[Title of the invention]

Cephalosporin antibiotic derivatives of manufacturing method

[Detailed description of the invention]

The present invention refers to represented by formula (I) or salts thereof of novel cephalosporin antibiotic derivatives relates to manufacturing method.

Wherein, R₁in mote Neel or the phenyl or 2-

Phenoxy,

R₂ hydrogen, lower alkyl , phenyl, substituted lower alkyl or substituted phenyl,

R₃ hydrogen, lower alkyl, or substituted lower alkyl,

Or indicative of binding a single A that is branched off [...] the builder is excellent in compatibility alkynyl or 1015 per square meter.

Compounds obtained by the present invention this type commercial (regular use) compared to antibiotic cephalosporin or progress of a condition characterised by being shows similar antimicrobial effects to antibiotics including,

A wide range of medical antibiotic excellent material has a utility value.

The present inventor are cephalosporin antibiotic chemical structure and the speculate on the correlation of antimicrobial activity, antibacterial is superior [...] having low toxicity in vivo and in vitro to produce on the aim production with conspicuously supports, publicly known or new 7-3 on acetoxy methyl Aminoacylamide [...][...] during uses of the formula (III) having heterocyclic thio in Neel chemical compoundcop clay pot and mercaptoacetyl substituted chemical substituted [...] a new structure have been synthesised subscriber selects a various forms of.

Example a mount bracket, on chemical represented by general formula (I) a new structure [...] on stepping on the gram-positive and negative bacilli being antibacterial spectrum overelaborates proteinases in particular. Vulgaris bacteria (Salmonella typhi) Salmonella or (Proteus Vulgaris) of the existing method, such as gram-negative use of a very small number of effective [...] even for fungi exhibits antimicrobial potent, stable and in addition also extremely low toxicity the present invention find a that complete in and out by a spring.

By the formula (I) obtained in the present invention a of the existing method publicly known [...][...] of the same salt, e.g. acid alkaline salts preferably it is assumed that the written form, formulations produce the same safety effect as conventional method ([...]) or administration by a wide range of gram-negative and positive bacteria, is effective in the use of for treating diseases by, of motor driving period is vulgaris on disease attributable to Salmonella serves treatment, not hitherto realized in particular an efficacious which are characterized by.

The present purpose of the invention compound (I) is then synthesized by synthesizing describing.

First, the method of the present invention first on class number 1 7 7-aminocephalosporanic acid deacetylase phenyl amino group, such as 2-acylated in mote Neellung stipendiary hour acetylation and or deacetylase publicly known compounds that are obtained by compounds of the general formula (II), e.g. 7-phenyl acetamido cephalosporanic or 7-(2- in mote Neel Oh set Oh America) the sample it buys in the salt carboxylic or their [...] (III) compounds represented by general after that, the sample it buys the salt carboxylic of these compounds or a corresponding mercaptoacetyl [...] method is reacting.

In formula R² hydrogen, e.g. lower alkyl,

1-4 alkyl carbon atoms, phenyl, substituted a lower alkyl-or a substituted phenyl,

R³ hydrogen, a lower alkyl-or a substituted lower alkyl A a single coupled or is a linear or branched, alkyl curing accelerator, inorganic filler, modifier or [...].

Written in the reactor the general formula (III) a the mote the chemical compound which comes specifically enumerate positive examples. off at the first and the second.

2-mercapto -1, 3, 4-triazole-5-carboxylic acid,

2-(2-mercapto -1, 3, 4-triazole-5-one)-alkanoic carboxylic acid,

In particular 2-(2-mercapto -1, 3, 4-triazole-5-one)-acetic acid,

3-(2-mercapto -1, 3, 4-triazole-5-one)-propionic acid,

2-(2-mercapto -1, 3, 4-triazole-5-one)-propionic acid,

1-alkyl-2-mercapto -1, 3, 4-triazole-5-carboxylic acid,

2-(1-alkyl-2-mercapto -1, 3, 4-triazole-5-one)-acetic acid,

3-(1-alkyl-2-mercapto -1, 3, 4-triazole-5-one)-propionic acid,

2-(1-alkyl-2-mercapto -1, 3, 4-triazole-5-one)-propionic acid,

3-(1-alkyl-2-mercapto -1, 3, 4-triazole-5-one)-acetic acid,

4-(1-alkyl-2-mercapto -1, 3, 4-triazole-5-one)- balletansan (Valerianic Acid),

1-phenyl (or substituted phenyl)-2-mercapto -1, 3, 4-triazole-5-carboxylic acid,

3-(2-mercapto -1, 3, 4-triazole-2-one)-acrylic acid,

3-(2-mercapto-1-alkyl -1, 3, 4-triazole-2-one)-acrylic acid,

3-[ 1-phenyl (or substituted phenyl)-2-mercapto -1, 3, 4-triazole-2-one]-acrylic acid,

