DK153155B - ANALOGY PROCEDURE FOR THE PREPARATION OF CEPHALOSPORINES - Google Patents

Description

DK 153155 B

The present invention relates to an analogous process for the preparation of novel cephalosporins of the general formula I

X-S-Y I

5 wherein X represents a desacetoxy-cephalosporinyl group of the formula r 2 -ch-co-nh - jp s-vj i3 J - iv ^ -CH2 - o '

COOH

represents hydrogen or methoxy, represents cyano, 4-pyridylthio, n-butyl, isobutyl, phenyl, hydroxyphenyl, cyclohexyl, 2-thienyl, 2-furyl, 1-tetrazolyl, 1-triazolyl, 1-pyrazolyl or 3- is hydrogen, hydroxy, hydroxymethyl, amino, azido, carboxy or sulfo, wherein from various groups R 1 can be substituted by hydroxy, halogen, lower alkyl or lower alkoxy, and if R 1 is a pyridylthio group, R 1 is hydrogen and Y represents at least one of the lower alkyl, lower alkenyl nitrogen atoms, lower alkoxy substituted lower alkyl, lower alkoxy, amino, mono- or di (lower alkyl) amino substituted and optionally at one or more carbon atoms having lower alkyl, halogen or oxo substituted pyrimidonyl, pyrazonyl, pyridazonyl or triazonyl group, wherein "lower" everywhere refers to groups having a maximum of 6 C atoms, or salts of these compounds and hydrates of these salts.

Examples of salts of compounds of formula I are alkali metal salts such as sodium and potassium salts, the ammonium salt, alkaline earth metal salts such as the calcium salt, salts with organic bases such as amines, e.g., N-ethylpiperidine, procaine, dibenzylamine, N, N'-dibenzylethyl. ethylenediamine, alkylamines or dialkylamines and salts with amino acids, for example arginine or lysine.

The compounds of formula I which contain a free basic group, 2

DK 153155B

e.g., an amino group, forms addition salts with organic or inorganic acids. Examples of such salts are hydrohalides, e.g. hydrochlorides, hydrobromides, hydroiodides and other mineral acid salts, e.g., sulfates, nitrates and phosphates, alkyl and mono-arylsulfonates such as ethane sulfonates, toluene sulfonates and benzenesulfonates, and other organic acid salts such as acetates, tartrates, , benzoates, salicylates and ascorbates.

The salts of the compounds of formula I may be hydrated. The hydration may be carried out during the preparation process 10 or may occur as a result of the hygroscopic properties of an initially anhydrous salt of a compound of formula I.

As used herein, the term "halogen" refers to chlorine, fluorine or bromine, which chlorine is preferred. The term "a lower alkyl group, lower alkoxy group or lower alkenyl group" refers to a straight or branched alkyl, alkoxy or alkenyl group having up to 6 carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, pentyl and hexyl, vinyl, propenyl, butenyl, pentenyl and hexenyl, with the alkyl groups having 4 carbon atoms, especially n-butyl and isobutyl being preferred.

Examples of particularly preferred compounds include those in which R 1 is 2-thienyl, 2-furyl, 1-tetrazolyl, 1-triazolyl, 1-pyrazolyl, 3-sydnonyl, phenyl, cyclohexyl, 4-pyridylthio or cyano, wherein, if 4-pyridylthio, R 1 is hydrogen.

Examples of such compounds are compounds in which Y is a 2-oxopyridin-4-yl group, a 2-oxopyrimidin-4-yl group, e.g., a 1-amino, 1-ethyl or 1-fcutoxy-1, 2-dihydro-2-oxopyrimidin-4-yl group or a 1-butoxy-1,2-dihydro-5-methylcyclo-2-oxopyrimidin-4-yl group, a 4-oxyrpyrin> 5.d5.n. 2-yig group, e.g. 1-etbyl-1,4-dihydro-6-methyl. -4-Cyclopyrimidin-2-yl group or a 1,4-dimethyl-1,6-dihydro-6-oxynyrimidin-2-yl moiety,

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3 a 2,6-dioxopyrimidin-4-yl group, a 2-oxopyrazin-3-yl group, a 2,3,5-trioxopyrazinyl-6-yl group, a 3-oxopyridazin-6-yl group, a 3-oxopyridazine-4 -yl group, a 5,6-dioxo-az-triazin-3-yl group, e.g., a 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 group or a 1,2,5,6-tetrahydro-1 -ethyl-5,6-dioxo-as-triazin-3-yl group, a 2-oxotriazin-4-yl group or a 2,4-dioxotriazin-6-yl group.

As substituents on a ring nitrogen atom may be mentioned lower alkyl or alkenyl, lower alkoxy, amino, mono or di (lower alkyl) amino, and as substituent on a ring carbon atom can be mentioned lower alkyl, halogen or oxo, wherein one is attached to a carbon atom lower alkyl group may again be substituted by hydroxy or lower alkoxy.

The lower alkyl, alkenyl or alkoxy groups listed above contain up to 6 carbon atoms. Examples of such alkyl groups are methyl and ethyl. Examples of such lower alkenyl groups are vinyl and allyl. Examples of such lower alkoxy groups are methoxy and ethoxy.

Particularly preferred compounds of formula I may be mentioned: 4

DK 153155 B

(7R) -3 - {[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-az-triazin-3-yl) thio] methyl} -7- [2- (2- thienyl) acetamido] -3-cephem-4-carboxylic acid, (7R) -3 - {[(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-az-triazin-3-yl) thio] methyl} -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid, 5 (7R) -3 - {[(1,4,5,6-tetrahydro-4-allyl) 5,6-dioxo-as-triazin-3-yl) thio] methyl) -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid, (7R) -3 - {[(1 4,5,5-Tetrahydro-4-butyl-5,6-dioxo-as-triazin-3-yl) thio] methyl} -7- [2- (2-thienyl) acetamido] -3-cephem-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-thienyl) acetamido] -3-cephem-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-thienyl) acetamido] -3-cephem-4-carboxylic acid (7R) -3 - {[(1, 4,5,6-Tetrahydro-1,4-diethyl-5,6-dioxo-az-triazin-3-yl) thio] methyl} -7- [2- (2-thienyl) acetamido] -3-cephem -4-carboxylic acid, (7R) -3 - {[(1,2,5,6-tetrahydro-1-ethyl-5,6-dioxo-ash) -triazin-3-yl) thio] methyl} -7- [2- (2-thienyl) acetamido] -3-cephem-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- (thienyl) acetamido] -3-cephem-4-carboxylic acid, (7R) -3 - {[(1-Ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl} 7 - [2 (2-thienyl) acetamido] -3-cephem-4 -carboxylic acid, (7R) -3 - {[(1-butoxy-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl} -7- [2- (2-thienyl) acetamido] -3- cephem-4-carboxylic acid, (7R) -3 - {[(1-butoxy-1,2-dihydro-5-methyl-2-oxo-4-pyrimidinyl) thio] methyl} -7- [2- (2 thienyl) acetamido] -3-cephem-4-carboxylic acid,

DK 153155 B

(7R) -3 - {[(1,4-dimethyl-1,6-dihydro-6-oxo-4-pyrimidinyl) thio] methyl} -7- [2- (2-thienyl) acetamido] -3- cephem-4-carboxylic acid, (7) -3 - ([(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl) -7- (2- (2-thienyl) -nyl) ) acetamido] -3-cephem-4-carboxylic acid, 5 (7R) -3 - {[(1-ethyl-1,4-dihydro-6-methyl-4-oxo-2-pyrimidinyl) thio] methyl} -7 - [2- (2-thienyl) acetamido -] - 3-cephem-4-carboxylic acid, (7R) -7- (2-cyanoacetamido) -3 - {[(1,4,5,6-tetrahydro-4-carboxylic acid) ethyl 5,6-dioxo-as-triazin-3-yl) thio] methyl} -3-cephem-4-carboxylic acid, 10 (7R) -3 - {[(1,4,5,6-tetrahydro-4) -ethyl-5,6-dioxo-as-triazin-3-yl) thio] methyl} -7 - [(R) -mandelamido] -3-cephem-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 -cephem-4-carboxylic acid, (7R) -3 - {[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) thio] methyl} - 7- [2- (5-oxo-1,2,3-oxodiazolidin-3-yl) acetamido] -3-cephem-4-carboxylic acid, (7R) -3 - {[(1-ethyl-1,2-yl) dihydro-2-oxo-4-pyrimidinyl) thio] methyl} -7- [2- (5-oxo-1,2,3-oxadiazolid (3-yl) acetamido] -3-cephem-4-carboxylic acid, 20 (7R) -3 - {[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazine) -3-yl) thio] methyl} -7- [2- (1H-tetrazol-1-yl) acetamido] -3-cephem-4-carboxylic acid, (7R) -3 - {[(1,4,5, 6-tetrahydro-4-ethyl-5,6-dioxo-az-triazin-3-yl) thio] methyl} -7 - [(R) -2-hydroxyhexanamido] -3-cephem-4-carboxylic acid, (7R ) -3- {[(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl} -7- [2- (3-sydnonyl) acetamido] -3-cephem-4-carboxylic acid , (7R) -3 - {[(1,4,5,6-Tetrahydro-4-ethyl-5,6-dioxo-az-triazine-3

DK 153155 B

a yl) thio] methyl} -7- [(R) -2-hydroxy-4-methylthalervalido] -3-cephem-4-carboxylic acid, (7R) -3 - {[(1,4,5,6- tetrahydro-4-ethyl-5,6-dioxo-az-triazin-3-yl) thio] methyl} -7 - [(R) -2-hydroxy-2- (cyclohexyl) acetamido] -3-cephem-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-cephem-4-carboxylic acid, (7R) -3- {[(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl} -7- [2- (1-tetrazolyl) acetamido] -3-cephem-4-carboxylic acid and salts thereof.

