CS228145B2 - Preparation of derivatives of 7-/2-hydroximino or substituted oxymino-2-/amino-substituted-1,2,4-thiadiazolyl/acetamido/-3-substituted methyl-3-cefem-4-carboxylate or 7-/2-hydroxyimino or substituted oxyimino 2-/amino/substituted/1,2,4-thiadiazolyl/acetamido/-3-substituted methyl-3-cefem-4-karboxylic acid - Google Patents

Description

The invention relates to a process for the preparation of novel cephem compounds and their pharmaceutically acceptable salts, wherein the new cephem compounds and their pharmaceutically acceptable salts have antimicrobial activity and can therefore be used for the treatment of infectious diseases in humans and animals. The novel ceremic compounds and their pharmaceutically acceptable salts are effective against numerous pathogenic microorganisms. They are therefore used as active ingredients of pharmaceutical preparations for the treatment of sick people and animals.

The present invention provides novel cephem compounds which are 7- [2-hydroxyimino- or substituted oxyimino-2- (amino-substituted-1,2,4-thiadiazolyl Jacetamido) -3-substituted methyl-3- derivatives. cephem-4-carboxylate or ⁶ 7- [2-hydroxyimino- or substituted oxylmino-2- (amino-substituted-1,2,4-thiadiazolyl) acetamido] -3-substituted methyl-3-cephem-4-carboxylic acid

(I) where is

R ¹ an amino group,

R @ ² is hydrogen, C1 -C4 alkyl optionally substituted by carboxy, C2 -C5 alkoxycarbonyl, C2 -C5 phenylalkoxycarbonyl, C1 -C4 alkylthio, phenyl or a halogen atom, a carbon atom, a C 2 -C 4 alkynyl group, a C 2 -C 4 alkynyl group, a C 1 -C 6 cycloalkyl group, a C 3 -C 6 cycloalkenyl group, or an oxo-substituted tetrahydrofuryl group,

R3 is a group of formula

where it means

X is hydrogen or carbamoyl; and

R ⁴ is COO- or is

R3 is 2-alkyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-trlazinylthio having 1 to 4 carbon atoms in the alkyl moiety; and

R4 is carboxy, the wavy line means that includes syn and anti isomers, with the proviso that R2 does not represent a cyclopentyl group, a cyclopentenyl group or a l-methyl-l-carboxyethyl group, where R3 represents a group of formula ^{± N} \ 2 ^ ~ ^CíJNH 2.

and pharmaceutically acceptable salts thereof, by reacting a compound of formula II

where

R ³ and R 4 are as defined above, or its reactive derivative at the amino group or a salt thereof, with a compound of formula III

where

R1 and R2 are as defined above, or a reactive derivative thereof on the carboxy group or a salt thereof, and optionally from a compound of formula I, wherein R2 represents a (C5 -C5) alkoxycarbonylalkyl group having from 1 to 4 carbon atoms. C 2 -C 5 alkyl or C 2 -C 5 phenylalkoxycarbonylalkyl eliminates the carboxy-protecting group to form a compound of formula I wherein R 2 is C 1 -C 4 carboxyalkoxy in the alkyl moiety, or from the obtained compound of formula I wherein R 2 is a triphenylalkyl group having 1 to 4 carbon atoms in the alkyl moiety, the hydroxy protecting group is eliminated to form a compound of formula I wherein R 2 is hydrogen.

Some of the starting materials used in the process of the invention are novel. . Some of the compounds of formula (II) may be prepared by the following methods:.

HOOC-CH-CH 2 CONH NH co

AND

NH

COOH (IX) or. her salt

Elimination of the amino protecting group at the 7-position

НООС-СМЧСН ^ СШ / ^- ун co

coo

I NH

(XI) or a salt thereof

the state of equilibrium mutual and such tautomerism can be expressed by the equation:

(XII) or a salt thereof wherein

X is as defined above and

R ^3e represents a group which may be substituted by a group of the general formula

where

X is as defined above.

Of the above compounds, the compounds of formula XI are novel.

As far as the compounds of the formula I and the starting materials of the formula III are concerned, these also include the tautomeric isomers.

That is, in the case of a group of the general formula

(where R ¹ is as defined above). contained in the molecule being prepared and the starting material, the group of the formula may also alternatively be present in its tautomeric form where:

R1 and are as defined above.

These types of tautomerism between the amino compound and the corresponding amino compound, as mentioned above, are well known in the literature and are obviously known to those skilled in the art. branch that. For example, both tautomeric forms of the isomers can be readily converted from one another and both tautomeric isomers belong to the same category of compound as such.

The invention therefore relates to both tautomeric forms of the compounds to be prepared and the starting materials. However, both prepared and starting compounds containing a group of such tautomeric isomers are referred to. always for a group of formulas

In addition, the compounds of formula (I), starting materials of formula (III), include prepared compounds of starting materials in the form of syn isomers and anti isomers. about their mixtures. For example, in the case of a compound of formula I, the syn isomer is a geometric isomer having a partial structure corresponding to the formula

RJ o R ² . each have the above-mentioned meaning of the anti-isomer. se. refers to another geometric isomer having a partial structure corresponding to the general formula

wherein (R 1 represents an imino group or a protected imino group). Both of these. groups ^: 'are' in

where

R 1 and R ² have the significances given above.

As for the other compounds to be prepared and the starting materials include the syn isomer and the anti isomer, such as the geometric isomers elucidated for the compound of formula I.

Suitable pharmaceutically acceptable salts of the compounds of formula (I) are conventional non-toxic salts, including metal salts such as alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium salts, magnesium salts, ammonium salts, organic base salts such as for example, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, organic acid salts such as acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, inorganic acid salts, such as, for example, the hydrochloride, hydrobromide, hydroiodide, thiocyanate, sulfate, phosphate, or salt of amino acids such as arginine, an aspartic acid or glutamic acid salt and the like.

By lower alkyl groups R @ 2 is C1 -C6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, tert-pentyl, hexyl and the like. similar groups, and preferably lower alkyl refers to a group having 1 to 4 carbon atoms.

The lower alkyl group R 2 'may be substituted with one to three suitable substituents, such as halogen atoms, for example chlorine, bromine, fluorine or iodine, carboxy, lower alkylthio, for example methylthio, ethylthio, propylthio, butylthio, aryl , for example, phenyl tolyl, xylyl, mesityl, cumenyl or the like.

Suitable alkenyl groups include vinyl, allyl, isopropenyl, 1-propenyl, 2-butenyl, 3-pentenyl and the like, preferably having from 2 to 4 carbon atoms.

Suitable lower alkynyl groups may include groups having 2 to 6 carbon atoms, such as, for example, ethynyl, 2-propynyl, 2-butynyl, 3-pentinyl, 3-hexinyl or the like, preferably 2 to 6 groups. 4 carbon atoms.

Suitable cyclo (lower) alkyl groups may include groups having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like, preferably groups having 4 to 6 carbon atoms.

Suitable cyclophenyl) alkenyl groups may include groups having 3 to 6 carbon atoms, such as cyclopentenyl, cyclohexenyl or the like, preferably groups having 5 to 6 carbon atoms.

The symbol used in formula I between a N atom and a group of formula O-R 2 means that both the son and the anti isomers of the compound are included.

A compound of formula I is prepared by reacting a compound of formula II or a reactive derivative thereof at the amino group or a salt thereof with a compound of formula III or a reactive derivative thereof at a carboxy group or a salt thereof.

A suitable reactive derivative at the amino group of a compound of formula (II) may include conventional reactive derivatives used in amidation, such as an iminotype or a Schiff base type tautomeric enaminotype isomer thereof. reacting a compound of Formula II with a carbonyl compound; a slyl derivative formed by reacting a compound of Formula II with a silyl compound such as bis-trimethylsilyl acetamide, trimethylsilylacetamide or the like; a derivative formed by reacting a compound of formula II with phosphorus trichloride or phosgene and the like.