2-[ 1-phenyl (or substituted phenyl)-2-mercapto -1, 3, 4-triazole-5-one]-acetic acid,

3-[ 1-phenyl (or substituted phenyl)-2-mercapto -1, 3, 4-triazole-5-one]-propionic acid,

2-[ 1-phenyl (or substituted phenyl)-2-mercapto -1, 3, 4-triazole-5-one]-propionic acid,

3-[ 1-phenyl (or substituted phenyl)-2-mercapto -1, 3, 4-triazole-5-one]- butyric acid (butyric acid),

4-[ 1-phenyl (or substituted phenyl)-2-mercapto -1, 3, 4-triazole-5-one]- balletansan. notifies a user or the like.

Competent or more glass carboxylic acid and general formula R³ OH (stage R³ has electricity as well as not hydrogen but same) alcohols represented by that are obtained by condensing the corresponding carboxylic acid ester having a side, generally original glass carboxylic acid equal as serves to the reactor, as one example of ester like this type , carboxylic acid represented by general formula (III) of lower alkyl ester, dialkylaminoalkyl ester, of benzil ester, of benzil ester substituted, alkoxy alkyl esters, etc..

Also, of general formula (III) SH groups the mote the chemical compound which comes base, e.g., alkali or alkaline earth hydroxide by reacting at and a corresponding mercaptoacetyl [...]. written uniformly.

Taught or more general formula (II) of a compound and a general formula (III) of the mote the chemical compound which comes reaction in solutions which the sanitary embodiment, generally pH 6-9 solvent in the embodiment to function desirably.

In particular preferably pH 6.5-8.0 function to aqueous solution to a temperature of 50 °C -70 ° C in acetone or function is solvent during such as lower alcohols is embodiment.

Of reagents to the reaction of solvent which other displayed fully dissolving the pH, a way that it does not react directly reagents also if solvent, use can be made of, any solvents.

Reagent in which reactions the reactor by the formula (II) compounds of general formula (III) compounds and (by compound carboxylic acid whether processes the musical piece data memorized) portion lines do not form solvent dissolving the at most salt by reacting is usually are of much.

A salt with the most to portion and (e.g. carboxylic the sample it buys the alkali salt) form, pre [...] general formula (II) and (III) salts of compound (carboxylate), effective operation and of preparing which the barrier arrangement is dispersed in solvent which may be, first into a state, in which the carboxylic acid or glass suspended in to the mixture of the dried metal precursor, wherein yet for adjusting the pH in order to form a salt of organic or inorganic suitable desired pH by adding a base of pH region may be a warming reaction..

Is treated with a water-entangling base used for variety of metal hydroxide or alkali carbonate, middle carbonic acid alkali , variety of organic amine type moveble is generally.

In doing so reaction part object by conventional publicly known method for treating (I) are separated, .been harvested is.

General formula (III) in the reactor is the mote the chemical compound which comes of claim includes when carries a type carboxylic acid ester having a, are in the active or inactive is pravastatin when derivative thereof, e.g. carboxylic acid represented by general formula (III) various organic or inorganic acids, mixing these compounds with an anhydride, active amides, it buys, the id , anhydride, active [...] when, the reaction pH relatively by extending the reaction time or a reception unit in the apparatus demodulates the course subjected to hydrolysable in reaction mixture.

As a result R³the half which it will know is hydrogen, the of the compound is (I) are obtained.

The reactor in which reactions of reagents paste is cured and used to speed up or to and react accordingly [...] ozone for, such the general formula (III) compounds and the derivatives in pravastatin..

Wherein the (I) object obtained [...] for example glass, mono [...] , mono alkali metal salt, alkaline earth metal salt, various other organic amines in the form such salt with discrete necessary, purification, acquires directory.