Compounds of formula I may be present as optically pure isomers and ice blends.

The process of the invention for preparing the compounds of formula I or salts and hydrates of these salts is characterized in that:

(a) a compound of general formula II

X '-W1 II

where X 'represents a group of formula

1 1 S

r2-ch-co-nh - j "^ i3 y ~ i ch2- o

R

20 10 o

wherein R · 1 ·, R and F, as defined above, and R represents a carboxy group protected by salt formation with an inorganic or tertiary organic base, and denotes a leaving group, in the presence of water, is reacted with a compound of the general formula 25 III

DK 153155B

7

H-S-Y III

wherein Y is as defined above and the protecting group is cleaved, or

(b) a compound of general formula IV

5 X "-S-Y IV

where Y has the meaning given above and X "represents a group of the formula r n h2n - ^ - -N CIi2 ~ 0 '

R

Wherein R and is as defined above are reacted with an acid of the general formula V

R2-CH-COOH v I 3 fr 15 wherein R 1 and R 2 have the meaning given above, or with a reactive functional derivative thereof, the protecting group is cleaved and the reaction product, if desired, converted to a salt.

For example, the protection of the carboxy group of group X "in a compound of formula IV may be effected by salt formation with an inorganic or tertiary organic base such as triethylamine.

As a leaving group W · in a compound of formula II, for example, halogens such as chlorine, bromine or iodine, acyloxy groups such as lower alkanoyloxy groups, e.g. acetoxy, lower alkyl or

DK 153155 B

arylsulfonyloxy groups such as mesyloxy or tosyloxy or an azido group.

The reaction of a compound of formula II and a compound of formula III can be carried out in a manner known per se, for example at a temperature between ca. 40 and 80 ° C, conveniently at about 60 ° C, in a polar solvent, for example in an alcohol such as a lower alkanol, e.g., ethanol and propanol, dimethylformamide, dimethylsulfoxide, preferably in water or a buffer solution having a pH of about . 6 to 7, preferably 6.5, over a period of 3 to 8, preferably 6, 10 hours.

For example, as reactive functional derivatives of acids of formula V, halides can be used, i.e. chlorides, bromides and fluorides, azides, anhydrides, especially mixed anhydrides with stronger acids, reactive esters, e.g., the N-hydroxysuccinimide ester, and amides, e.g., imidazolides.

The reaction of a compound of formula IV and an acid of formula V or a reactive functional derivative thereof can be carried out in a manner known per se. Thus, for example, a free acid of formula V can be condensed with one of the aforementioned esters of formula IV by means of a carbodiimide such as dicyclohexylcarbodiimide, in an inert solvent such as ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, benzene or dimethylformamide. the ester group is cleaved. Instead of carbodiimides, oxazolium salts can also be used as a condensing agent, for example N-ethyl-5-phenyl-isoxazolium-3'-sulfonate.

In another embodiment, a salt of an acid of formula IV, e.g., a trialkylammonium salt, is reacted with a reactive functional derivative of an acid of formula V as listed above in an inert, e.g., one of the solvents listed above.

The reaction of a compound of formula IV and a compound of formula V or a reactive functional derivative thereof may conveniently be carried out at temperatures between ca. +5 and -40 ° C, e.g. 0 ° C.

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Upon completion of reaction of a compound of formula II or IV and a compound of formula III and V, respectively, the protecting group is split off. If the protecting group is a benzyl group (benzyl ester), it can be decomposed by catalytic hydrogenation, for example by means of a noble metal catalyst, for example palladium / carbon. When the protecting group is a silyl group (silyl ester), this group can be particularly easily split off by treating the reaction product with water.

Finally, when the carboxy group of an acid of formula IV is protected by salt formation (e.g. with triethylamine), the cleavage of this salt-forming protecting group can be effected by treatment with acid at a relatively low temperature, e.g. 0 - approx. 10 ° C. As acid for this purpose can be used, for example, hydrochloric acid, sulfuric acid, phosphoric acid or citric acid.

The compounds of formula II are known and can be prepared in a manner known per se from the corresponding cephalosporins, i. from compounds of the general formula X-O-CO-CH 3 where X has the meaning given above.

Examples of compounds of formula II include 20 alkali metal salts, e.g., the sodium salt, of cephalothin, 7-α-methoxycephalothine, cephacetrile, (7R) -mandelamido-cephalosporanoic acid, and 7- (3-Southern nonacetamido) cephalosporanoic acid and zwitterion cephalosinic acid.

The compounds of formula III are, for some, new and for some known. The novel compounds of formula III can be prepared analogously to the preparation of known compounds.

Thus, a 1-substituted 2-oxo-4-mercaptopyridine can be prepared from the corresponding substituted 4-chloro-2-oxopyridine [Chem. Ber.

99. 255 (1966)] by nucleophilic replacement, e.g., with an alkali metal hydrogen sulfide.

Similarly, a 1,3-disubstituted 2,6-dioxo-1,2,3,6-tetrahydrohydro-2

DK 153155 B

4-mercaptopyrimidine is prepared from the corresponding 4-chloro-2,6-dioxo-1,2,3,6-tetrahydropyrimidine.

The 5,6-Dioxo-3-mercapto-as-triazines can be prepared from the corresponding substituted thiosemicarbazides by analogy with the synthesis of 5 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto -as-triaz in, j fr.

Dissertation by K.H. Ongania (Innsbruck 1972).

A thiol of formula III having a double bond between the carbon atom substituted with the mercapto group and a neighboring nitrogen atom may be in the form of the tautomeric thioketone.

A compound of formula IV can be prepared by reacting a compound of general formula X "-W1 wherein X" and having the meaning given above, with a compound of formula III. The reaction may be carried out under the same conditions as described for the reaction of a compound of formula II and a compound of formula III.

The compounds of formula V and the reactive functional derivatives thereof are known or analogous to known compounds and can be prepared in a manner known per se.

20

The compounds of formula V which contain an asymmetric carbon atom usually occur in the form of racemic mixtures. The cleavage of such racemates into the optically active isomers can be carried out in known manner. Thus, for example, diastereomers can be obtained from the racemic mixture by means of an optically active decomposition agent, for example an optically active base, for example α, α- (1-naphthyl) ethylamine or α-methylbenzylamine, which can react with the carboxy group. The resulting diastereomers are separated by selective crystallization and then converted to the corresponding optical isomers.

A compound of formula I in D-form can be prepared by either a compound of formula I present in the form of an isomer mixture, in a manner known per se, e.g.

DK 153155 B

11 crystallization of a salt, e.g., the calcium salt, is cleaved and the desired D form is isolated or compounds of formula III or IV reacted with a D-form compound of formula II or V or a reactive functional derivative of such compound 5 of formula V, the latter method being preferred.

The compounds of formula I, the salts thereof and the hydrates of these salts are antibiotically active, especially bactericidal. They have broad spectrum of action against Gram-positive and Gram-negative microorganisms, especially against penicillinase-positive staphylococci as well as various 10 cephalosporinase-positive Gram-negative bacteria, e.g., Escherichia coli, Proteus, Klebsiella, Aerobacter and Serratia species.

The compounds of formula I as well as the pharmaceutically tolerable salts and hydrated forms thereof can be used for the treatment and prophylaxis of infectious diseases as well as disinfectants. For adults, a daily dose of approx. 1 - approx. Particular preference is given to parenteral administration of the subject compounds.

The antimicrobial activity of two of the compounds of the invention, namely the sodium salt of (7R) -3 - ([(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3 yl) thio] methyl) -7- [2- (5-oxo-1,2,3-oxadiazolidin-3-yl) acetamido] -3-cephem-4-carboxylic acid (compound A in the table below) and the sodium salt of (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] -25 -3-cephem-4-carboxylic acid (Compound B of the table below) is shown in the CD5Q values listed below (mg / kg subcutaneously in mice) : 12

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Compound Penicillin-Sensitive Penicillin-resistant Escherichia staphylococcer staphylococcer coli A 0.25 5.5 0.38 5 _ B 0.60 3.2 0.90 10 The acute toxicity (LD50) of these substances by intravenous administration in mice is 2000 - 4000 mg / kg for the substance A and 1000 - 2000 mg / kg for the substance B.