A suitable salt of a compound of formula (II) may include an acid addition salt such as an organic acid addition salt such as acetate, maleate, tartrate, benzenesulfonate, toluenesulfonate, or an inorganic acid such as hydrochloride, hydrobromide, sulfate, phosphate, metal salt. such as sodium salt, potassium salt, calcium salt and magnesium salt, ammonium salt, organic amine salt such as triethylamine salt, dicyclohexylamine salt and the like.

Suitable reaction derivatives on the carboxy group of a compound of formula III may include acid halides, acid anhydride, activated amide, activated ester, and the like. Suitable examples include acid chloride, acid azide, mixed acid anhydride with an acid such as a substituted phosphoric acid such as dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid; dialkyl phosphoric acid, sulfuric acid, thiosulfuric acid, sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid such as pivalic acid, pentanoic acid, isopentanoic acid, 2-ethyl-butyric acid, acetic acid or trichloro228145 acetic acid or aromatic a carboxylic acid such as benzoic acid; symmetric acid anhydride; activated with amidimidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester such as cyanomethyl ester, methoxymethyl ester, dimethylimidomethyl] (CH 3) 2 N = CH-ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenyl nitrophenyl ester, phenylazophenyl ester, phenylazophenyl ester , p-cresylthioester, carboxymethylthioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolylthioester or ester with N, N-dimethylhydroxylamine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide or 1-hydroxy- 6-chloro-1H-benzotriazole and similar derivatives. These reactive derivatives may optionally be selected from those used in connection with the compound of formula III.

Salts of compounds of formula III may be a salt with inorganic bases such as alkali metal salts such as sodium and potassium, or salts with metals ^and] kaiických earth metals such as calcium and magnesium salts. salts with organic bases such as trimethylamine, triethylamine, pyridine, acid salts such as hydrochloric or hydrobromic acid or the like.

The reaction is generally carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, Ν, Ν-dimethylformamide, pyridine or any organic solvent that does not adversely affect the reaction. Of these solvents, hydrophilic solvents can be used in admixture with water.

When the compound of formula (III) is used in free acid or salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as N, N-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinethylcarbodiimide, N-cyclohexyl- N'- (4-diethylaminocyclohexyl) carbodiimide, N, N-diethylcarbodiimide, Ν, Ν-diisopropylcarbodiimide, N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide, Ν, Ν-carbonylbis (2-methylimidazole), pentamethylenketene-N-cyclohexyl , diphenylketene-N-cyclohexylimine, ethoxyacetylene, ethyl polyphosphate, isopropyl polyphosphate, diethylphosphoric chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, oxalyl chloride, triphenylphosphine, N-ethyl-7-hydroxybenzisoxazoliumfluorobisulfonate-5-fluorobisulfonate 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole, the so-called Vilsmeier reagent, eg (chloromethylene) dimethylammonium chloride prepared by the reaction of dim ethylformamide with thiohyl chloride or phosgene, a compound prepared by reacting dimethylformamide with oxy10 phosphorus chloride or in the presence of a similar reagent.

The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal hydroxide, an alkali metal bicarbonate, an alkali metal carbonate, an alkali metal acetate, tri- (lower-alkylamine, pyrydine, N- (lower alkylmorpholine, N, N-di) (lower alkylbenzylamine, N, N-di (lower jalkylaniline, as exemplified below) or in the presence of similar bases. If the base or the condensing agent is liquid, it can also be used as a solvent. cooling or at room temperature.

In this reaction, the syn-isomers of the compounds of the formula I can be obtained, preferably by reacting the compound of the formula I with the syn-isomer of the compound of the formula III.

In the above reactions and / or in the aforementioned post-treatment of the reaction products of the invention, the aforementioned geometric isomer and / or the tautomeric isomer may optionally be converted to another geometric isomer and / or the tautomeric isomer and these cases are also included within the scope of the invention .

When the compound of formula (I) prepared has a free carboxy group and / or a free amino group, it can be converted into a pharmaceutically acceptable salt as described above by known methods.

The compound of formula (I) prepared by the process of the invention has significant antimicrobial properties and high antibacterial activity and inhibits the growth of numerous microorganisms including pathogenic gram-positive and gram-negative bacteria.

For the therapeutic administration of the cephalosporin compounds prepared by the process of the invention, they are used in the form of pharmaceutical preparations comprising a compound of formula I together with pharmaceutically acceptable carriers, such as organic or inorganic solids or liquids, suitable for oral, parenteral or external administration.

The pharmaceutical preparations may be in solid form, such as in the form of capsules, tablets, dragees, ointments or suppositories, or in liquid form, such as solutions, suspensions or emulsions. Optionally, the pharmaceutical preparations may contain adjuvants, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives in addition to the compound of formula (I).

Although the dose of the compound of formula I may vary depending on the age and condition of the patient, a mean single dose of about 50 mg, 100 mg, 250 mg and 500 mg of the compound of formula I has proven effective for treating infectious diseases caused by numerous pathogenic bacteria. In general, a daily dose of 1 mg / individual, up to 1000 mg / individual or greater can be administered.

In order to demonstrate the efficacy of the compounds of the formula I according to the invention, the results of the antimicrobial activity tests of the representative compounds of the formula I prepared according to the invention are given below.

Test method

Full loop overnight. cultured cultures of each test strain in trypticase soy broth (10 ⁸ viable cells per ml) were applied to the infusion agar (HI-agar) containing graduated antibiotic concentrations and expressed as the minimum inhibitory concentration (MIC) as m m / ml after incubation for 20 hours at 37 ° C.

Test compounds

1) 7- [2-Ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-pyridinomethyl) -3-cephem-4-carboxylate (syn isomer)

2) 7- [2-Ayloxy-amino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-pyridinomethyl) -3-cephem-4-carboxamide syn isomer]] 7- [2- (2-Propinyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl] acetamido] -3- (1-pyridinomethyl) -3-cephem- 4-carboxylate (syn isomer)

4) 7- (4-cyclopentyloxyimino) -4- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-methyl-4-carboxylate) -3-cephem-4-carboxylate (syn isomer)

5) 7- (2- (2-cyclopenten-1-yloxyimino) -2-

- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-pyridinomethyl) -3-cephem-4-carboxylate (syn isomer)

6) 7- [2-Methoxyimino-2- (5-amino-1,2,4-

-thiadiazol-3-yl] -3- (1-pyridinio methyl) -3-cephem-4-carboxylate (syn isomer)

7) 7- (2-Isopropoxyimino) 2- (5-amino-1,2,4-

thiadiazol-3-yl) acetyl-3- (2-methyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazin-3-yl) thiomethyl-3-cephem-4 -carboxylic acid (syn isomer)

8) 7- [2-Ethoxyimino 12,2 (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (4-carbamyl-1-pyridiniomethyl) -3-cephem-4-carboxylate (syn isomer)

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As regards the nomenclature of compounds (3-pyridinium methyl compounds) prepared by the process of the invention, there is some established nomenclature. For example, compound A is referred to as 7- [2-methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-pyridinomethyl) -3-cephem-4 carboxylate (syn isomer) or N- [7- (2-methoxyimino-2- (5-amino-1,2,4-thiadiazol-3yl) acetamido [-3-cetem-3-ylmethyl] pyridinium-4 Furthermore, the hydrochloric acid salt of compound (B) is referred to as 1 - [(7-amino-4-carboxy-3-cephem-3-yl) methyl] pyridinium chloride, or N- (7-amino- 3-chloro-3-ylmethyl] pyridinium-4-carboxylate hydrochloride.

Other compounds prepared by the process according to the invention and falling within the scope of the invention are known in the art.

The following examples illustrate the process according to the invention but do not limit it in any way.

Preparation 1

Preparation of methyl 5-amino-1,2,4-thladiazole-3-carboxylate

To a solution of 1-ethoxycarbonylformamidine hydrobromide (16.6 g) in absolute methanol (84 mL) was added a solution of sodium (1.93 g) in absolute methanol (42 mL) at 0 ° C. To the mixture were added alternately bromine (12.8 g) and a solution of sodium (1.93 g) in absolute methanol (42 mL) at 0 ° C, and then potassium thiocyanate (8.1 g) in absolute methanol was added to the suspension. (100 mL). The reaction mixture was stirred for one hour at 0 ° C and for another six hours at room temperature. The mixture was evaporated to dryness through cellulose powder and the filtrate. The residue was dissolved in a mixture of ethyl acetate and water, and then the ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was triturated with diethyl ether to give methyl 4-amino-1H-thiadiazole-3-carboxylate (9.0 g), m.p. 202-205 ° C.