Glass [...] or mono carboxylic the sample it buys the salt is not required if the de-ghosted composite (I) object in the form same conditions generally common in base by reacting salt the phone can be (transformation).

Yet, in general formula (I) second method of the present invention thereby, a desired compound in order to produce the general formula (IV) 7-amino-cephalosporanic acid of general formula (III) salts or discretely represented by thiol of these compounds carboxylic the sample it buys the salt[...] mercaptoacetyl stores contents of the information document over the compound reacting on the compounds represented by general formula (V) are obtained,

(Wherein R², R³, A generates and transmits a generic type (I) as equal to)

Obtained wherein then represented by the general formula (V) carboxylic acid compound the sample it buys the salt carboxylic of these compounds, or carboxyl ester, anhydride or mixed anhydride as closing a form to derivatives of formula (VI) i.e., R¹-CH₃ COOH (wherein, R¹ exhibits atom or a phenoxy in mote Neel is phenyl or 2-) of carboxylic acid represented by reactive in pravastatin by zero for acylating poly-generated applied to the end.

(V) compounds of general formula on carboxyl organosilylpolyphos phoric ester or phosphorous (or ester of chlorides or discretely) configured as anhydride mixed which is closed when the number 1 of a general formula (V) of 7 Unexampled class amino attempt corresponding silazanes (Silazane) or oh phosphoric acid amide style closed. when subjected to or activated.

Hence the such a case 7 even number 1 on desired class amino object is to permit a reliable and exact reaction is acylated are obtained is (I).

Water is recycled, hydrous solvent, generally free of water with medium by reacting organic solvent depending on the nature of reagents is connected to protect user's private life. by finding the.

The present which is used in acylated number i.e., R¹ CH₂ COOH in general formula (IV) carboxylic acid of pravastatin as entangling reactive derivative in a listed below.

I.e., (halides) it buys, the id of carboxylic acid, anhydride, anhydride, mixing these compounds with an organic and inorganic acids, having an electron-substituent e.g., nitro and in the molecule or the like halogen with it is long an alcohol or phenolic a thiophosphorus phenol esters is so-called active esters, active amides e.g. di cyclohexyl carbodiimide such as additional carboxylic acid of the carbodiimide compound, carboxylic sample childbirth etc. called carboxylic acid also the shoe will do, the id type as to the aromatic hydrocarbon (pseudo halides).

The resulting structured materials, an acylated reaction is typically for acylating poly-tertiary amino group number 1 for erase, an erase abort when publicly known of reaction conditions preferably by acylated and is with each other, and performs diverse.

E.g., acid chloride used round the leucorrhea to -10 ° C temperature of the water as for example, function acetone, chloroform, dichloro methane such as with a suitable solvent in the presence of a suitable base gradually it buys the claw roller id degree of molar 1-3 acylated in applied is usually are of much the reaction.

In doing so generated piles (I) method for treating processed by the publicly known to separate, acquires directory. If necessary under standard conditions and by conventional C1-. may telephone slat thereof.

Or more method on which a layer of snow obtained by general formula of (I) or (V) in a fullerene derivative is denoted by chemical when indicative of binding a single A, deacidification reaction again these compounds represented by general formula (I ') or (V') to compounds which make a positive indicated as can be inducing.

(Wherein R¹ and R² generates and transmits a generic type (I) and (V) and a equal).

I.e., the present inventor month derivative is represented by the following general formula (I) and (V) during a single A indicative of binding a transition time is at least twice the and is extremely same response against acid decarburisation under conditions (I ') and over a general formula of (V') high yield a fullerene derivative is denoted by chemical generates process to another integral part comprising a side reactions not subject to reduce such variations as in the we have found.

In general formula (I) and (V) compounds of general formula (I ') and (V') a phosphorescence compound is a compound represented by pH=6 hereinafter solvent in the reaction is typically, room temperature is performed on easily ∼ 100 °C hereinafter.

Obtained wherein the compounds of the general formula (I')gram-positive and gram-negative of bacteria for a potent antibacterial action, a plate antibacterial number as is with utility value. Yet general formula (V ') as the acylation of the latter and publicly known the compounds represented by general method i.e., in general formula (V) compounds of general formula (I) can solve lower with reaction acylated to give compounds of general formula (I') the multiplexer provides a path for represented by the general compounds of general formula (I')used either as catalyst manufacturing intermediate has a value.