3- (Heterocyclyl-thiomethyl) cephalosporins, similar to the compounds prepared by the process of the present invention, are described, for example, in Swedish Patent Nos. 74.14994-9, 74.12904-0 and 74.15914-6, and in U.S. Patent No. 3,867. 380 and 3,796,801. However, none of the thio-heretocyclic radicals specifically described in the aforementioned literature sites fall, for example, the pyrimidinylthioradicals found in the compounds of Swedish Patent Nos. 74,14994-9 and 74,15914-6 and in U.S. Patent Nos. 3,867,380, further, under the definition of the radical -SY found in the compounds of formula I. Compared to the compounds described in the above literature, the novel compounds prepared by the process of the present invention also have advantageous properties, eg lower CDjq values.

In the table below, the technical progress achieved according to the present invention is illustrated by in vivo tests on mice infected with penicillin-resistant Staphylococcus 30 aureus strains.

For comparison, the following compounds were used: A = 3- (1-methyltetrazol-5-ylthiomethyl) -7-D-mandelamido-3-cephem-4

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13 carboxylic acid (USP 3,796,801; active ingredient in a marketed product) B - 7- (Da-amino-p-hydroxyphenylacetamido) 3- (1,2,3-triazol-5-ylthiomethyl) -3-cephem-4 carboxylic acid (USP 3,867,380; active ingredient in a marketed product) C-7- (Da-amino-p-hydroxyphenylacetamido) -3- (pyrimidin-4-ylthiomethyl) -3-cephem-4-carboxylic acid.

The novel compounds are identified in the table by the number of the example according to which the compound is prepared.

TABLE

Compound CD50 (mg / kg, mouse, subcutaneously)

Staphylococcus aureus, resistant to penicillin 15 A 15 B 19 C 18 20 5 5.5 6 3.8 7 8.8 8 7.3 10 5.8 25 14 5.8 16 5.6 17 7.0 18 5, 5 19 8.8 30 30 6.4 31 7.0 35 8.3 14

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The following test report and related results show that the compounds prepared by the process of the present invention are also superior to Cephacetril.

Investigation of systemic action against Escherichia coli.

The compounds were dissolved in a physiological saline solution (0.95%). A group of 5 mice weighing 18-19 g was used for each dose level of the compounds and for untreated control groups. The animals were infected intraperitoneally with 8 times the minimum lethal infection dose of a culture that had grown 10 overnight. The compounds were administered subcutaneously 3 times, namely 1 hour, 2 1/2 hours and 4 hours after infection, respectively.

The ratio of living to dead was counted daily for 8 days. The CD50 values were determined after 4 days. The results are shown in the table below:

TABLE

Compound prepared GD50 (msAS subcutaneously) of Example No. Escherichia coli 20 1 0.4 2 0.5 3 0.9 5 0.4 6 3.2 25 8 1.1 9 2.1 10 1.2 11 1, 9 13 2.9 30 14 0.6 DK 153155 3 15

Table continued 15 1.4 16 0.5 17 0.6 5 18 0.4 19 1.6 20 0.9 21 1.8 22 1.8 10 23 2.2 24 0.7 25 1.2 26 0 , 5 27 0.9 15 28 1.0 29 1.5 31 1.4 32 0.2 33 0.5 20 34 1.4 35 1.2 36 0.9 37 1.1 38 0.2 25 39 1.1 40 1.1 41 2.6 43 0.4 45 1.9 30 47 1.4

Gephacetril 5.8 Pharmaceutical compositions, preferably dry pellets, may contain the compounds of formula I, salts thereof or hydrated forms of these salts, optionally in admixture with another therapeutically active substance.

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The process according to the invention is further illustrated by the following examples:

Example 1.

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

4.4 g of cephalothin sodium salt [ajjj = + 130 ° (c = 1 in water)) is stirred in 100 ml of water with 2.25 g, 4,5,6-tetrahydro-4-ethyl-5,6-dioxo -3-mercapto-as-triazine and 1.05 g of sodium bicarbonate for 6 hours at 10 60 ° C under a nitrogen atmosphere and at pH approx. 6.5. The reaction mixture is then cooled to 10 ° C and adjusted to pH 2 by the addition of 2N hydrochloric acid solution. The thus precipitated substance is isolated by suction filtration and washed with 25 ml of ice water. The substance is dissolved in acetone and the solution is evaporated in vacuo. The residue obtained is dissolved in dimethylformamide and to the solution is added 7.5 ml of a 2N solution of the sodium salt of 2-ethyl-capric acid in ethyl acetate.

Upon dilution with ethyl acetate, the desired compound crystallizes. This is isolated by suction filtration, washed with ethyl acetate, ether and petroleum ether in the order indicated and dried in vacuo. Yield 4.5 g (80% of theory). Melting point> 170 ° C (dec.); [ce] + = + 13.1 ° (c = 0.800 in water).

The 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine used in the process described above can be prepared as follows: 120 g of 4-ethylthiosemicarbazide are reacted in the presence of 23 g of sodium in 1 liter of methanol for 4 hours with 116 g of oxalic acid dimethyl ester at the boiling point of the reaction mixture. The triazine is isolated from the reaction mixture in the form of the sodium salt and then obtained by acidification of an aqueous solution, mp 189 - 190 ° C.

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

17

Example 2.

This compound is prepared by analogy to the process described in Example 1 from 4.18 g of cephalothin sodium salt and 1.91 g of 1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-3 mercapto-as-triazine; yield 2.8 g (54.1% of theory). Melting point 200 - 205 ° C (dec.); [α] D 20 = -2.7 ° (c = 0.592 in water).

The triazine used in the process described above is prepared analogously to the process described in Example 1 from 176 g of 4-methylthiosemicarbazide and 198 g of oxalic acid dimethyl ester.

Melting point 218 - 220 ° C (dec.).

Example 3

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

This compound is prepared analogously to the procedure described in Example 1 from 6.27 g of cephalothin sodium salt and 3.33 g of 1,4,5,6-tetrahydro-4-allyl-5,6-dioxo-3-mercapto as-triazine. Yield 3.0 g (36.8% of theory). Melting point> 180 ° C (dec.); [α] = +19.7 ° (c = 0.376 in water).

The triazine used for the process described above is prepared analogously to the process described in Example 1 from 26.2 g of 4-allylthiosemicarbazide and 23.6 g of oxalic acid dimethyl ester. Melting point 138 - 140 ° C.

Preparation of the sodium salt of (7R) -3 - ([(1,4,5,6-tetrhydro-4-butyl-5,6-dioxo-as-triazin-3-yl) thio] methyl) -7- [2 - (2-thienyl) acetamido] -3-cephem-4-carboxylic acid.

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Example 4

This compound is prepared analogously to the process described in Example 1 from 6.27 g of cephalothin sodium salt and 3.62 g of 1,4,5,6-tetrahydro-4-butyl-5,6-dioxo-3-mercapto as-triazine. Yield 3.0 g (35.7% of theory). Melting point> 160 ° C (dec.); [α] g ° - + 17.6 ° (c = 0.640 in water).

The triazine used in the process described above is prepared analogously to the process described in Example 1 from 14.7 g of 4-butylthiosemicarbazide and 11.8 g of oxalic acid dimethyl ester.

Melting point 180 - 181 ° C.

Example 5

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

This compound is prepared analogously to the procedure described in Example 1 from 6.27 g of cephalothin sodium salt and 3.65 g of 1,4,5,6-tetrahydro-4- (2-methoxyethyl) -5,6-dioxo-2 3-mercapto-as- triazine. Yield 2.0 g (23.8% of theory), [ajfj® = + 10 ° (c = 0.280 in water).

The triazine used in the process described above is prepared analogously to the process described in Example 1 from 14.9 g of 4- (2-methoxyethyl) thiosemicarbazide and 11.8 g of oxalic acid dimethyl ester. Melting point 158 - 160 ° C.

Example 6

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

P! f .1 P ”? »1 p? - p * i

Lh \ s 00 I 0 0 O

This compound is prepared by analogy to the procedure described in Example 1 from 6.27 g of cephalothin sodium salt and 2.6 g of 1,4,5,6-tetrahydro-1,4-dimethyl-5,6-dioxo-3. -mercapto-as-triazine. Yield 4.6 g (58.0% of theory). [a] §® - -9.55 ° (c = 0.461 in water).

The triazine used in the process described above is prepared analogously to the process described in Example 1 from 11.9 g of 1,4-dimethylthiosemicarbazide and 11.8 g of oxalic acid dimethyl ester. Melting point 231 - 233 ° C (decomposition).

Example 7

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

This compound is prepared analogously to the procedure described in Example 1 from 6.27 g of cephalothin sodium salt and 2.01 g of 1,4,5,6-tetrahydro-1,4-diethyl-5,6-dioxo-3-mercapto. -as-triazine.

Yield 5.5 g (65.7% of theory). Melting point> 175 ° G (decomposition). [α] βΟ - + 10.2 ° (c - 0.547 in water).

The triazine used in the process described above is prepared analogously to the process described in Example 1 from 14.7 g of 1,4-diethylsemicarbazide and 11.8 g of oxalic acid dimethyl ester.

Melting point 177 - 179 ° C.

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

20

DK 153155 B

Example 8.

This compound is prepared by analogy to the process described in Example 1 from 10.45 g of cephalothin sodium salt and 4.8 g of 1,2,5,6-tetrahydro-1-ethyl-5,6-dioxo-3-mercapto as-triazine. Yield 7.0 g (52.6% of theory). Melting point 210 - 215 ° C (decomposition), [as] + = 8.85 ° (c = 0.181 in water).