LU (nujol):

3400, 3250, 3100, 1710, 1610, 1540 cm

NMR (d6 -DMSO) δ:

3.85 (3 H, s),

8.25 (2 H, s)

Preparation 2

Preparation of methyl 5-formamido-1,2,4-thiadiazole-3-carboxylate

To a mixture of formic acid (33 g) and acetic anhydride (22 g) was added. methyl 5-amino-1,2,4-thiadiazole-3-carboxylate (6.2 g) was added, and then the mixture was stirred at room temperature for two days. The reaction mixture was concentrated under reduced pressure and the residue was triturated with a mixture of diethyl ether and n-hexane to give methyl 5-formamido-1,2,4-thiacliazole-3-carboxylate (7.2 g), m.p. 215 [deg.] C.

1C (nujol):

3100, 1720, 1680 cm ^-1

NMR (d6 -DMSO):

3.90 (3 H, s),

8.85 (1H, s)

Preparation 3

Preparation of 5-formamido-3- (2-methylthio-2-methylsulfinylacetyl) -1,2,4-thiadiazole

To a mixture of methyl 5-formamido-1,2,4-thiadiazo-3-barboxylate (9.2 g) and methyl methylthiomethylsulfoxide (6.1 g) in N, N-dimethylformamide (100 mL) was added 50% sodium hydride (7.1 g) with cooling in an ice bath. The mixture was stirred for one hour at ambient temperature and for another hour at 40 ° C. After cooling to ambient temperature, methylene chloride (300 mL) was added to the reaction mixture, and the resulting precipitate was collected by filtration and washed with methylene chloride. The precipitate was added to a stirred mixture of hydrochloric acid (14.7 mL), ice water (200 mL) and methylene chloride (200 mL). The insoluble material was filtered off and the methylene chloride layer was separated from the filtrate. The solution was dried over anhydrous magnesium sulfate, evaporated and the residue triturated with diethyl ether to give 5-formamido-3- (2-methylthio-2-methylsulfinylacetyl) -1,2,4-thiadiazole (4.5 g) at a temperature mp 130-132 ° C,

IR (nujol):

3100, 1680, 1670 cm

NMR (d6 -DMSO) <5:

2,22 1

I (3H. 2s)

2.28 J

2,68 | (212, 2s)

2.85 I

5.70 (1H, 2s)

5.80

8.86 (1 H, s)

Preparation 4

Preparation of 5-methyl- (5-formamido-1,2,4-thiadiazol-3-yl) thi. oglyoxylate

A mixture of 5-formamido-3- (2-methylthio-2-methylsulfinylacetyl) -l, 2 ₅ 4-thiadiazole (0.85 g) and sodium periodate (0.2 g) in glacial acetic acid (10 ml) was stirred . 45 min at 70 ° C. The reaction mixture was evaporated and the residue was dissolved in a mixture of ethyl acetate and water. The pH of the mixture was adjusted to 7 with aqueous sodium bicarbonate and the mixture was treated with an aqueous solution of thiosulfate. sodium. The organic layer was separated, dried over anhydrous magnesium sulfate. and evaporate to dryness. The residue was triturated with diethyl ether and petroleum ether to give 5-methyl (5-formamide-1,2,4-thiadiazol-3-yl) thioglyoxylate (280 mg), m.p. 186-187 ° C.

IR (nujol):

3100, 1680, 1660 cm @ -1

NMR (d6 -DMSO)

5:

2.55 (3 H, s),

8.95 (1 H, s)

Preparation 5

Preparation of 2-methoxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

A mixture of S-methyl- (5-formamido-1,2,4-thiadiazol-3-yl) thioglyoxylate (231 mg) in methanol (2 mL) and 1 N aqueous potassium hydroxide solution (3.5 mL) was stirred for one hour at The mixture was adjusted to pH 7.6 with hydrochloric acid, then O-methylhydroxylamine hydrochloride (90 mg) was added and stirred for 30 minutes at ambient temperature. The pH of the concentrated aqueous solution was adjusted to 4 with hydrochloric acid and washed with ethyl acetate, the pH of the aqueous layer was adjusted to 1 with hydrochloric acid, saturated sodium chloride, and extracted with ethyl acetate. Collected by filtration and dried to give 2-methoxyimino-2- (5-formylamido-1,2,4-thiadiazol-3-yl) -acetic acid (syn isomer) (80 mg), m.p. 185 up to 186 degrees Celsius.

IC (nujol):

3150, 1720, 1690 cm ¹

NMR (d6 -DMSO)

8:

3.98 (3 H, s),

8.84 (1 H, s)

Preparation 6

Preparation of 2-methoxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

A mixture of 5-formamido-3- (2-methylthio-2-methylsulfinylacetyl) -l, _2? 4-thiadiazole (3.2 g) and sodium periodate (0.8 g) in glacial acid. acetic acid (32 mL) was stirred at 70 ° C for 45 min. The reaction mixture was evaporated and the residue was washed with n-hexane and then methanol (20 ml) and 1N aqueous potassium hydroxide solution (40 ml) were added. The solution was stirred for one hour at ambient temperature. The pH of the reaction mixture was adjusted to 8 N with hydrochloric acid, then O-methylhydroxylamine hydrochloride (0.96 g) was added and stirred for 1 hour at ambient temperature. The reaction mixture was neutralized with aqueous sodium bicarbonate solution and concentrated to remove methanol. The resulting aqueous solution was washed with ethyl acetate, adjusted to pH 10 with saturated sodium chloride hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, evaporated, and the residue triturated with diisopropyl ether to give 2-methoxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) ( 1.02 g), m.p. 185-186 ° C.

Preparation 7

Preparation of 2-methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer)

A solution of 2-methoxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (1.4 g) in 1 N aqueous sodium hydroxide solution (19.1 mL) was maintained. The solution was treated with concentrated hydrochloric acid (1.9 mL) with cooling in an ice bath, saturated with sodium chloride, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated. The residue was triturated with diethyl acetate to give 2-methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (0.9 g), m.p. 180 to 182 ° C (dec.).

IC (nujol):

3450, 3250, 3100, 1715, 1610, 1530 cm 1

NMR (d6 -DMSO):

3.90 (3 H, s),

8.10 (3H, broad s)

Preparation 8

A mixture of 5-formamido-3- (2-methylthio-2-ethylsulfinylacetyl) -1,2,4-thiodiazole (10-g) and sodium periodate (2.0 g) in glacial acetic acid (50 ml) Stir for 50 minutes at 70 ° C. The solvent was evaporated and the residue was evaporated. - 1N aqueous sodium hydroxide solution (160 ml) was added to the residue and the mixture was stirred for one hour at ambient temperature. O-ethylhydroxylamine hydrochloride (3.5 g) was added to the reaction mixture and the solution was adjusted to pH 3-4 with 10% hydrochloric acid and then stirred for one hour at ambient temperature. Insoluble material was filtered off, the filtrate was washed with ethyl acetate, adjusted to pH 10 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was dried over magnesium sulphate and evaporated to dryness. The residue was triturated with diethyl ether and diisopropyl ether to give 2-ethoxyimino-2- (5-formamido-1,2,4-thiadlazol-3-yl) acetic acid (syn isomer) (4.5 g), m.p. 165-168 ° C (dec.).

IR (nujol):

3450, 3170, 3050, 1730, 1690, 1595,

1565 cm ^_1

NMR (d6 -DMSO)

WITH:

1.30 (3 H, t, J = 7 Hz),

4.40 (2H, q, J = 7Hz);

8.87 (1 H, s)

Preparation 9

The following compounds were obtained in a manner similar to Preparation 8.

1. 2-Propoxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), m.p. 168-170 ° C (dec.).