In addition the present invention in which is used as a starting material represented by general formula (III) the mote the chemical compound which comes e.g. formula (VIII) compounds represented by general heating in the presence of a caustic alkali or carbonate dehydroring-closing ([...]) may be by high yield in the.

(Wherein R², R³, A has over the as a general formula of)

Hereinafter embodiment the present invention describes the requirements and/or at least two.

[In the embodiment 1]

7-(2-thienyl acetamido) [...] 836 milligram and 2-(2-mercapto -1, 3, 4-triazole-5-one) acetic acid 460 milligram molar to 5 milliliter possible with conventional, such as sodium bicarbonate aqueous solution -0.5N herein further applied 12 milliliter is dissolved in 62 °C -65 ° C same 5.5 time warming section.

round the leucorrhea by the application of 10 milliliter moving alram after reaction, 8 milliliter-hydrochloride 1N, under stirring gradually applied to filter out determined white one deposited on the counter electrode was washed.

Washing and then directly ether is sufficiently cleaning and the powder of the glass as a powdery white in the form of n-NHC 7-(2- in mote Neel Oh set amido)-3-(5-carboxymethyl -1, 3, 4-triazole-2-aminocapronitrile one) thiomethyl-3-cephem-4-carboxylic acid 810 milligram (82%)this method enables an accurate.

NMR spectrum (D₂ O-NaHCO₃-DSS) δ (PPM):

3.65 (1 for heavy, 2H, -CH₂-COONa), 3.82 (1 for heavy, 2H, -CH₂-CONH), 5.0 (2 for heavy, 1H, H on 6, J=5HZ), 5.50 (2 for heavy, 1H, H on 7, J=5HZ),

The product 3 milliliter with water 200 milligram sodium hypochlorite aqueous solution which is prepared by suspension to low level no 0.1N-hydroxide dissolved then with grudge pH 6,

Filtrate filtration drying under reduced pressure the guiding rail 210 milligram about [...] dinitrate, this method enables an accurate.

Di sodium an ultra-violet radiation absorbing spectrum as follows.

7-on (in mote Neel Oh set Oh America 2-)-3-(5-carboxymethyl -1, 3, 4-triazole-2-one) thiomethyl-3-cephem-4-carboxylic acid 500 milligram of acetic acid ethyl, methanol and acetone (about 1:1:5) in a solvent mixture of an aprotic are melted in 2-ethylhexanoic of potassium acetone solution (normal solution 1) one deposited on the counter electrode by the application of 2 milliliter [...] precipitation, acetone and washing d potassium salt thereon di carboxylic acid of this method enables an accurate 460 milligram.

NMR spectrum as useful internal standard (main) DSS i.e., 3-trimethylsilyl)-propanesulfonic acid sodium with the outer face of its methyl proton chemical shift (Shift) δ (PPM) based on signal to pick up the.

The antibacterial spectrum d potassium saltsample consultationthe next ticket can be mass-produced.

Stage, brackets in order to compare and number the user, 7-(2-thienyl acetamido) cephalosporanic sodium depth of layer containing a filler concentration microbistatic.

Again test treat infections in vivo of the compounds (in Vivo) in (maus, administration in Vivo) ED₅₀ value, and simultaneously with the testing (milligram/kg) ([...]) a garnish of a medicament ED₅₀ value comparison with were as follows. computer system transmits a first packet pair.

Subject bacteria (gastrointestinal pathogens)

A, Salmonella typhi W-901-10

B, Proteus Vulgaris C-73-9 ([...] intracellularly and extracellularly producing main)

C, Salmonella Enteritidis No.11

D, Staphylococcus aureus Smith S-424

^*d potassium salt

Furthermore, acute toxicity (in Vivo administration) for mouse, capable of producing a recognizing code, a recording time when compared with an medicament result is composed of 3.

[In the embodiment 2]

7-(2-thienyl acetamido) 836 milligram sodium cephalosporanic which 5 milliliter with water,

Herein 3-(2-mercapto -1, 3, 4-triazole-5-one) propionic acid 520 milligram on the then 0.5N-bicarbonate aqueous solution pH 7.0-6.95 12 milliliter is applied to a light with the dissolved. The solution into an nitrogen airflow among the warming to 60 °C -65 ° C time 6.