The triazine used in the process described above can be prepared as follows: 46.5 g of 1-ethylthiosemicarbazide are reacted in 700 ml of acetone at 40 ° C with 48 g of oxalic acid monomethyl ester chloride. To 34.3 g of the product obtained is added 9.2 g of sodium methylate in 300 ml of methanol. The triazine is isolated from the reaction mixture in the form of the sodium salt and then obtained by acidification in an aqueous solution, mp 213 - 214 ° C (dec.).

Example 9

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

This compound is prepared analogously to the procedure described in Example 1 from 5.16 g of 7-α-methoxy-cephalothine sodium salt [α] + = + 194.5 ° (c - 0.308 in water)) and 1.82 µl , 4,5,6-tetrahydro-4-methyl-5,6-dioxo-3-mercapto-as-triazine. Yield 1.0 g (15.9% of theory); [α] Y® = + 54.6 ° (c = 0.308 in water).

\ί \ 153155 8

Preparation of the sodium salt of (7R) -3 - ([(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl) -7- [2- (2-thienyl) acetamido] -3 -eephem-4-carboxylic acid.

Example 10.

This compound is prepared by analogy to the procedure described in Example 1 from 4.18 g of cephalothin sodium salt and 1.8 g of 1-ethyl-1,2-dihydro-4-mercapto-2-oxo-pyrimidine. Yield 3.2 g (65.3% of theory). Melting point> 190 ° C (dec.); [α] D = -58 ° (c = 0.570 in water).

Example 11.

Preparation of the sodium salt of (7R) -3 - ([(1-butoxy-1,2-dihydro-2-oxo-4-pyrimidinyl) thiomethyl) -7- [2- (2-thienyl) acetamido] -3-cephem -4-carboxylic acid.

This compound is prepared analogously to the procedure described in Example 1 from 4.18 g of cephalothin sodium salt and 2.2 g of 1-butoxy-1,2-dihydro-4-mercapto-2-oxo-pyrimidine. Yield 3.8 g (70% of theory). [α] D = -83.6 ° (c = 0.850 in water).

The pyrimidine used in the above process is prepared from 2 g of 1-butoxyuracil and 4 g of phosphorus pentasulfide. Melting point 99 - 100 ° C.

Example 12.

Preparation of the sodium salt of (7R) -3 - ([(1-butoxy-1,2-dihydro-5-methyl-2-oxo-4-pyrimidinyl) thio] methyl) -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid.

This compound is prepared analogously to the procedure described in Example 1 from 6.0 g of cephalothin sodium salt and 3.36 g of 1-butoxy-1,2-dihydro-4-mercapto-5-methyl-2-oxo-pyrimidine. Yield 0.8 g (9.7% of theory). Melting point> 170 ° C (decomposition).

22

DK 153155 B

The pyrimidine used in the above process can be prepared analogously to the process described in Example 11 by reacting 25 g of 1-butoxy-5-methyluracil and 50 g of phosphorus pentasulfide. 1-Butoxy-5-methyluracil is prepared by reacting 110 5 g of butoxyurea and 184 g of β, / 3-diethoxy-α-methylpropionic acid ester.

Example 13

Preparation of the sodium salt of (7R) -3 - ([(1,4-dimethyl-1,6-dihydro-6-oxo-2-pyrimidinyl) thiomethyl) -7- [2- (2-thienyl) acetamido] -3 -cephem - 4-carboxylic acid.

This compound is prepared by analogy to the procedure described in Example 1 from 4.18 g of cephalothin sodium salt and 1.8 g of 1,4-dimethyl-1,6-dihydro-2-mercapto-6-oxo-pyrimidine. Yield 1.35 g (26.3% of theory). Melting point 200 - 210 ° C (decomposition).

- + 9.5 ° (c = 0.348 in water).

Example 14.

Preparation of the sodium salt of (7R) -3 - ([(1-ethyl-1,4-dihydro-6-methyl-4-oxo-2-pyrimidinyl) thio] methyl) -7- [2- (2-thienyl) acet-amido] -3-cephem-4-carboxylic acid.

This compound is prepared by analogy to the procedure described in Example 1 from 6.27 g of cephalothin sodium salt and 2.98 g of 1-ethyl-1,4-dihydro-2-mercapto-6-methyl-4-oxopyrimidine. Yield 3.2 g (40.4% of theory). Melting point> 170 ° C (dec.); [α] p = -14.4 ° (c = 0.333 in methanol).

The pyrimidine used in the above process can be prepared as follows: 18 g of N-ethylthiourea is dissolved in 50 ml of acetic acid, boiled under reflux and 17.2 g of the diket is added dropwise. The mixture is then refluxed for 20 minutes and evaporated to 50 ml.

DK 153155 3 23

While cooling and stirring, add 50 ml of water. The yellow crystals precipitate. They are isolated by suction filtration and recrystallized from tetrahydrofuran. Melting point 190 ° C.

Example 15

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

This compound is prepared analogously to the procedure described in Example 1 from 9.5 g of cephacetril sodium salt and 5.46 g of 1,4,5,6-10-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto. -as-triazine. Yield 3.3 g (26.8% of theory), [α] D = + 7.85 ° (c = 0.1785 in water).

Example 16.

Preparation of the sodium salt of (7R) -3 - ([(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) thio] methyl) -7 - [( R) -mandelamido] -3-15 cephem-4-carboxylic acid.

This compound is prepared analogously to the procedure described in Example 1 from 8.0 g of the sodium salt of (7R) -mandelamido-cephalosporanoic acid and 3.72 g, 4,5,6-tetrahydro-4-ethyl-5,6-dioxo. -3-mercapto-as-triazine. Yield 1.7 g (16.8% of theory).

[Α] D = -19.6 ° (c - 0.500 in water).

Example 17

Preparation of (7R) -7 - [(R) -2-amino-2-phenylacetamido] - 3 - ([(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazine) - 3-yl) thio] methyl) -3-cephem-4-carboxylic acid.

This compound is prepared analogously to the procedure described in Example 1 from 8.1 g of cephaloglycine and 3.78 g of 1,4,5,6-tetra-24.

DK 153155 B

hydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine and isolated in the form of the zwitterion. Yield 4.19 g (40.5% of theory). Melting point> 180 ° C (dec.), [Et] -86.3 ° (c - 0.276 in dimethylformamide).

Example 18.

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

This compound is prepared analogously to the procedure described in Example 1 from 7.7 g of the sodium salt of 7- (3-Southern nonacetamido) -10 cephalosporanoic acid and 3.46 g, 4,5,6-tetrahydro-4-ethyl-5, 6-dioxo-3-mercapto-as-triazine. Yield 3.3 g (31% of theory). Melting point> 210 ° C (dec.). = + 17.9 ° (c = 0.380 in water).

Example 19.

Preparation of the sodium salt of (7R) -3 - ([(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl) -7- [2- (5-oxo-1,2 (3-oxadiazolidin-3-yl) acetamidoj-3-cephem-4-carboxylic acid.

This compound is prepared analogously to the procedure described in Example 1 from 11.6 g of the sodium salt of 7- (3-Southern nonacetamido) cephalosporanoic acid and 4.7 g of 1-ethyl-1,2-dihydro-4-mercapto 2-20 oxo-pyrimidine. Yield 3.6 g (23.2% of theory). [ct] §® = -43.7 ° (c = 0.600 in water).

Example 20

Preparation of the sodium salt of (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] -3-cephem-4-carboxylic acid.

1.28 g of tetrazole-1-acetic acid are dissolved in a mixture of 50 ml of tetrahydrofuran and 5 ml of dimethylformamide. Add to this solution

DK 153155 B

25 -20 ° C 1.18 ml of N-methylmorpholine and 1.4 ml of chloroformic acid isobutyl ester in the order indicated, after which it is stirred for 20 minutes at a temperature between -10 and -20 ° C. Then, an ice-cold solution of it is added from 3.85 g of 7-amino-3-desacetoxy-3 - [(1,4,5,6-tetra-5-hydro-4-ethyl-5,6-dioxo-ash). triazin-3-yl) thio] cephalosporanoic acid and 1.4 ml of triethylamine obtained salt in 50 ml of water. The reaction mixture is then stirred for 30 minutes at 0 ° C and for 1 hour at 20 ° C. The reaction mixture is evaporated in vacuo and the aqueous phase is acidified with 5 ml of 2N hydrochloric acid solution to precipitate the desired substance as the crude 10 acid. This acid is isolated by suction filtration, washed with a lot of ethyl acetate and dissolved in dimethylformamide. To this solution is added a 2N solution of the sodium salt of 2-ethylcaproic acid in ethyl acetate and then diluted with ethanol and ether to precipitate the desired crude sodium salt (3.3 g). Thus, for purification, the 15 recovered substance is dissolved in 20 ml of water and 60 ml of ethanol are added, to precipitate a dark resin which is discarded. The filtrate is evaporated in vacuo and the residue is treated with ethanol and ether to give 2.3 g (44.5% of theory) of pure material as a light beige powder, m.p. 210 ° G (dec.) And [a] j) ® = + 23 ° (c = 0.824 in water).