IR (nujol):

3250, 3140, 1720, 1690, 1590, 1530 cm ^-1

NMR (d6 -DMSO):.

0.90 (3H, t, J = 6 Hz),

1,4- 1,9- (2H, - m),

4.17 (2H, t, J = 6 Hz),

8.85 (1 H, s)

2. 2-Isopropoxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), m.p. 180-182 ° C.

IC (nujol):

3230, 1720 - 1690, 1590 - 1530 ^cm-1

NMR (d 6 -DMSO)

S: ·. .....

1.25 '- (6H, - d, j = - 6Hz),

4.2-4.7 (1 H, - m),

8.85 (1H, s).

Preparation 10

A mixture of 2-ethoxyimino-2- (5-formamido-1,2,4-thiadiazole-2-acetic acid (syn isomer) (4.4 g) and 1N aqueous sodium hydroxide solution (54 ml) was stirred for The mixture was cooled in an ice bath, acidified with hydrochloric acid (5.4 mL) and extracted with ethyl acetate, dried over magnesium sulfate and evaporated to dryness. 2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (2.92 g), m.p. 168-170 ° C (dec.

IC (nujol):

3450, 3370, 3250, 3150, 1665, 1610,

1530 cm @ -1

NMR (d6 -DMSO)

223145 δ:

1.22 (3Η, t, J = 7Hz),

4.17 (1H, q, J = 7Hz)

8.17 (2H, broad s)

Preparation 11

In a similar manner as described in Preparation 10, the following compounds were prepared:

1) 2-Propoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), m.p. 100-103 ° C (dec.)

IR (nujol):

3620, 3520, 3350, 3120, 2600, 2500

1720, 1620, 1550 cm ¹

NMR (d6 -DMSO) δ:

1.00 (3H, t, J = 6Hz)

1.3-2.0 (2H, m),

4.13 (2H, t, J = 6 Hz),

8.17 (2H, broad s)

2) 2-Isopropoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), m.p. 152-155 ° C (dec.)

IR (nujol):

3450, 3300, 3200, 1730, 1620, 1530 cm @ -1

NMR (ds-DMSO) δ:

1.22 (6H, d, J = 61-z),

4.1 - 4.6 (1H, m),

8.20 (2H, broad s)

Preparation 12

1) A mixture of N-hydroxyphthalmide (8.15 g), triethylamine (5.05 g), N, N-dimethylformamide (60 ml) and 1-bromo-2-cyclohexene (8.05 g) was stirred for 3.5 hours. The reaction mixture was poured into water (300 mL) and the precipitated crystals were collected by filtration, washed successively with water and n-hexane and then dried to give N- (2-cyclohexen-1-yloxy) -thalimide - ( 9.8 g), m.p. 87 ° C.

IR (nujol):

1770, 1720, 1610 cm ^-1

NMR (d 6 -DMSO) .....

δ:

1.50 - 2.17 (6H, m)

4.60 - 4.77 (1H, m),

5.73 - 6.27 (2H, m),

7.91 (4H, s)

2) A mixture of Η-ΙΙζΙΐίίίίίββΗϊηίά- (58.2 g j 1-chloro-2-cyclopentene (36.9 g), triethylamine - (53.9 g) in acetonitrile (370 mL) was treated with the same according to the procedure described in paragraph 1, to give N- (2-cyclopenten-1-yloxylthalimide) (56.5 g)

IR (nujol):

1780, 1730, 1610 cm ^-1

NMR (d6 -DMSO) δ:

7.92 (3 H, s),

6.28 (1 H, m),

6.00 (1 H, m),

5.42 (1 H, m),

2.9 - 1.98 (4H, m)

Preparation 13

1) A mixture of N- (2-cyclopenten-1-yloxy) phthalimide (22.9 g) and hydrazine hydrate (4.75 g) in ethanol (115 mL) was maintained at reflux for 5 minutes. The reaction mixture was filtered. The filtrate containing (2-cyclopenten-1-yl) oxfamine was added to a solution of sodium 2- (5-orniamido-1,2,4-thiadiazol-3-yl) glyoxylate (22.4 g) in water. The mixture was adjusted to 21 with 10% hydrochloric acid, stirred for two hours and then concentrated, the pH of the concentrate was adjusted to 10 with 10% hydrochloric acid, and the precipitate was collected by filtration and dried to give 2- (2- cyclopenten-1-yl) oxyimino-2- (5-tormamido-1,2,4-thiacliazol-3-yl) Acetic acid (syn isomer) (20.0 g), m.p. 150 ° C (dec.).

IR (nujol):

3400, 3100, 1720, 1690, 1540 cm'1

NMR (d6 -DMSO) δ:

1.80 - 2.50 (4H, m),

5.30 - 5.50 (1H, m),

5.83 - 6.30 (2H, m),

8.90 (1 H, s)

2) A mixture of N- (2-cyclohexen-1-yloxy) -thalimide (40 mL), hydrazine hydrate (1.5 g) in ethanol - (40 mL) was refluxed for 5 minutes. cooled and filtered to give a filtrate containing (2-cyclohexen-1-yl) oxyamine (filtrate A) Separately a mixture of S-methyl 2- (54 (-amido-1,2,4-thiadiazol-3-yl) of thioglyoxylate (6.93 g) in aqueous 1N sodium hydroxide solution (90 ml) was stirred for 30 minutes at room temperature The reaction mixture containing 2- (5-formamido-1,2,4-thiadiazol-3-yl) The sodium glyoxylate was adjusted to pH 7 with 10% hydrochloric acid and filtrate A was added thereto, and then the pH was adjusted to 3 with 10% hydrochloric acid, and the mixture was stirred at room temperature for three hours. Ethyl acetate was added to the concentrate, and the pH of the mixture was adjusted to 110 with 10% hydrochloric acid. -cyclohexen-1-yl) oxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (2.5 g). The ethyl acetate layer was separated from the filtrate and evaporated. The residue was triturated with diethyl ether to give the same compound (1.5 g). The total yield was 4.0 grams. M.p. 190 DEG-192 DEG C. (dec.).

IC (nujol):

3550, 3400, 3200, 2500, 1690, 1590

1540 cm ^-1

NMR (d6 -DMSO)

WITH:

1.5-2.3 (6H, m),

4.73 - 5.0 (1H, m),

5.76 - 6.23 (2H, m),

8.97 (1 H, s),

13.60 (1H, broad s)

3) To a solution of sodium hydroxide (11.2 g) in water (140 mL) is added S-methyl 2- (5-formamido-1,2,4-thiadiazol-3-yl) thioglyoxylate (27 g) at temperature 10 ° C and the mixture is stirred for 30 minutes at 20 ° C. The reaction mixture containing sodium 2- (5-formamido-1,2,4-thiadiazol-3-yl) glyoxylate was cooled, adjusted to pH 7 with 10% hydrochloric acid, and cyclopenyloxyamine solution (15.3 mL) was added. g) in ethanol (150 mL). The pH of the mixture was adjusted to 3 with 10% hydrochloric acid and stirred for 1.5 hours. The pH of the reaction mixture was adjusted to 7 with aqueous sodium bicarbonate solution and then evaporated to remove ethanol. The residue was washed with ethyl acetate. Ethyl acetate was added to the aqueous layer and the pH of the mixture was adjusted to 1 with 10% hydrochloric acid. The precipitate was collected by filtration to give 2-cyclopentyloxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl). Acetic acid (syn isomer) (3.99 g). The filtrate was extracted with ethyl acetate, and the extract was dried over magnesium sulfate and then concentrated. The precipitate was collected by filtration and washed with diethyl ether to give the same compound in 8.1 g. The total yield was 12.09 g, mp 180-185 ° C (dec.).