A round the leucorrhea by the application of 5 milliliter moving alram then, with stirring, in a 8.5 milliliter 1N-hydrochloride acidic by the application of white and is used to electro-deposit in that filtration determination, was washed.

Sequentially repeated ether immediately same which washes the pH in the second powder middle sodium carbonate solution -0.5N wherein the filtration of the slurry suspension on the 6.0-6.4 a, of decompressing the filtrate, dichloromethane, benzene, acetone, was removing water at room temperature.

Finally, with the drying kitchen oxide 5 was very dry vacuum night by. 7-(2-thienyl acetamido)-3-[ 5-(2-carboxylic ethyl)-1, 3, 4-triazole-2-one] thiomethyl-3-cephem-4-carboxylic acid of [...] dinitrate, are obtained as.

Is the quantity 55 milligram (50% yield).

NMR spectrum (D₂ O-DSS) δ (PPM): 2.81 about an A₂ B₂ for laterally symmetrical with (4H, ), 3.86 (singlet line, 2H, ), 5.02 (2 for heavy, 1H, H on 6, J=4.5Hz), 5.58 (2 for heavy 1H, H on 7, J=4.5Hz),

Ultraviolet absorption spectrum: , The antibacterial spectrum sample consultationthe next ticket can be mass-produced.

[In the embodiment 3]

7-(2- mote ethyl acetamido) [...] 836 milligram and 3-(2-mercapto-1-methyl -1, 3, 4-triazole-5-one) propionic acid takes an 560 milligram, in the embodiment 2 the same reaction conditions in reaction processing the same the embodiment,

7-(2-thienyl acetamido) 3-[ 5-(2-carboxylic luck thread ethyl)-1-methyl -1, 3, 4-triazole-2-one] thiomethyl-3-cephem-4-carboxylic acid of 660 [...] dinitrate, (58%)this method enables an accurate.

NMR spectrum (D₂ O-DSS) δ (PPM): 2.82 symmetrically axis as its center a A₂ B₂ for symmetrical type (4H, ), 3.87 (2H for heavy 2, ), 4.99 (2 for heavy, 1H, H on 6, J=5HZ), 5.53 (1H, H on 7, J=5HZ)

Ultraviolet absorption spectrum:

The following table and equal antibacterial spectrum.

[In the embodiment 4]

7-(2- in mote Neel Oh set Oh America) and 358 milligram [...] 3-(2-mercapto-1-phenyl -1, 3, 4-triazole-5-one) propionic acid 256 milligram bicarbonate -0.5N and a 5 milliliter with water applied to 4.12 milliliter of aqueous solution dissolved in 4.5 63 °C -65 ° C water bathin air current nitrogen was period of time without danger of decomposition.

Cooling after reaction, 5 milliliter moving alram with stirring, in a-hydrochloride 1N and a white one deposited on the counter electrode by the application of 3 milliliter filtration determination was washed. Cleaning is sufficiently ether that immediately is the powder was used to.

7-(2- mote ethyl acetamido)-3-[ 5-(2-carboxylic ethyl)-1-phenyl -1, 3, 4- mote Oh it will doze -2-one] thiomethyl-3-cephem-4-carboxylic acid 440 milligram this method enables an accurate. (87.5% yield). In the embodiment 2 same same [...] dinitrate, the signal processor processes the obtained.

[...] dinitrate, NMR (D₂ O-DSS) δ (PPM): 2.61 about a for a wide in a symmetrical (4H, ), 3.84 (1 for heavy, 2H, ), 4.92 (2 for heavy, 1H, H on 6, J=4.8HZ), 5.58 (2 for heavy, 1H, H on 7, J=4.8HZ)

Ultraviolet absorption spectrum

The following table and equal antibacterial spectrum.

[In the embodiment 5]

7-(2-thienyl acetamido) [...] 836 milligram and 2-(2-mercapto-1-methyl -1, 3, 4-triazole-5-one) acetic acid 520 milligram 12 milliliter middle sodium carbonate aqueous solution -0.5N and a 5 milliliter with water applied to the obtained by dissolving nitrogen airflow among water bath of 60 °C -65 ° C to 4.5 time warming section.

