,4,5,6-tetrahydro-4- (2-methoxy-ethyl) -5,6-dioxo-3-mercapto- Prepared by reacting with astriazine.

21) Reaction of the compound of formula (II) derived from cephalotin with 1,4,5,6-tetrahydro-1,4-dimethyl-5,6-dioxo-3-mercapto-as-triazine Manufacturing method.

22) A compound of formula II derived from cephalotin is combined with 1,4,5,6-tetrahydro-1,4-diethyl-5,6-dioxo-3-mercapto-as-triazine. Method of making by reacting.

23) Prepared by reacting a compound of formula II derived from cephalotin with 1,4,5,6-tetrahydro-1-ethyl-5,6-dioxo-3-mercapto-as-triazine How to.

24) 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-3-mercapto- is a compound of formula (II) derived from 7-α-methoxy-cephalotin. Prepared by reacting with astriazine.

25) A process for preparing a compound of formula II derived from cephalotin by reacting with 1-ethyl-1,2-dihydro-4-mercapto-2-oxo-pyrimidine.

26) A process for preparing a compound of formula II derived from cephalotin by reacting with 1-butoxy-1,2-dihydro-4-mercapto-2-oxo-pyrimidine.

27) A process prepared by reacting a compound of formula II derived from cephalotin with 1-butoxy-1,2-dihydro-4-mercapto-5-methyl-2-oxo-pyrimidine.

28) A process for preparing a compound of formula II derived from cephalotin with 1,4-dimethyl-1,6-dihydro-2-mercapto-6-oxo-pyrimidine.

29) A process for preparing a compound of formula II derived from cephalotin by reacting with 1-ethyl-1,4-dihydro-2-mercapto-6-methyl-4-oxo-pyrimidine.

30) A process for preparing a compound of formula (II) derived from cephalotin by reacting with 1-amino-1,2-dihydro-4-mercapto-2-oxo-pyrimidine.

31) Prepared by reacting a compound of formula II derived from cephacetyl with 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine How to.

32) (7R) 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mer containing a compound of formula (II) derived from mandelamido-cephalosporanic acid Prepared by reacting with capto-as-triazine.

33) Prepared by reacting a compound of formula II derived from cephalo glycine with 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine How to.

34) A compound of the formula (II) derived from 7- (3-sidnonacetamido) -cephalosporanic acid was prepared as 1,4,5,6-tetrahydro-4-5,6-dioxo- Prepared by reacting with 3-mercapto-as-triazine.

35) A compound of formula (II) derived from 7- (3-sidone acetamido) -cephalosporanic acid was prepared as 1-ethyl-1,2-dihydro-4-mercapto-2-oxo- Prepared by reacting with pyrimidine.

36) 7-amino-3-deacetoxy-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] A process for preparing a compound of formula IV derived from cephalosporanic acid with tetrazol-1-acetinic acid or a reactive derivative thereof.

37) 7-amino-3-deacetoxy-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] A process for preparing a compound of formula (IV) derived from cephalosporanic acid with α-hydroxycapuroin acid or a reactive derivative thereof.

38) 7-amino-3-deacetoxy-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] -A method for preparing a compound of formula (IV) derived from cephalosporanic acid by reacting with α-hydroxyisocapuroin acid or a reactive derivative thereof.

39) 7-amino-3-deacetoxy-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] -A method for producing a compound of formula IV derived from cephalosporanic acid by reacting with cyclohexyl-α-hydroxyacetinic acid or a reactive derivative thereof.

40) 7-amino-3-deacetoxy-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] A process for preparing a compound of formula (IV) derived from cephalosporanic acid with hurryl-2-acetinic acid or a reactive derivative thereof.

41) Derived from 7-amino-3-deacetoxy-3-[(1-amino-1,2-dihydro-2-oxo-pyrimidin-4-yl) -thio] -cephalosporanic acid Prepared by reacting a compound of formula (IV) with cydnonyl-3-acetinic acid or a reactive derivative thereof.

42) Derived from 7-amino-3-deacetoxy-3-[(1-amino-1,2-dihydro-2-oxopyrimidin-4-yl) -thio] -cephalosporinic acid Prepared by reacting the compound of formula IV with tetrazolyl-3-acetinic acid.

Claims (1)

Reacting a compound of general formula (II) with a compound of general formula (III) or reacting a compound of general formula (IV) with an acid of general formula (V) or a reactive derivative thereof and separating the protecting group A method for producing acyl derivatives and salts thereof. X-S-Y (I) X'-W ₁ (II) H-S-Y (III) X "-S-Y (IV) Z-OH (V) X is deacetoxy-cephalosporinyl group Y is an optionally substituted hexagonal heterocyclic group containing 1,2 or 3 nitrogen atoms but not aromatic and not enolated with an aromatic group (at least one of which is substituted with at least one nitrogen atom and adjacent carbon atoms) To form an amide group with the niyl group) X 'is a deacetoxy-cephalosporinyl group corresponding to X in the structural formula (I) but in which the carboxyl group at the 4 position exists in a protected form. W ₁ is a glass atom or a free radical X "is a deacetoxy-cephalosporinyl group corresponding to X in the formula (I) but in which the carboxyl group at the 4 position exists in a protected form. Z is an acyl group considered as a substituent of the amino group at the 7-position of cephalosporin.