IC (nujol):

3130, 3040, 2680, 2610, 2520, 1720

1690, 1660, 1550 cm ^-1

NMR (d6 -DMSO) <5:

1.33-210 (8H, m),

4.67 - 5.0 (1H, m),

8.88 (1 H, s),

13.50 (1 H, s)

Preparation 14

A mixture of 2- (2-cyclopenten-1-yl) oxyimino-2- (5-formamido-1,2,4-thiadlazol-3-yl) acetic acid (syn isomer) (20.0 g) and 1N aqueous sodium hydroxide solution (200 mL) was stirred for one hour at 50-55 ° C, cooled, adjusted to pH 7 with 10% hydrochloric acid, and ethyl acetate was added, and the mixture was adjusted with 10% hydrochloric acid. The extract was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated, and the residue was dusted with diisopropyl ether to give 2- (2-cyclopenten-1-yl) oxyimino-2- ( 5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), m.p. 150 DEG C. (dec.)

IC (nujol):

3300, 3150, 1710, 1620, 1520 ст ^-1

NMR (d6 -DMSO)

5:

1.80 - 2.50 (4H, m),

5.30 - 5.50 (1H, m),

5.83 - 6.30 (2H, m),

8.20 (2H, s)

Preparation 15

The following compounds were obtained in a similar manner as described in Preparation 14:

1) 2- (2-cyclohexen-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), m.p. 173 ° C.

IC (nujol):

3400, 3300, 3200, 1720, 1620, 1600, 1520 cm -1

NMR (d 6 -DMSO) δ:. '

1.50 - 2.17 (6Η, m),

4.53 - 4.83 (1Η, m),

5.57 - 6.13 (2H, m),

8.18 (2 H, s). :

2) 2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), m.p. 160-165 ° C (dec.)

IR (nujol):

3470, '3290, 3200, - 2400, 1715, 1615, -1600, 1520 cm ^-1

NMR (d6 -DMSO) δ:

1.17-2.10 (8H, m),

4.60 - 4.97 (1H, m),

8.22 (2 H, s)

A n d - 16

A mixture of 5-formamido-3- (2-methylthto-2-methylsulfinylacetyl) -1,2,4-thiadiazole (10 g) and sodium iodoate (2.0 g) in glacial acetic acid (50 mL) was stirred for 50 minutes at -70 ° C. The solvent was evaporated and the residue was washed with n-hexane. A 1N aqueous sodium hydroxide solution (160 ml) was added to the residue and the mixture was stirred for 1 hour at ambient temperature. To the reaction mixture was added (4.31 g) and the pH of the solution was adjusted to 3-4 with 10% hydrochloric acid and then stirred for a period of time. one hour at ambient temperature. The insoluble material is then filtered off, the filtrate is washed with ethyl acetate and its pH value is adjusted to 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was dried (MgSO4) and evaporated to dryness. The residue was triturated with a mixture of diethyl ether and - diisopropyl ether to give 2-allyloxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid- (Syn Isomer) (5.6 g), mp 169-172 ° C (dec.).

IR (nujol):

3130, 2500, 1720, 1690, 1590, 1550 cm ^-1

NMR (ds-DMSO) δ:

4.79 (2H, d, J = 6Hz),

5.1-5.6 (2H, m),

5.8 - 6.4 (1H, m),

8.88 (1 H, s)

Preparation 17

The following compounds were prepared in a similar manner to that described in Preparation 16 :,

1) 2- (2-Propinyloxyimino) -2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), m.p. 150-155 ° C (dec.)

IR (nujol):

3570, - 3360, 3260, 1720, 1670, 3120, 1550, 1530 cm -1

NMR (d6 -DMSO)

5:

3.55 (1 H, t, J = 2 Hz),

4.88 (2H, d, J = 2 Hz),

8.85 (1 H, s)

2) 2-Hydroxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), m.p. 240-241 ° C (dec.)

IR (nujol):

3550, 3460, 1665, 1635, 1560 cm ^-1

Preparations 18

A solution of S-methyl- (5-formamido-1,2,4-thiadiazol-3-yl) thioglyoxylate (6.64 g) in 1 N aqueous sodium hydroxide solution (80 mL) was - adjusted to 10% - hydrochloric acid to pH 8.5 and stirred for 30 minutes at ambient temperature. Separately, a mixture of N- (2,2,2-rifluoroethoxy) phthalimide (8.78 g) and hydrazine hydrate (1.7 g) in ethanol (40 mL) was maintained at reflux for 5 min. cooled in an ice bath. The resulting precipitate was filtered off and washed with ethanol. The filtrate and wash solution were combined and the combined solution containing O-2,2,2-trifluoroethyl) hydroxylamine. is added to the aqueous solution prepared above. The pH of the mixture was adjusted to 3-4 with 10% hydrochloric acid, and the mixture was stirred for - one and a half hours at ambient temperature. The solution was neutralized with aqueous sodium bicarbonate solution, concentrated to half volume in vacuo and washed with ethyl acetate. The aqueous solution - acidified with 10% hydrochloric acid and extracted - with ethyl acetate. The extract was dried over magnesium sulphate, evaporated to dryness and the residue triturated with diisopropyl ether to give 2- (2,2,2-trifluoroethoxyimino-2) -5- (formamido-1,2,4). (thiadiazol-3-yl) acetic acid (syn isomer) (2.46 g), m.p. 180-185 ° C (dec.).

NMR (d6 -DMSO)

8:

4.80 and 5.07 (2H, ABq, J = 9 Hz),

8.85 (1 H, s)

Preparation 19

In a similar manner as described in Preparation 18, the following compound was prepared:

2-Methylthiomethoxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid [syn isomer], m.p. 146-148 ° C (dec.).

IR (nujol):

Í.W

3300, 2600, 2550, 1730, 1705, 1680, 1600, 1530 ^cm-1

NMR (d 6 -DMSO) δ;

2.23 (3 H, s),

5.40 (2 H, s), 8.87 (1 H, s)

Preparations and - 20

A mixture of S-methylb (5-formamido-T, 2,4-thtediazol-3-yl) thioglyoxylate (6 g) and an aqueous solution (50 ml) of sodium hydroxide (4.2 g) was stirred for one hour. hours at a temperature of 50 to 55 ° C. The mixture was cooled to ambient temperature, and the pH was adjusted to 7 with 10% hydrochloric acid. Separately, a mixture of N- (ethoxycarbonylmelthi) -4-phthalimide (12.9 g) and hydrazine hydrate was added. - (2.08 g) in ethanol (60 ml) - held at reflux for 5 minutes and then cooled - in an ice bath. The resulting precipitate was filtered off and washed with ethanol. The filtrate and wash solution were combined and the combined solution containing O- (ethoxycarbonylmethyl) hydroxylamine was added to the above aqueous solution. The pH of the mixture was adjusted to 3-4 with 10% hydrochloric acid and stirred for one and a half hours at ambient temperature. The solution was neutralized with aqueous sodium bicarbonate solution, concentrated to half volume in vacuo and washed with ethyl acetate. The aqueous solution was acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract was dried over magnesium sulfate, evaporated to dryness and the residue triturated with diisopropyl ether to give 2-ethoxykarbonylmethoxylmlno-2- (Tamino - ^. A-thiadiazobS-yjoctová acid ^- (syn - isomer) - (1.8 g) mp 135-140 ° C (dec.).

IC (nujol):

3500, 3330, 3210, 2670, 2550, 1740, 1610, 1540 cm ^-1

NMR (d6 -DMSO)

1.24 (3H, t, J = -7Hz),

4.14. (2H, q, J = 7 Hz);

4.80 (2 H, s),

8.15 (2H, broad lat.)

Preparation 21

The following compound was prepared in a manner similar to that described in Preparation 20:

2- (1-Ethoxycarbonyl-1-methyl-ethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) -acetic acid (syn isomer), m.p. 165-168 ° C (dec.).

IR (nujol):

3450, 3350, 3240, 1750, 1730, 1530 cm ^-1

NMR - (d 6 -DMSO) d:

1.18 (3H, - t, J - 7 Hz),

1.50 - (6H, s), - .......

4.15 (2H, - q, J = 7Hz);

8.23 - (2H, broad - s)

Prp-ava - 22

The following compounds were prepared in a similar manner as described in Preparation 14:. ... ....... .

(1) -2-Allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), m.p. - 93-95 ° C - (dec.)