After reaction the same in the embodiment 2 dinitrate, Image-processing the signal processor processes the [...] i.e., 7-(2-thienyl acetamido)-3-(5-carboxymethyl-1-methyl -1, 3, 4-triazole-2-one) thiomethyl-3-cephem-4-carboxylic acid of [...] dinitrate, 714 milligram is obtained. (64.5% yield).

NMR spectrum (D₂ O-DSS) δ (PPM): 3.59 (1 for heavy, 3H, ), 3.78 (1 for heavy, 2H, ), 3.88 (1 for heavy, 2H, ), 5.02 (2 for heavy, 1H, H on 6, J=5HZ), 5.55 (2 for heavy, 1H, H on 7, J=5HZ),

Ultraviolet absorption spectrum

The following table and equal antibacterial spectrum.

[In the embodiment 6]

7-(2-thienyl acetamido) [...] 418 milligram and 2-mercapto -1, 3, 4-triazole-5-carboxylic acid 218 milligram possible with conventional water 20 milliliter, bicarbonate -0.5N pH 6.8 by applying an aqueous solution among airflow nitrogen then on while warming time 10 to 60 °C -63 ° C stirring section.

A 5 milliliter moving alram part round the leucorrheaafter inflicting,round the leucorrhea surfacing and the hydrochloric acid -1N one deposited on the counter electrode on pH 1.8 [...] determination, washed it with the ethyl acetic acid, acetone and methanol in a solvent mixture of an aprotic which, herein defined 2 milliliter acetone solution of potassium methyl hexanoic 2-1 gradually applied to filter out one deposited on the counter electrode white precipitation was then being washed with ethyl acetic acid.

7-(2-thienyl acetamido)-3-(5-carboxylic -1, 3, 4-triazole-2-one) thiomethyl-3-cephem-4-carboxylic acid of d potassium salt is composed of.

The quantity 440 milligram (85.75%)was.

NMR spectrum (D₂ O-DSS) δ (PPM): 5.01 (2 for heavy, 1H, H on 6, J=4.8HZ), 5.55 (2 for heavy, 1H, H on 7, J=4.8HZ), 3.84 (1 for heavy, 2H, ), Ultraviolet absorption spectrum

The following table and equal antibacterial spectrum.

[In the embodiment 7]

7-(2-thienyl acetamido) 2-mercapto-1-and 418 milligram sodium cephalosporanic methyl -1, 3, 4-triazole-5-carboxylic acid 312 milligram in the embodiment 2 of the signal processor processes the same 7-(2-thienyl acetamido)-3-(5-carboxylic-1-methyl -1, 3, 4-triazole-5-one) thiomethyl-3-cephem-4-carboxylic acid of this method enables an accurate [...] dinitrate, 520 milligram.

NMR spectrum (D₂ O-DSS) δ (PPM): 3.66 (1 for heavy, 3H, to coat the N-CH₃), 5.02 (2 for heavy, 1H, H on 6, J=4.8HZ), 5.58 (2 for heavy, 1H, H on 7, J=4.8HZ)

Ultraviolet absorption spectrum

The following table and equal antibacterial spectrum.

[In the embodiment 8]

7-(2-thienyl acetamido) 418 milligram and [...] 2-mercapto-1-phenyl -1, 3, 4-triazole-5-carboxylic acid in 265 milligram the signal processor processes the same in the embodiment 2 7-(2-thienyl acetamido)-3-(5-carboxylic-1-phenyl -1, 3, 4-triazole-5-one) thiomethyl-3-cephem-4-carboxylic acid of dinitrate, [...] is composed of.

NMR spectrum (D₂ O-DSS) δ (PPM): 4.76 (2 for heavy, 1H, H on 6, J=4.6HZ), 5.54 (2 for heavy, 1H, H on 7, J=4.6HZ), 3.80 (2H for heavy 1, )

Ultraviolet absorption spectrum

The following table and equal antibacterial spectrum.

[In the embodiment 9-13]

it is one example compounds of general formula (II) 7-(2-thienyl acetamido) cephalosporanic the next ticket as sodium displayed on the general formula (III) various a polythiol compound in the embodiment 2 and the same manner as the calculator each reacting the next ticket various displayed on the post thereby, a desired compound (I) is obtained.

[In the embodiment 14-17]

7-amino-cephalosporanic acid suspended in 50 milliliter 5.44g anhydrous chloroform, cooling (0 °C), with stirring, in a 10 milliliter triethylamine herein 4g anhydrous chloroform was a solution is dripped.