The 7-amino-3-des-acetoxy-3 - [(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) method used in the above procedure thio] cephalosporanoic acid is prepared as follows: 2.72 g of 7-amino-cephalosporanoic acid is suspended together with 1,4,5,6-25 tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine in 100 ml of water.

To this suspension is added 1.85 g of sodium bicarbonate to form a solution of pH 6.4. This solution is stirred for 3 hours at 60 ° C under a nitrogen atmosphere. The solution is cooled to 20 ° C and stirred with the addition of 1 g of activated charcoal under nitrogen atmosphere for an additional 1 hour. After filtration, the filtrate is adjusted to pH 3.8 by the addition of 2N hydrochloric acid solution, cooled to 0 ° C and stirred for 1 hour to crystallize the substance. This is isolated by suction filtration, washed with a small amount of ice water, acetone, ether and petroleum ether in the order indicated and dried in high vacuum at 50 ° C. Yield 2.3 g (60% of theory) of beige powder, mp 230 - 235 ° C (decomposition).

26 DK 1531553

The 7-amino-3-desacetoxy-3-1 (1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) -thio] cephalosporanoic acid used in the process described above can also be prepared in another way, as described below: 5.1 g of 7-amino-3-azido-3-desacetoxy-cephalosporanoic acid is stirred with 5.16 g, 4,5,6-tetrahydro-4-ethyl-acid. 5,6-dioxo-3-mercapto-as-triazine and 4.2 g of sodium bicarbonate in 200 ml of a pH 7.0 buffer for 6 hours at 60 ° C under a nitrogen atmosphere. The reaction solution is cooled to 256C and then adjusted to pH 3.5 by the addition of 2N 10 hydrochloric acid solution. The desired substance is crystallized and isolated by suction filtration (2.2 g). Evaporation of the mother liquor yields an additional 1.7 g. Total yield 3.9 g (50% of theory).

Example 21.

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

4.4 g of 7- amino-3-desacetoxy-3 - [(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) thio] cephalosporanoic acid is dissolved at 0 With stirring in a mixture of 44 ml of water and 44 ml of acetone by adding 20 g of 2.5 g of potassium hydrogen carbonate. Then, at 0 ° C, with stirring, a solution of 3 g of (R) -2-dichloroacetoxy-n-capric acid chloride (boiling point q 5 m Hg +) · 30 ml of acetone is added dropwise and stirred for 2 hours at 0 ° C. For 1 hour at 20 ° C. Of the filtered solution, the acetone is distilled off under reduced pressure at 30 ° C. The aqueous solution is added to potassium carbonate and stirred for 45 minutes at a pH of 9.5, then extracted twice with ethyl acetate. and adjusted at 0 ° C to a pH of 1.5 - 2.0 by the addition of 3N sulfuric acid solution Extracted with ethyl acetate with the addition of dimethylformamide The ethyl acetate solution is washed several times with 10% sodium chloride solution, dried with magnesium sulfate and evaporated under reduced pressure at 25 DEG C. The residue is dissolved in 100 ml of isopropanol and 12 ml of a 2N solution of the sodium salt of 2-ethylcaproic acid in isopropanol is added.

DK 153155 B

27 a beige powder with melting point of 183 ° C (decomposition); - + 8.2® (c = 1.00 in water). Yield 56% of theory.

Example 22.

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

This compound is prepared analogously to the process described in Example 21 from 3.5 g of 7-amino-3-desacetoxy-3 - [(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo) -as-triazin-3-yl) thio] cephalosporanoic acid and 2.4 g (R) -2-dichloroacetoxy-isocaproic acid chloride (boiling point 0.2 mm Hg + 63-64 ° C). Yield 51% of theory; melting point from 180 ° C (dec.); [α] D = + 6.0 ° (c * = 1.00 in water).

Example 23

Preparation of the sodium salt, of (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-cephem-4-carboxylic acid.

This compound is prepared analogously to the process described in Example 21 from 3.9 g of 7-amino-3-desacetoxy-3 - [(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo) -as-triazin-3-yl) thio] cephalosporanoic acid and 2.9 g (R) -2-dichloroacetoxy-2- (cyclohexyl) acetyl chloride (boiling point 0.5 mmjg = 105 - 107 ° C). Yield 37% of theory; melting point from 190 ° C (dec.); [α] D = + 2.8 ° (c = 0.50 in water).

Example 24.

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

DK 153155 B

3.85 g of 7-amino-3-desacetoxy-3 - [(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) thio] cephalosporanoic acid are dissolved under stirring at 0 ° C in a mixture of 40 ml of water and 40 ml of acetone with the addition of 2.4 g of potassium hydrogen carbonate. A solution of 5 1.45 g of 2- (2-furyl) acetyl chloride in 15 ml of acetone is added dropwise at -5 ° C and stirred for 3 hours at -5 ° C and for 1.5 hours at 20 ° C. The reaction solution is extracted twice with ethyl acetate and the aqueous phase is acidified to pH 2 at 0 ° C with 3N sulfuric acid solution. Extract with ethyl acetate with the addition of dimethylformamide, wash three times with 10% 10% sodium chloride solution and dry over magnesium sulfate and evaporate the solution under reduced pressure at 25 ° C. The residue is dissolved in methanol and 8 ml of a 2N solution of the sodium salt of 2-ethylcaproic acid in isopropanol is added and the crude sodium salt is precipitated with diethyl ether, isolated by suction filtration, washed with diethyl ether and then recrystallized from water with the addition of acetone. A beige powder is obtained having a melting point of 180 ° C (decomposition); [α] D 20 + 18.4 (c - 1.0 in water); yield 43% of theory.

Example 25

Preparation of the sodium salt of (7R) -3 - ([(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl) -7- [2- (2-thienyl) acetamido] - 3-cephem-4-carboxylic acid.

This compound is prepared analogously to the procedure described in Example 1 from 8.36 g of cephalothin sodium salt and 3.0 g of 1-amino-25-1,2-dihydro-4-mercapto-2-oxo-pyrimidine. Yield 4.1 g (40.2% of theory); mp> 185 ° C (dec.); [α] D = -78.5 ° (c = 0.439 in water).

The pyrimidine used for the process described above is prepared from 8.6 g of 1-benzylidene aminouracil [mp 220 DEG-223 DEG C.; literature: Monatshefte fur Chemie 96, 1735 (1965)] and 12 g of phosphorus pentasulfide in pyridine followed by hydrolysis with hydrochloric acid.

DK 153155B

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

Example 26

This compound is prepared by analogy to the procedure described in Example 1 from 8.36 g of eephalothin sodium salt and 3.34 g of 1,2,5,6-tetrahydro-5,6-dioxo-3-mercapto-2-methyl. -as-triazine. Yield 5.8 g (56% of theory); mp 185 ° C (dec.); = -49.3 ° (c = 0.450 in water).

The triazine used in the process described above is prepared analogously to the process described in Example 1 from 31.5 g of 2-methylthiosemicarbazide and 35.4 g of oxalic acid dimethyl ester.

Melting point 260 ° C.

Example 27

Preparation of the sodium salt of (7R) -3 - ([(1,2-dihydro-1-methyl-2-oxo-4-pyrimidinyl) thio] methyl) -7- [2- (2-thienyl) acetamido] - 3-cephem-4-carboxylic acid.

This compound is prepared analogously to the procedure described in Example 1 from 8.36 g of eephalothin sodium salt and 2.98 g of 1,2-20 dihydro-4-mercapto-1-methyl-2-oxo-pyrimidine. Yield 6.3 g (62.4% of theory); mp 180 ° C (dec.); [α] Y® = -67.7 ° c = 0.604 in water).

Example 28.

Preparation of the sodium salt of (7R) -3 - ([(1,2-dihydro-1-methoxy-2-oxo-4-pyrimidinyl) thio] methyl) -7- [2- (2-thienyl) acetamido] - 3-cephem-4-carboxylic acid.

This compound is prepared analogously to the process described in Example 1 from 8.36 g of eephalothin sodium salt and 3.32 g of 1.2

DK 153155 B

Dihydro-4-mercap to -1-methoxy-2-oxo-pyrimidine. Yield 6.3 g (61.2% of theory). Melting point 175 - 180 ° C (dec.); [.alpha.] D @ 20 = -90.6 ° (c - 0.338 in water).

The pyrimidine used for the process described above is prepared analogously to the process described in Example 11 from 6 g of 1-methoxyuracil and 18 g of phosphorus pentasulfide. Melting point 177 ° C.

Example 29.

Preparation of the sodium salt of (7R) -3 - ([(1-ethoxy-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl) -7- [2- (2-thienyl) acetamido] -3 -cephem-4-10 carboxylic acid.

This compound is prepared by analogy to the procedure described in Example 1 from 6.27 g of cephalothin sodium salt and 2.75 g of 1-ethoxy-1,2-dihydro-4-mercapto-2-oxo-pyrimidine. Yield 3.5 g (44% of theory). Melting point> 180 ° C (decomposition), [α] D + -15 -74.28 (c - 0.525 in water).