IR (nujol):

3430, 3100, - 1710, - 1615, 1525 cm

NMR (d6 -DMSO) δ:

4.72 (2H, d, J = 6 Hz),

5.1-5.5 (2H, m),

5.7 - 6.3 (1H, m),

8.17 (1H, broad s)

2) 2- (2-Propynylimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), m.p. 155-157 ° C (dec.)

IC (nujol):

3500, 3310, 3160, 2600, 2480, 1745, 1610, 1535 cm ^@ -1

NMR (d6 -DMSO)

WITH:

3.53 (1H, t, J = 2Hz),

4.87 (2H, d, J = 2 Hz),

8.23 (2H, broad s)

3) 2- (2,2,2-Trifluoroethoxylmino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), m.p. 140-143 ° C (dec.) decomposition)

IC (nujol):

3450, 3350, 3260, 1745, 1670, 1645, 1615, 1515 cm ^{@ 4} ;

NMR (d 6 -DMSO) δ: .........

4.72 and 4.95 (2H, ABq, J = 9 Hz),

8.25 (2H, broad s)

4) 2-Methylthiomethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), m.p. 140-143 ° C. (with decomposition)

IC (nujol):

3500, 3300, 3150, 2670, 2580, 1740, 1615,

1605, 1530 cm ^-1

NMR (d6 -DMSO) δ:

2.22 (3H, s).

5.33 (2 H, s),

8.20 (2H, broad s)

5) 2-Trityloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), m.p. 173-174 ° C (dec.)

IC (nujol):

3450, 1735, 1620, 1540 cm -1

NMR (d6 -DMSO) δ:

7.35 (15H, s);

8.23 (2H, s)

Preparation 23

To a mixture of 2-hydroxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (9.5 g) a. dimethylformamide (80 ml) was added with stirring. at ambient temperature trityl chloride (22.8 g) and triethy laminate (4.1 g) are then added sequentially after stirring for 3 minutes. The resulting mixture was stirred for 10 minutes and then ethyl acetate (250 mL) was added. The mixture was washed three times with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. Aqueous sodium bicarbonate (50 mL) and diisopropyl ether (100 mL) were added to the residue. The precipitates were collected by filtration and the aqueous layer was separated from the filtrate. The separated precipitates are suspended in a separate aqueous layer and ethyl acetate is added to the suspension. The mixture was adjusted to 2 with 10% hydrochloric acid and extracted with ethyl acetate. Dry the extract over magnesium sulfate and concentrate. under vacuum. The residue was washed with hexane to give 2-trityloxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) · (17.1 g), m.p. 175 up to 176 ° C (dec.).

IC (nujol):

3180, 3070, 1700, 1600, 1540 ^cm-1 "

NMR (d 6 -DMSO) δ:

7.35 (15H, s);

8.83 (1 H, s),

13.52 (1H, broad s)

Preparation 24

The following compounds were obtained in a similar manner to that described in Preparation 12- (1).

1) N- (1-t-butoxycarbonylethoxy) phthalimide, m.p. 80-82 ° C

NMR (d6 -DMSO) ............ ...............

δ.

1.42 (9H, s);

1.48 (3H, d, J = 7 Hz),

4.72 (1H, q, J = 7Hz)

7.86 (4 H, s)

2) N- (1-t-butoxycarbonyl-1-methylethoxy) phthalimide, m.p. 96-100 ° C

NMR (d6 -DMSO) δ:

1.42 (9H, s);

1.48 (6H, s);

7.87 (4 H, s)

30

3) N- (1-Benzyloxycarbonylethoxy) phthalimide, m.p. 65-68 ° C

IC (nujol):

1790, 1740, 1450, 1210, 1190, 1110, 1080, 980, 880, 735, 700 cm ^-1

4) N- (2-Oxo-3-tetrahydrofuryloxy) -phthalimide, m.p. 140-142 ° C

IC (nujol):

1785, 1760, 1720, 1605, 1215, 1185, 870, 695 cm ^-1

Preparation 25

The following compounds are obtained in a similar manner as described in the preparation.

20 May

1) 2- (tert-Butoxycarbonylmethoxylmino) -2- (5-ata-1,2,44'1-naphthalen-3-yl) acetic acid (syn isomer), m.p. 150-155 ° C (dec.)

Ic (nujol):

3420, 3230, 3100, 1725, 1610, 1530

NMR (ds-DMSO)

δ.

1.45 (9H, s);

4.70 (2 H, s),

8.12 (2H, broad s)

2) 2- (1-tert-Butoxycarbonylethoxyiminio) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), m.p. 155 to 156 degrees Celsius (with decomposition)

IC (nujol):

3400, 3300, 3200, 1720, 1710, 1620,

1520 cm ¹

NMR (d6 -DMSO)

5:

1.2-1.7 (12H, m);

4.72 (1 H, q, J = Hz),

8.2 (2H, broad s)

3) 2- (1-tert-Butoxycarbonyl-1-methylethoxyimino-) -2- (5-amino-1,2,4-1: hiadazol-3-yl) acetic acid (syn isomer), m.p. 181 ° C (dec.)

IC (nujol):

3400, 3300, 3200, 1745, 1715, 1630,

1530 cm * ¹

NMR (d6 -DMSO) δ:

1.38 (9H, s);

1.43 (6 H, s),

8.15 (2H, broad)

2-2- (1-Benzyloxycarbonyl) -2-

- (5-amino-1,2,4- hiadiazo-1-3-yl) acetic acid (syn isomer), m.p. 129-133 ° C (dec.)

IC (nujol):

3300, 3200, 1720, 1620, 1530 cm <

NMR (d6 -DMSO) β:

1.45 (3H, d, J = 6 Hz),

4.97 (1 H, q, J = 6 Hz),

5.18 (2 H, s),

7.31 (5 H, s),

8.17 (2H, broad s)

Axle 26

S-meCiy! (5-formamido-1,2,4-thiadiazol-3-yl) thloglyoxylate (64.8 g) and 1-carboxy-3-hydroxypropoxyamine, prepared by refluxing a mixture of N- (2-oxo) Of 3-tetrahydrofuryloxy) phthalimide (65 g), concentrated hydrochloric acid and water (200 mL) for one hour, was treated in a similar manner to that described in Preparation 20 to give 2- (1-carboxy-3). Hydroxypropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (33.2 g), m.p. 186-188 ° C (dec.)

IC (nujol):

3400, 3250, 3100, 1710, 1620, 1540

NMR (d6 -DMSO) <:

1.73-2.10 (2H, m),

3.50 (2H, t, J = 6 Hz);

4.73 (1 H, t, J = 6 Hz),

8.13 (2 H, s)

Preparation 27

To a solution of 2- (1-carboxy-3-hydroxypropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (33.0 g) in methanol (2 Anhydrous magnesium sulfate (120 g) and acetic anhydride (60 g) were added. The mixture was stirred at ambient temperature for 30 minutes, filtered and the filtrate evaporated to dryness. The residue was triturated in acetone (200 mL) and ethyl acetate (1 L) was added to this mixture. The mixture was stirred at ambient temperature for one hour and the precipitate was collected by filtration and washed with ethyl acetate.

The precipitate was dissolved in water [200 mL] and then ethyl acetate (500 mL), acetone (200 mL) and 6N hydrochloric acid (40 mL) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated in diethyl ether, filtered and washed with diisopropyl ether to give 2- (2-oxo-3-tetrahydrofuryloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl). acetic acid (syn Isomer) (26.5 g), m.p. 185-187 ° C (dec.).

IR (nujol):

3400, 3300, 3200, 1775, 1730, 1640, 1605, 1535 cm ¹

NMR (d6 -DMSO) δ:

2.27-2.70 (2H, m)

4.17 - 4.50 (2H, m),

5.27 (1 H, t, J = 8 Hz),

8.22 (2 H, s)

Preparation 28

The following compound was prepared in a similar manner to that described in Preparation 20:

2-Methoxycarbonyl-ethyxyimino-2- (5-amino-2,4,4-thiadiazol-3-yl) -acetic acid (syn isomer), m.p. 190-193 ° C (dec.)