Same sufficiently is cooled to -5 ° C [...] herein with stirring, in a a 20 milliliter 3.75g anhydrous chloroform the solution is dripped.

In -5 ° C time 1, time 2 in 20 °C again putting 100 milliliter moving alram obtain a lead line having a sufficiently which agitates the, sap layer a pH 7.5 the chloroform of decompressing the treatment of 40 °C hereinafter which agitates the by the application of 100 milliliter ethyl acetic acid pH 1.8 a sap layer gradually.

Acetic acid ([...]) the washed ethyl layerseparating then 0.5N-such as sodium bicarbonate aqueous solution is sufficiently applied a light with the pH 6.2 which agitates the sap layer.

Sap layer ([...]) to a fraction is concentrated to was very dry.

7-aminocephalosporanic sodium (lung stipend city Oh set Oh America) this method enables an accurate 5.0g.

NMR spectrum (D₂ O-DSS) δ (PPM): 2.10 (1 for heavy, 3H, ); 3.17 and 3.58 (AB 4 for heavy, 2H, 2 on , JAB=17HZ); 4.60 (1 for heavy, 2H, ); 5.075 (2 for heavy, 1H, -H on 6, J=4.8HZ); 5.73 (2 for heavy, 1H, -H on 7, J=4.8HZ); 6.87-7.45 (for, 5H, proton benzene ring).

7-a vehicle involves (lung stipend city Oh set amide) cephalosporanic as sodium salt of a variety of represented by general formula (III) in the embodiment 2 and the same manner as the calculator the mote the chemical compound which comes each post reacting variety of displayed on the next ticket -pipe scaffolds and thereby, a desired compound (I) is obtained.

[In the embodiment 18-21]

7-amino-cephalosporanic acid and suspended in anhydrous chloroform 30 milliliter 2.72g, 0 °C of the laminated board is cooled with stirring, in a was applying 2.20g triethylamine herein.

Is cooled to -5 ° C same sufficiently with stirring, in a 10 milliliter 1.85g chloride phenylacetic acid herein anhydrous chloroform was a solution is dripped.

1-5 ° C in time, obtain a lead line having a time 2 at room temperature, moving alram 50 milliliter putting a pH sufficiently with stirring, in a sap layer dispersed with more 7.5, 40 °C hereinafter under of decompressing chloroform treatment of sap layer is applied to with stirring, in a 50 milliliter ethyl acetic acid pH 1.8 a gradually.

Acetic acid ([...]) ethyl layer then washed the fraction is concentrated to 0.5N-metal, such as sodium bicarbonate solution pH layer sap by both the 1.8 a gradually.

Sap was very dry lyophilized to fraction is concentrated to layer.

7-aminocephalosporanic sodium (phenyl acetamido) this method enables an accurate 3.76g.

NMR spectrum (D₂ O-DSS) δ (PPM); 2.10 (1 for heavy, 3H, ); 3.68 3.31 and (AB4 for heavy, 2H, 2 on , J_AB = 18HZ); 3.71 (1 for heavy, 2H, ); 5.10 (2 for heavy, 1H, -H on 6, J=4.7HZ); 5.65 (2 for heavy, 1H, -H on 7, J=4.7HZ); 7.42 (1 for heavy, 5H, benzene ring proton); 4.95 and 4.71 (2 for heavy, 2H, on 3-CH₂-, J=13HZ) purpose 7-(phenyl acetamido) cephalosporanic as sodium salt of general formula (III) in the embodiment 2 and a variety of represented by the same manner as the calculator the mote the chemical compound which comes each post reacting variety of displayed on the next ticket results thereby, a desired compound (I) is obtained.

[In the embodiment 22]

7-(2-thienyl acetamido)-3-(2-carboxylic-1-methyl -1, 3, 4-triazole-5-one) thiomethyl-3-cephem-4-carboxylic acid of a 4 milliliter aqueous solutions containing 539 milligram [...] dinitrate, round the leucorrhea , with stirring, in a 2 milliliter 1N-hydrochloride precipitate white one electrodeposition pitch can be fabricated in an amount being small but-water flushed by the filtering. Dissolved in the nonaqueous solvent 4 milliliter acetone immediately same-shaped the adsorption was filtering obtain a lead line having a to take ground is prevented from being too small.