The pyrimidine used for the process described above is prepared analogously to the process described in Example 11 from 6.4 g of 1-ethoxyuracil and 18 g of phosphorus pentasulfide. Mp 119-120 ° C.

Example 30.

Preparation of the sodium salt of (7R) -3 - ([(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl) thiomethyl) -7- [2- (2-thienyl) acetamido] -3-cephem -4-carboxylic acid.

This compound is prepared analogously to the procedure described in Example 1 from 1.25 g of cephalothin sodium salt and 0.470 g of 1,6-dihydro-3-mercapto-1-methyl-6-oxo-pyridazine. Yield 1.0 g (66.7% of theory); mp> 215 ° C (decomposition); [α] - -49.7 ° (c - 0.332 in water).

DK 153155 B

31

The pyridazine used in the process described above is prepared from 2.88 g of 3-chloro-1,6-dihydro-1-methyl-6-oxo-pyridazine [m.p. 91 - 92 ° C; literature: Monatshefte fur Chemie 99. 33 (1968)] and 5.88 g of sodium hydrogen sulfide in ethanol at 130 ° C and 5 to 5 ato pressure; mp 115 ° C.

Example 31.

Preparation of the sodium salt of (7R) -3 - ([(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl) -7- [2- (3-sydnonyl) acetamido] -3 -cephem-4-carboxylic acid.

This compound is prepared analogously to the process described in Example 20 from 9.5 g of south non-3-acetic acid and 21.4 g of 7-amino-3-desacetoxy-3- [1-amino-1,2-dihydro-2 - oxo-pyrimidin-4-yl-thio] ce -phalosporanoic acid. Yield 9.7 g (32% of theory); melting point from 200 ° C (dec.); [α] D = -61.3 ° (c * 0.5 in water).

Example 32.

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

This compound is prepared analogously to the procedure described in Example 1 by reacting 24.5 g of Dβ-hydroxy-N-tert-butyl-oxy-carbonyl-cephaloglycine and 8.66 g, 4,5,6-tetrahydro-4 ethyl 5,6-dioxo-3-mercapto-as-triazine and subsequent removal of the tert-butyloxy-carbonyl protecting group with formic acid. Yield 5.7 g (23% of theory); melting point from 200 ° C (dec.); [α] D = -79.8 ° (c 25 "0.3 in dimethylformamide).

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

Example 33

32

DK 153155 B

This compound is prepared analogously to the procedure described in Example 1 from 6.0 g of cepbapirin and 2.56 g of 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-ash. triazine. Yield 1.9 g (26% of theory); melting point from 205 ° C (dec.); [α] β ° - + 36.2 ° (c - 0.5 in water).

Example 34.

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

This compound is prepared analogously to the procedure described in Example 1 from 6 g (pyrazol-1-yl-methyl) cephalosporin sodium salt and 3.12 g, 4,5,6-tetrahydro-4-ethyl-5,6 dioxo-3-mercapto-as-triazine. Yield 4.0 g (51% of theory); mp 190 DEG C. (decomposition).

Example 35.

Preparation of the sodium salt of (7R) -3 - ([(1,2,3,6-tetrahydro-2,6-dioxo-1-methyl-s-triazin-4-yl) thio] methyl) -7- [ 2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid.

This compound is prepared by analogy to the procedure described in Example 1 from 8.36 g of cephalothin sodium salt and 3.34 g of 1,2,3,6-tetrahydro-2,6-dioxo-4-mercapto-1-methyl s-triazine. Yield 5.5 g (53% of theory). Melting point from 200 ° C (dec.); [a] $ ® - -43 ° (c - 0.1 in water).

DK 153155 B

33

The 1,2,3,6-tetra-hydro-2,6-dioxo-4-mercapto-1-methyl-s-triazine used in the process described above can be prepared as follows:

To a solution of 14.8 g of sodium in 1000 ml of methanol is added 39.9 g of 5-methyl-2-thiobiuret and 72 g of diethyl carbonate and refluxed for 24 hours. The reaction solution is evaporated in a vacuum to a volume of 200 ml. The thus crystallized substance is isolated by suction filtration, dissolved in 200 ml of water and acidified with 2N hydrochloric acid solution. The precipitated compound is isolated by suction filtration and recrystallized from 350 ml of ethanol. Yield 11.2 g (23% of theory) of colorless substance, m.p. 275 ° C.

The 5-methyl-2-thiobiurene used for the process described above can be prepared as follows:

To a solution of 76 g of thiourea in 1000 ml of dimethylformamide 15 is added 65.4 ml of methyl isocyanate and then stirred for 72 hours at 50-55 ° C. The reaction solution is evaporated in vacuo and the residue is recrystallized from water. Yield 79.4 g (60% of theory) of colorless substance, m.p. 209 - 210 ° C.

Example 36.

Preparation of the sodium salt of (7R) -3 - ([(1-ethyl-5-chloro-1,2-di-hydro-2-oxo-4-pyrimidinyl) thio] methyl) -7- [2- (2 thienyl) acetamido] -3-cephem-4-carboxylic acid.

This compound is prepared by analogy to the procedure described in Example 1 from 6.27 g of cephalothin sodium salt and 3.04 g of 1-25 ethyl-5-chloro-1,2-dihydro-4-mercapto-2-oxo-pyrimidine. Yield 3.5 g (42% of theory). Melting point from 185 DEG C. (decomposition); [α] $ 0 = -95.2 ° (c = 0.394 in water).

The 1-ethyl-5-chloro-1,2-dihydro-4-mercapto-2-oxo-pyrimidine used for the process described above can be prepared as follows:

DK 153155 B

34 1.74 g of 1-ethyl-5-chloruracil is first mixed with 4.44 g of phosphorus pentasulfide and 0.1 ml of water, then 30 ml of pyridine is added and boiled at reflux for 3 3/4 hours. The reaction mixture is evaporated in vacuo at 40 ° C and the residue is suspended in 30 ml of water and 5 ml of 2N hydrochloric acid solution are added. The crystalline substance is isolated by suction filtration, washed with water and recrystallized from ethanol. Yield 1.3 g (68% of theory) of yellow substance, mp 217 -220DC.

The 1-ethyl-5-10 chloruracil used for the procedure described above can be prepared as follows: In a solution of 9.9 g of 1-ethyluracil in 150 ml of glacial acetic acid, chlorine is introduced for as long (about 1/2 hour) until iodine potassium starch paper reacts positively and 1-ethyluracil by thin layer chromatography can no longer be detected. The reaction mixture is evaporated in vacuo at 40 ° C and the crystalline residue is recrystallized from 300 ml of ethanol. Yield 10.0 g (81% of theory) colorless fine needles, mp 244 - 247 ° C.

The 1-ethyluracil used in the above procedure can be prepared as follows: To a solution of 15.0 g of sodium in 700 ml of ethanol is added 44 g of N-ethylurea and 105 g / J, - diethoxypropionic acid ethyl ester. Then the yellow solution is kept at 25 ° C for 3 hours and refluxed for 15 hours. The solution is evaporated in vacuo and the residue is dissolved in 300 ml of water, cooled to 0 ° C and acidified with 100 ml of concentrated hydrochloric acid to give a crystalline intermediate (43 g). This is isolated by suction filtration, washed with 100 ml of ice water and then heated to 80-100 ° C in 250 ml of water until the conversion to the desired water-soluble 1-ethyluracil is complete. The solution is evaporated in vacuo at 40 ° C and the residue obtained is recrystallized from ethanol ether. Yield 14.0 g (20% of theory) colorless substance, m.p. 150 ° C.

Example 37.

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

35

DK 153155 B

This compound is prepared analogously to the process described in Example 20 from 2.95 g of tetrazole-1-acetic acid and 8.55 g of 7-amino-3 - [(1,2,5,6-tetrahydro-2-methyl-1 5,6-dioxo-as-triazin-3-yl) thio] cephalosporanic acid. Yield 4.65 g (40% of theory). Melting point 220 - 230 ° C (dec.); [.alpha.] .delta. = 53.6 ° (c = 0.321 in water).

Example 38

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

This compound is prepared analogously to the process described in Example 21 from 9.25 g of DO-dichloroacetyl-mandelic acid chloride and 11.1 g of 7-amino-3-desacetoxy-3 - [(1,2,5,6-tetrahydro-hydroxy) 2-methyl-5,6-dioxo-as-triazin-3-yl) thio] cephalosporanic acid. Yield 4.3 g (27% of theory). Melting point 200 - 210 ° C (dec.); [Α] g ° = 66.8 ° (c - 0.296 in water).

Example 39

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

This compound is prepared analogously to the process described in Example 20 from 5.76 g of sydnon-3-acetic acid and 14.95 g of 7-amino-3-desacetoxy-3 - [(1,2,5,6-tetrahydrohydrocarbon) 2-methyl-5,6-dioxo-as-triazin-3-yl) thio] cephalosporanic acid. Yield 7.0 g (33% of theory).

Melting point from 200 ° C (dec.); -25.5 ° (c = 0.227).

Preparation of the sodium salt of (7R) -3 - [([1- (dimethylamino) -1,2-dihydro-2-oxo-4-pyrimidinyl] thio) methyl] -7- [2- (2-thienyl) acetamido] - 3-cephem-4-carboxylic acid.