IR (nujol):

3380, 3280, 3180, 1750, 1710, 1610, 1510, 1260, 1230 cm ^"1

NMR (d6 -DMSO) δ:

3.73 (3 H, s),

4.87 (2 H, s),

8.2 (2 H, bs)

Preparation 29

To a mixture of sodium iodide (80 g) and pyridine (11.36 g) in water (40 mL) was added 7- [D5-carboxyt5t (3-phenylureidovaleramido) cephalosporanate sodium (40 g) at 50 ° C with stirring and stirring The reaction mixture was then diluted with water (80 ml), adjusted to pH 3.5 with 6N hydrochloric acid, and subjected to column chromatography on a non-ionic adsorption resin "Diaion HP". -20 "(trademark of Mitsubishi Chemical Industries) (600 ml) After washing the column with water (2.4 liters), the eluate is taken up with 35% aqueous isopropyl alcohol preheated to 45 ° C. N, N-dimethylformamide (100 mL) was added and the mixture was concentrated to 120 mL under reduced pressure, and isopropyl alcohol (1 L) was added to the residue with stirring for 1 hour, and the resulting precipitate was collected by filtration, washed isopropanol and dried, or there was thus obtained 7- [D-5-carboxy-5- (3-phenylureido) valeramido] -3- (1-pyridinomethyl) -3-tert-methyl-4-carboxylate (22.0 g), m.p. 180. up to 185 ° C (dec.).

IR (nujol):

3300, 1780, 1720, 1680, 1610, 1540

1500 cm ¹

NMR (d 6 -DMSO + D 6) δ:

1.4-1.8 (4H, m),

2.0-2.3 (2H, m),

3.14, 3.54 (2H, ABq, J = 17 Hz),

4.0 - 4.2 (1H, m),

5.04 (1 H, d, J = 4Hz),

5.24, 5.62 (2H, ABq, J = 14 Hz),

5.60 (1 H, d, J = 4Hz),

6.7 - 7.5 (5H, m),

8.0 - 8.2 (2H, m);

8.45 - 8.70 (1H, m),

9.28 - 9.42 (2H, m).

Preparation 30

To a mixture of 7- [D-5-carboxymethyl- (3-phenylureido) valeramido) -3- (1-pyridinomethyl) -3-cephem-4-carboxylate (2.77 g) and N, N-dimethylaniline ( 4.2 g) in methylene chloride (30 ml) dropwise trimethylsilyl chloride (3.3 g) at ambient temperature with stirring and continue for 30 minutes. The mixture was cooled to -30 ° C and phosphorus pentachloride (2.1 g) was added with stirring, which was continued for one hour at -30 to -25 ° C. The reaction mixture was added to a solution of 1,3-butanediol (4.5 g) in methylene chloride (30 mL) at -20 ° C with stirring, which was continued for 1,5 1.5 hours at room temperature. The resulting precipitate was collected by filtration, washed with methylene chloride to give the crude product (2.1 g) of 1 - [(7-amino-4-carboxy-3-cephem-3-yl) methyl) pyridinium chloride hydrochloride dihydrate. Into the raw. 1N hydrochloric acid (8 ml) was added to the product and the mixture was stirred for 30 minutes at ambient temperature. Insoluble material was filtered off and the filtrate was cooled in an ice bath, then isopropyl alcohol (20 ml) was added with stirring228145

8:

her. Isopropyl alcohol (25 ml) was added to the mixture and the resulting precipitate was filtered off, washed with the same solvent and acetone and dried to give pure product (1.15 g), m.p. 140-145 ° C (dec.).

NMR (D2O)

3.53, 3.80 (2H, ABq, J = 18 Hz),

5.30 (1 H, d, J = 4 Hz)

5.45 (1H, d, J 1 - 4Hh,

5.53, 5.83 (2H, ABq, J = 14Hz),

8.00 - 8.33 (2H, m),

8.50 - 8.33 (1H, mj)

8.90 - 9.13 (2H, m).

Example 1

В

C-CONH 11 '

N - OCgMg *

To a cold solution of phosphorous pentachloride (2.64 g) in methylene chloride (25 mL) was added 2-ethoxyimino-2- (5-amino-1,2,4-triazole-diazol-5-yl) -acetic acid (syn isomer) (2 48 g) at -20 ° C and the mixture is stirred for 35 minutes at -20 to -14 ° C. Cold diisopropyl ether (75 ml) is added to the mixture at a temperature below -10 ° C with stirring in which The precipitate obtained is filtered off, washed with diisopropyl ether and kept in a desiccator for several minutes.

Separately heat a mixture of 1 - [(7-amino-4'-carboxy-3-cephem-3-yl) methyl] pyridinium chloride hydrochloride dihydrate (3.27 g) and trimethylsilylacetamide (16 g) in methylene chloride (30 mL) to 35 ° C until a solution is formed which is then cooled to -20 ° C. The cold solution is added to the precipitate prepared above and the mixture is stirred for 25 minutes at -18 to -12 ° C and for a further 10 minutes at -12 to -3 ° C. A solution of sodium bicarbonate (4 g) in water (30 mL) was added to the reaction mixture and the aqueous layer was separated, adjusted to pH 1 with 6N hydrochloric acid, washed with ethyl acetate, and then adjusted to pH 4 with aqueous sodium bicarbonate. The aqueous solution was passed through an alumina column (10 g) and then subjected to column chromatography on a nonionic adsorption resin Diaion HP-20 (trademark of Mitsubishi Chemical Industries) (100 mL). After washing the column with water, eluting with 20% aqueous methanol. The eluates containing the compound to be prepared are combined, evaporated to remove methanol under reduced pressure, and lyophilized to give a white powder of 7- (2-ethoxyimino-2- (5-aminol, 2,4-thiadiazol-3-yl) acetamido] -3 - (1-pyridinomethyl) -3-fem-4-carboxylate (syn isomer) (2.39 g), m.p. 155-165 ° C (dec.).

IR (nujol):

3400 - 3150, 1770, 1660, 1610, 1530 cm 1

NMR (ds-DMSO) δ:

1.21 (3H, t, J = 7 Hz),

2.9-3.7 (2H, m),

4.12 (2H, q, J = 7 Hz),

5.05 (1 H, d, J = 5 Hz),

5.19, 5.68 (2H, ABq, J = 14 Hz),

5.7 (1 H, m),

8.1 (4H, m).

8.6 (1 H, m),

9.4 (3 H, m)

Example 2

To a cold solution of phosphorus pentachloride (1.25 g) in methylene chloride (30 mL) was added 2- (2-cyclopenten-1-yloxyimino) -2- (5-amino-1,2,4-thiadiazole-3- yl acetic acid (syn isomer) (1.5 g) at -15 ° C and stirred for 30 minutes at -13 to -10 ° C. Separately the mixture of N- [7-amino-3-cephem 3-ylmethyl] pyridinium-4-carboxylate dihydrochloride (1.82 g) and trimethylsilylacetamide (10 g) in methylene chloride (50 ml) were stirred for 10 minutes at room temperature and then cooled to -10 ° C. The solution was added to the above activated mixture and stirred for 15 minutes at -10 degrees C. The reaction mixture was poured into an aqueous solution (100 mL) of sodium bicarbonate (3.6 g) and stirred for 15 minutes at room temperature. The aqueous layer was separated, adjusted to pH 2 with 10% hydrochloric acid, and washed with ethyl acetate. graphics using Diaion HP-20 nonionic adsorption resin (trademark of Mitsubishi Chemical Industries) (100 mL). After washing the column with water, elution is performed with 40% aqueous methanol. The eluates containing the compound are collected, evaporated to remove methanol under reduced pressure, and lyophilized to give a white powder of N- [7- {2- (2-cyclopenten-1-yloxyimino) -2- (5- amino-1,2,4-thladiazol-3-yl) acetamido-3-chloro-3-ylmethyl] pyridinium-4-carboxylate (syn isomer), m.p. 190-195 ° C (dec.), ( 1.5 g).