Filtrate of decompressing under 30 °C hereinafter and removing the solvent by a is applied to ethanol residues middle sodium carbonate aqueous solution -0.5N pH=6 applied then controlled and which, when concentrated in 30 °C hereinafter 7-(2- in mote Neel Oh set Oh America)-3-(1-methyl -1, 3, 4-triazole-5-one) thiomethyl-3-cephem-4-carboxylic acid of natrium salts of applicants are compositions thereof.

Then sufficiently cooled was then being washed with ethanol by [...].

The quantity 403 milligram (85%)was. Again from the same been recovery wavefronts are of 20 milligram (89.5% the total).

NMR spectrum (D₂ O-DSS) δ (PPM); 3.70 (1 for heavy, 3H, to coat the N-CH₃); 3.88 (1 for heavy, 2H, -CH₂-CONH); 5.02 (2 for heavy, 1H, H on 6, J=5.0HZ); 5.56 (2 for heavy, 1H, H on 7, J=5.0HZ); 8.50 (1H for heavy 1, the annular pro ton which will doze triazine).

Antibacterial spectrum;

[...]. Corynebacterium Ml / (Escherichia cdi) 6.25 γ

Proteinases overelaborates. Ml / (Protens Vnlgaris) 50 γ vulgaris

Salmonella (Salmonella) 1.56 γ Ml/

star blood[...]. Ml / (Staphylococcns anrens) 0.78 γ ulmarius outer

Pseudomonas. Erucamide (Psendomonas Aernginosa) C-73-28 1.56γ labor and management Ml/

[...] , the neural Ml / (Kiebsiella pnaenmonia) C-73-20 0.98γ

[In the embodiment 23]

7-(2-thienyl acetamido)-3-(2-carboxylic -1, 3, 4-triazole-5-one) thiomethyl-3-cephem-4-carboxylic acid of the same in the embodiment 22 in 525 milligram [...] dinitrate, the signal processor processes the 7-(2-thienyl acetamido)-3-(1, 3, 4-triazole-5-one) thiomethyl 3-cephem-4-carboxylic acid of natrium salts of 412 milligram (yield 90%)is obtained.

NMR spectrum (D₂ O-DSS) δ (PPM); 3.81 (1 for heavy, 2H, ); 4.04 (a wide 1 for heavy, 2H, ); 4.96 (2 for heavy, 1H, H on 6, J=4.8HZ); 5.525 (2 for heavy, 1H, H on 7, J=4.8HZ); 8.22 (1 for heavy, 1H, the annular pro ton which will doze triazine).

Antibacterial spectrum;

[...]. Corynebacterium Ml / (Etcherichia Coli) 12.5 γ

Proteinases overelaborates. Ml / (Protens Vnlgaris) 25 γ vulgaris

Salmonella (Salmonella) 6.25 γ Ml/

star blood[...]. Ml / (Staphylococcus anreus) 0.20 γ ulmarius outer

[In the embodiment 24]

7-(2-thienyl acetamido)-3-(2-carboxylic-1-phenyl -1, 3, 4-triazole-5-one) thiomethyl-3-cephem-4-carboxylic acid of the same in the embodiment 22 in 602 milligram [...] dinitrate, the signal processor processes the 7-(2-thienyl acetamido)-3-(1-phenyl -1, 3, 4-triazole-5-one) thiomethyl-3-cephem-4-carboxylic acid of natrium salts of 505 milligram (yield 94%)is obtained.

NMR spectrum (DMSO-d₆-TMS) δ (PPM); 3.56 (such that the wider 1 for heavy, 2H, 2 on ); 3.76 (1 for heavy, 2H, ); 4.96 (2 for heavy, 1H, H on 6, J=5.0HZ); 5.63 (2 in 2 for heavy, 1H, H on 7); 8.85 (1 for heavy, 1H, the annular pro ton which will doze triazine); 9.13 (2 for heavy, 1H, , J=8HZ)

Antibacterial spectrum;

[...]. Corynebacterium Ml / (Escherichia Coli) 25 γ

Proteinases overelaborates. Ml / (Protens Vulgaris) 100 γ vulgaris

Salmonella (Salmonella) 12.5 γ Ml/

star blood[...]. Ml / (Staphylococcus anreus) 0.2 γ ulmarius outer