Example 40.

36

DK 153155 B

This compound is prepared analogously to the process described in Example 1 from 3.34 g of cephalothin sodium salt and 1.42 g of 1,2-dihydro-1-dimethylamino-4-mercapto-2-oxo-pyrimidine. Yield 2.4 g (57% of theory). Melting point from 165 ° C (dec.); [α] β ° - -65.2 ° (c - 0.557 in water).

Example 41.

Preparation of the sodium salt of (7R) -3 - ([(3-chloro-1,6-dihydro-1-methyl-6-oxo-4-pyridazinyl) thio] methyl) -7 - [(2-thienyl) acetamido] -3-cephem-4-carboxylic acid.

This compound is prepared analogously to the procedure described in Example 1 from 8.36 g of cephalothin sodium salt and 3.7 g of 3-chloro-1,6-dihydro-4-mercapto-1-methyl-6-oxo-pyridazine. Yield 4.7 g (44% of theory). Melting point 225 - 230 ° C (decomposition); [.alpha.] D @ + + 5.35 "(c - 0.522 in water).

The 3-chloro-1,6-20 dihydro-4-mercapto-1-methyl-6-oxo-pyridazine used in the process described above can be prepared as follows:

To a solution of 17.9 g of 3,4-dichloro-1,6-dihydro-1-methyl-6-oxo-pyridazine in 200 ml of methanol is added a solution of 14.8 g of sodium hydrogen sulfide monohydrate in 200 ml of methanol. . The reaction mixture is stirred for 1 1/2 hours at 25 ° C under nitrogen atmosphere. Then, a little insoluble matter is filtered off and the filtrate is evaporated in vacuo. The residue is suspended in 150 ml of water, adjusted to acidic reaction by addition of 1N hydrochloric acid solution and extracted three times. The combined ethyl acetate extracts are washed with water and dried

DK 153155 B

37 over sodium sulfate and evaporated in vacuo. The resulting residue is recrystallized from ethanol. Yield: 9 g of yellow needles, melting point 163 ° C.

The 3,4-dichloro-1,6-dihydro-1-methyl-6-oxo-pyridazine used in the process described above can be prepared as follows: 67.75 g of 3,4-dichloro-6-hydroxy-pyridazine dissolve in 205 ml of 2N sodium hydroxide solution and dropwise add 36 ml of dimethyl sulfate. Then, the reaction mixture is heated to 70 ° C for 1/2 hour, cooled and extracted twice with chloroform. The combined chloroform extracts 10 are washed with water, dried over sodium sulfate and evaporated in vacuo.

The residue is recrystallized from high boiling petroleum ether. Yield 54 g (73% of theory). Melting point 97 ° C.

Example 42

Preparation of the sodium salt of (7R) -3 - ([(1,2-dihydro-1,6-dimethyl-2-oxo-4-pyridyl) thio] methyl) -7- [2- (2-thienyl) acetamido ] -3-cephem-4-carboxylic acid.

This compound is prepared analogously to the procedure described in Example 1 from 7.55 g of cephalothin sodium salt and 2.95 g of 1,2-dihydro-1,6-dimethyl-4-mercapto-2-oxo-pyridine. Yield 3.0 g (31% of theory). Melting point 178 - 185 ° C (dec.); [α] D = + 46.2 ° (c = 0.353 in water).

Example 43

Preparation of the sodium salt of (7R) -3 - ([(4-ethyl-1,4,5,6-tetrahydro-5,6-dioxo-as-triazin-3-yl) thio] methyl) -7 - (2-phenylacetamido) -25 3-cephem-4-carboxylic acid.

This compound is prepared analogously to the procedure described in Example 1 from 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 triazine. Yield 2.2 g

DK 153155 B

38 (21% of theory). Melting point 190 - 200 ° C (dec.); [α] β ° - + 19.8 ° (c - 0.339 in water).

Example 44

Preparation of the Disodium Salt of (7R) -7 - [(RS) -2-Sulfo-2-phenyl-acetamido] -3 - ([(1,4,5,6-tetrahydro-4-ethyl-5,6-yl) dioxo-as-triazin-3-yl) thiomethylmethyl-3-cephem-4-carboxylic acid.

9.07 g (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-cephem-4-10 carboxylic acid sodium salt is dissolved in 100 ml of water and 2.8 g of sodium sulfite are added. The reaction solution is stirred at 25 ° C for 4 1/2 hours and then sieved to pH 2 by the addition of 2N hydrochloric acid solution. The resulting precipitate is filtered off and discarded.

The filtrate is extracted twice with 100 ml of ethyl acetate each time.

The ethyl acetate extracts are also discarded. The aqueous phase containing the desired substance is then evaporated in vacuo at 40 ° C to a volume of approx. 30 ml and chromatographed on a column of 400 g Amberlite XAD-2 (grain size: 300 - ΙΟΟΟμ). Yield 1.0 g (10.6% of theory). Melting point from 230 ° C (dec.); [Α] g ° - -5.0 ° (c - 0.1 in water).

The (7R) -7 - [(RS) -2-bromo-2-phenylacetamido] -3 - ([(4,5, 4,5,6-tetrahydro-4-ethyl-5,6- dioxo-as-triazin-3-yl) thio] methyl) -3-cephem-4-carboxylic acid sodium salt is prepared analogously to the procedure described in Example 21 from 23.1 g of 7-amino-3-desacetoxy-3- [(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) thio] cephalosporanoic acid and 14.0 g of DL-α-bromophenylacetic acid chloride. Yield 10 g (28% of theory). Melting point from 190 ° C (decomposition).

Example 45

Preparation of the sodium salt of (7R) -3 - ([(1-ethyl-1,2-dihydro-2-oxo-3-pyrazinyl) thio] methyl) -7- [2- (2-thienyl) acetamido] - 3-cephem-4-carboxylic acid.

DK 153155 B

39

This compound is prepared analogously to the process described in Example 1 from 6.27 g of cephalothin sodium salt and 2.50 g of 1-ethyl-1,2-dihydro-3-mercapto-2-oxo-pyrazine. Yield 5.0 g (65% of theory). Melting point from 175 ° C (dec.); [e] §® = + 12.2 ° (c - 0.5 in water).

The 1-ethyl-1,2-dihydro-3-mercapto-2-oxo-pyrazine used for the process described above can be prepared as follows:

To a solution of 22.2 g of sodium hydroxide sulfur-monohydrate in 1000 ml of methanol is added 23.7 g of 1-ethyl-3-chloro-1,2-dihydro-2-oxo-pyrazine and 10 stir for 3 hours at 25 ° C. The precipitated sodium chloride is filtered off and the yellow filtrate is evaporated in vacuo at 40 ° C. The evaporation residue is recrystallized from ethanol. Yield 8.0 g (34% of theory) of yellow crude. For purification, 5.0 g is suspended in 50 ml of 0.5N hydrochloric acid solution, which is strongly acidified with the addition of 10 ml of 2N hydrochloric acid solution, then the mixture is stirred for 10 minutes at 25 ° C and stored overnight in a refrigerator. The orange-yellow crystals thus formed (3.65 g) are isolated by suction filtration, washed with a small amount of ice water and dried in vacuo at 50 ° C. Melting point 204 - 206 ° C (dec.).

Example 46.

Preparation of the sodium salt of (7R) -3 - ([(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) thio] methyl) -7- [2 - (2-Thienyl) ace t -amido] -3-cephem-4-carboxylic acid (variant of the procedure described in Example 1).

4.0 g of (7R) -3- (azidomethyl) -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid sodium salt (m.p. 170 DEG C. decomp.; = + 134.4 ° (c = 0.5 in water)) is stirred in 100 ml of buffer at pH 7.0 with 2.07 µl, 4,5,6-tetrahydro-4-ethyl-5,6- dioxo-3-mereapto-as-triazine and 1.01 g of sodium bicarbonate for 24 hours at 50-55 ° C under a nitrogen atmosphere. The reaction mixture is then cooled to 25 ° C and adjusted to pH 2 by the addition of 2N hydrochloric acid solution. The crude acid thus precipitated is isolated by suction filtration,

DK 153155 B

40 is washed with water to be purified and then stirred with 100 ml of ethyl acetate for 10 minutes. The acid thus purified is isolated by suction filtration (1.3 g), suspended in 25 ml of methanol and 2.5 ml of a 2N solution of 2-ethylcaproic acid sodium salt in ethyl acetate is added to form a solution. By dilution with 100 ml of ethyl acetate, the desired sodium salt is precipitated. Yield 1.25 g (24% of theory). The substance thus obtained is identical in all properties to that of Example 1.

Example 47.

Preparation of the sodium salt of (7R) -3 - ([(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl) -7- [2- (1-tetrazolyl) acetamido] - 3-cephem-4-carboxylic acid.

This compound is prepared analogously to the process described in Example 20 from 6.4 g of tetrazole-1-acetic acid and 17.75 g of 7-amino-3-desacetoxy-3 - [(1-amino-1,2-dihydro-2 2-oxopyrimidin-4-yl) -thio] cephalosporanoic acid. Yield 8.0 g (33% of theory); mp 190 DEG C. (decomposition).

Example 48.

Preparation of dry ampoules for intramuscular administration: In a usual manner, a lyophilisate of 1 g of the sodium salt of (7R) -3 - ([(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxosase) is prepared) -1-thiazole-3-yl) -thio] methyl) -7- [2- (1H-tetrazol-1-yl) acetamido] -3-cephem-4-carboxylic acid and this is filled into an ampoule. Prior to administration, add 2.5 ml of a 2% lidocary hydrochloride solution.

Claims (29)

1. C r 2 -ch-co-nh - ^^ R 3 ^ - N vXx CH 2 ~ 0 Ό wherein R, R and RJ have the meaning given above and R represents a salt protected by an inorganic or tertiary organic base carboxy group, and denotes a leaving group, in the presence of water, reacting with a compound of general formula III HSY III 15 where Y has the meaning given above and the protecting group is split off, or b) a compound of general formula IV X "-SY IV where Y has the meaning given above and X "represents a group 20 of the formula * lu" 2 "-j-j 'S" j J-u ch2- ° R DK 153155 B where R and r is reacted with an acid of the general formula V R2-CH-COOH in V Rd 5 where R 1 and R 2 have the meaning given above, or with a reactive functional derivative thereof, the protecting group is cleaved and the reaction product, if desired, is converted into a salt. 1. Analogous Process for Preparation of Cephalosporins of General Formula I Process according to claim 1, 10, characterized in that (7R) -3 - ([(1,4, 5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazine-3 yl) thio] methyl} -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid and salts thereof. Process according to claim 1, characterized in that (7R) -3 - ([(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl) is prepared) ) thio] methyl} -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid and salts thereof. Process according to claim 1, characterized in that (7R) -3- {[(1,4,5,6-te trahydro-4-al ly 1 - 5,6-dioxo-as-tr iaz in - 3-yl) thio] methyl} - 7 - [2- (2-20 thienyl) acetamido] -3-cephem-4-carboxylic acid and its salts. Process according to claim 1, characterized in that (7R) -3 - {[(1,4,5,6-thea trahydro-4-butyl-5,6-dioxo-as-triazin-3-yl) is prepared ) thio] methyl} -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid and its salts. 5 X '-W1 II where X' represents a group of formula R1 H I> Process according to claim 1, characterized in that (7R) -3 - {[(1,4,5,6-tetrahydro-4- (2-methoxyethyl) -5,6-dioxo-as-triazine) is prepared. 3-yl) thio] methyl} - 7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid and its salts. DK 153155 B ΡΓΛ: ηίίί ·. · 3!: ·: Γϋ ..- ί ..! η <7/1 ί '·· η! ~ J-!> .. · / 44 v r.r.s.nr. Ίηΐ / ηζ Process according to claim 1, characterized in that (7R) -3- {[(1,4,5,6-te trahydro-1,4-dime thyl-5,6-dioxo-as - trazazin-3-yl) thio] methyl} -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid and its salts. Process according to claim 1, characterized in that (7R) -3- {[(1,4,5,6-thea trahydro-1,4-diethyl-5,6-dioxo-as-triazine-3) is prepared. -yl) thio] methyl} -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid and salts thereof. Process according to Claim 1, 10, characterized in that (7R) -3 - {[(1,2,5,6-tetrahydro-1-ethyl-5,6-dioxo-as-triazin-3-yl) is prepared ) thiomethyl) -7- [2- (2-thienyl) acetamido] -3-cephem-4-carboxylic acid and salts thereof. Process according to claim 1, characterized in that (7S) -7-methoxy-3-15 {[(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazine) is prepared. -3-yl) thio] methyl) -7- [2- (thienyl) acetamido] -3-cephem-4-carboxylic acid and salts thereof. X-S-Y I wherein X represents a desacetoxy-cephalosporinyl group of formula r1 B I I r2-ch-co-nh - K "I, IL RJ s? -— CH2" 0 in COOH where R ^ represents hydrogen or methoxy, R ^ represents cyano, 4- pyridylthio, n-butyl, isobutyl, phenyl, hydroxyphenyl, cyclohexyl, 2-thienyl, 2-furyl, 1-tetrazolyl, 1-triazolyl, 1 -pyrazolyl or 3-sydnonyl, and R ^ is hydrogen, hydroxy, hydroxymethyl, amino, azido, carboxy or sulfo, wherein from various groups R ^ may be substituted by hydroxy, halogen, lower alkyl or lower alkoxy, and if a pyridylthio group, R 1 is hydrogen, and Y represents at least one of the lower alkyl, lower alkenyl nitrogen atoms, lower alkoxy substituted lower alkyl, lower alkoxy, amino, mono- or di (lower alkyl) amino substituted and optionally by one or more lower alkyl, halogen or oxo substituted carbon atoms, pyrimidonyl, pyrazonyl, pyridazonyl or triazonyl group, the "lower" throughout referring to groups DK 153155 B having not more than 6 C atoms, or salts of these compounds and hydrates of these salts, characterized a) a compound of the general formula II Process according to claim 1, characterized in that (7R) -3-1 [(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl) thiojmethyl) -7- [2- ( 2-thienyl) acetamido] -3-cephem-4-carboxylic acid and its salts. Process according to claim 1, characterized in that (7R) -3 - {[(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl) -7- [2- (2-thienyl) acetamido] -25 3-cephem-4-carboxylic acid and its salts. Process according to claim 1, characterized in that (7R) -3- {[(1-butoxy- / 1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl) -7- [ 2- (2- thienyl) acetamido] -3-cephem-4-carboxylic acid and its salts. A process according to claim 1, DK-1,231 dihydro-5-methyl-2-oxo-4-pyrimidinyl) thiomethyl} -7- (2- (2-thienyl) acetamido] -3-cephem-4 carboxylic acid and salts thereof. Process according to claim 1, characterized in that (7R) -3 - {[(1,4-5 dimethyl-1,6-dihydro-6-oxo-4-pyrimidinyl) thiomethyl} -7- [2 - (2- (thienyl) acetamido] -3-cephem-4-carboxylic acid and its salts. Process according to claim 1, characterized in that (7R) -3 - {[(1-ethyl-1,4-dihydro-6-methyl-4-oxo-2-pyrimidinyl) thiomethyl] -7- [ 2- (2-10 thienyl) acetamido] -3-cephem-4-carboxylic acid and its salts. Process according to Claim 1, characterized in that (7R) -7- (2-cyanoacetamido) -3 - {[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo) is prepared. as-triazin-3-yl) thiomethyl-3-cephem-4-carboxylic acid and its salts. Process according to claim 1, characterized in that (7R) -3 - {[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) is prepared) thio J methyl} -7 - [(R) -mandelamido] -3-cephem-4-carboxylic acid and its salts. Process according to Claim 1, 20, characterized in that (7R) -7- [(R) -2-amino-2-phenylacetamido] -3 - {[(1,4,5,6-tetrahydro-4) is prepared. -ethyl-5,6-dioxo-as-triazin-3-yl) thio] -methyl} -3-cephem-4-carboxylic acid and its salts. Process according to claim 1, characterized in that (7R) -3 - {[(1,4,5,6-25 tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) is prepared ) thio] methyl) -7- [2- (5-oxo-1,2,3-oxodiazolidin-3-yl) acetamido J-3-cephem-4-carboxylic acid and its salts. Process according to claim 1, characterized in that (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-cephem-4-carboxylic acid and its salts. DK 153155 B Process according to claim 1, characterized in that (7R) -3 - {[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) is prepared) thio] methyl} -7- [2- (1-H-triazol-1-yl) acetamide] -3-cephem-4-carboxylic acid and its salts. Process according to claim 1, characterized in that (7R) -3- {[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) is prepared) thio] methyl} -7 - [(R) -2-hydroxyhexanamido] -3-cephem-4-carboxylic acid and its salts. Process according to Claim 1, 10, characterized in that (7R) -3 - {[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) is prepared ) thio] methyl} -7 - [(R) -2-hydroxy-4-methylvaleramido] -3-cephem-4-carboxylic acid and its salts. Process according to claim 1, characterized in that (7R) -3 - {[(1, 4,5, 6,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) is prepared ) thio] methyl} -7 [(R) -2-hydroxy-2- (cyclohexyl) acetamido] -3-cephem-4-carboxylic acid and salts thereof. Process according to claim 1, characterized in that (7R) -3 - {[(1,4,5,6-20 tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl) is prepared ) thio] methyl} -7- [2- (2-furyl) acetamido] -3-cephem-4-carboxylic acid and salts thereof. Process according to claim 1, characterized in that (7R) -3 - {[(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl] -7- [2- (3-Sydnonyl) acetamido] -25 3-cephem-4-carboxylic acid and its salts. Process according to claim 1, characterized in that (7R) -3 - {[(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl) thio] methyl] -7- [2- (1-tetrazolyl) acetamido] -3-cephem-4-carboxylic acid and its salts. DK 153155 B Process according to claim 1, characterized in that (7R) -7- (R) -mandelamido-3 - {[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo- (3-cephem-4-carboxylic acid and salts thereof.