IR (nujol):

3350, 3200, 1780, 1660, 1620, 1530 cm ' ¹

NMR (D 2 O + NaHCO 3) δ:

1.9 - 2.5 (4H, m)

3.23, 3.60 (2H, ABq, J = 16 Hz),

5.2 - 6.1 (7H, m),

7.9-9.1 (5H, m).

Example 3

To the cold. To a solution of phosphorus pentachloride (1.46 g) in methylene chloride [30 mL] was added 2- (1-methyl-1-ethoxycarboklethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid. (syn isomer) (2.11 g) at -18 ° C and stirred for 30 minutes at -14 ° C to -11 ^Q C. to the reaction mixture was added dry n-hexane (90 ml) at The mixture is stirred for several minutes and the solvent is removed by decantation. The residue was triturated with n-hexane and collected by filtration to give an activated acid powder.

Separately, a mixture of N- [7-amino-3-cephem-3-ylmethyl] pyridinium-4-carboxylate dihydrochloride (2 g) and trimethylsilylacetamide (10 g) in methylene chloride was stirred for 10 minutes at room temperature and cooled to -18 °. C.

The powder prepared above was added to the cold solution and the mixture was stirred for 30 minutes at -13 to -10 ° C and for 30 minutes at -5 to 0 ° C. The reaction mixture was poured into an aqueous solution (100 mL) of sodium bicarbonate (3.6 g) and stirred for 15 minutes at room temperature and then adjusted to pH 1 with 6N hydrochloric acid. The aqueous layer was separated, washed with ethyl acetate and subjected to a column chromatography on Diaion HP-20 nonionic adsorption resin (100 ml). After washing the column with water, 5% aqueous ethanol and 10% aqueous ethanol in succession, elution is performed with 20% aqueous ethanol. The eluates containing the compound to be prepared are collected, evaporated to remove ethanol under reduced pressure, and lyophilized to give N- [7- (1- (1-methyl-1-ethoxycarbonklethoxkimino) -2- (5-amino-1,2)). 1,4-thiadiazol-3-yl) acetamido-3-cephem-3-ylmethyl] pyridinium 4-carboxylate (syn isomer) (1.30 g) as a white powder, m.p. 164-168 ° C (dec.) ).

IR (nujol):

3350-3150, 1770, 1720, 1670, 1620, 1520 cm @ -1

NMR (d6 -DMSO)

WITH:

1.15 (3 H, t, J = 7 Hz),

1.45 (6H, s).

3.03 and 3.55 (2H, ABq, J = 18 Hz),

4.10 (2H, q, J = 7 Hz)

5.11 (1 H, d, J = 5 Hz),

5.20 and 5.67 (2N, ABq, J = 13Hz),

5.75 (1H, 2d, J = 5 and 8Hz),

8.20 (4H, m).

8.57 (1H, m);

9.47 (3 H, m).

Example 4

The following compounds were prepared in a similar manner as described in Examples 1-3.

1) 7- [2-Propoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-pyridinomethyl) -3-cephem-4-carboxylate (syn isomer) mp 230-240 ° C (dec.).

IR (nujol):

3400 - 3200, 1770, 1670 - 1600, 1530 cm ^-1

NMR (d6 -DMSO)

8:

0.85 (3H, t, J = 7 Hz),

1.6 (2H, m);

3.06, 3.55 (2H, ABq, J = 18 Hz),

4.04 (2H, t, J = 6Hz),

5.06 (1H, d, J = 5 Hz),

5.18, 5.70 (2H, ABq J = 14 Hz),

5.74 (1H, dd, J = 5 and 8Hz),

8.2 (4H, m).

8.6 (lH, m)

9.5 (3 H, m).

2) 7- [2-Methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-pyridintomethyl) -3-cephem-4-carboxylate (syn isomer) mp 250-260 ° C (dec.).

IR (nujol):

3400-3100, 1770, 1650, 1610, 1520 cm ^-1

NMR (d6 -DMSO) δ:

3.07-3.57 (2H, ABq, J = 18 Hz),

3.86 (3 H, s),

5.06 (1H, d, J = 5 Hz),

5.19, 5.69 (2H, ABq, J = 14 Hz),

5.73 (1H, dd, J = 5.8Hz),

8.0 - 8.3 (4H, m),

8.4 - 8.7 (1H, m),

9.3-9.6 (3H, m).

3) 7- [2-Isopropoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-pyridinomethyl) -3-cephem-4-carboxylate (syn isomer) mp 160-165 ° C (dec.).

IR (nujol):

3270, 3180, 1770, 1660, 1610, 1525 cm ¹

NMR (d 6 -DMSO + D 2) δ:

1.22 (6H, d, J = 6 Hz),

3.15, 3.57 (2H, ABq, J = 18 Hz),

4.17 - 4.60 (1H, m),

5.12 (1H, d, J = 5 Hz),

5.33, 5.70 (2H, ABq, 1 = 14Hz),

5.78 (1H, d, J = 5 Hz),

8.0 - 8.4 (2H, m),

8.47 - 8.83 (1H, m),

9.53 - 9.67 (2H, m).

4) N- [7- {2- (tert-butoxycarbonylmethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido} -3-chloro-2-ylmethyl] pyridinium-4 -carboxylate (syn isomer), m.p. 150-155 ° C (dec.).

IR (nujol):

3300, 3200, 1770, 1680, 1620, 1530 cm ^-1

5) N- [7- [2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido-3-cephem-3-ylmethyl] pyridinium-4-carboxylate (syn isomer m.p. 150-155 ° C (dec.).

IR (nujol):

3350, 3200, 1780, 1680, 1530 cm ^-1

6) N - [- {2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido {-3-cephem-3-ylmethyl] pyridinium-4-carboxylate (syn isomer 180 DEG-185 DEG C. (with decomposition).

IR (nujol):

3300, 3200, 1780, 1670, 1620, 1530 cm ^-1

7) N- [7- {2- (1-carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido [-3-cephem-3-ylmethyl] -4 ' 170 DEG-175 DEG C. (with decomposition), m.p. 170 DEG-175 DEG.

IR (nujol):

3300, 3160, 1770, 1680, 1610, 1560,

1520 cm ^-1

8) N- [7- {2- (1-tert-Butoxycarbonylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamide O (-3-chloro-3-ylmethyl)] pyridinium 4-carboxylate (syn isomer), m.p. 160-165 ° C (dec.).

IR (nujol):

3290, 3160, 1770, 1725, 1670, 1620,

1525 cm ¹

NMR (CD 3 OD -I-D 6)

WITH:

1.2 - 1.6 (12H, m),

3.20 and 3.67 (2H, ABq, J = 18Hz),

4.40 - 4.90 (1H, m),

5.20 (1 H, d, J ~ -5Hz),

5.33 - 5.80 (2H, m),

5.92 (lH, d, J = -5Hz),

7.9-9.4 (5H, m).

9) N - [7- [2- (1-Carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido; -3-cephem-3-ylmethyl] pyridinium-4 -carboxylate (syn isomer), m.p. 175-180 ° C (dec.).

IC (nujol):

3300, 3200, 1775, 1670, 1620, 1520 ^cm-1

10) N- [7- [2- (1-Benzyloxycarbonyl-ethylethoxyimino) 2- (5-amino-1,2,4-thiadiazoil-3-yl) acetamido] -3-cephem-3-ylmethyl] pyridinium-4 -carboxylate (syn isomer), m.p. 178-182 ° C (dec.).

IR (nujol):

3250, 3150, 1770, 1670, 1620, 1520 cm ^-1

NMR (d 6 -DMSO + D 6) δ:

1.45 (3H, d, J = 7 Hz),

3.10 and 3.60 (2H, ABq, J = 16 Hz),

4.87 (1 H, q, J = 7 Hz),

5.20 (2H, s),

4.97 - 5.10 (2H, m),

5.25 (1H, d, J = 5Hz)

5.83 (1H, d, J = 51Is),

7.43 (5 H, s),

8.27 (2 H, m),

8.63 (1 H, m),

9.38 (2 H, m).

11) N- [7,2-Ethoxycarbonylmethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido-3-cephem-3-ylmethyl] pyrimidine-4-carboxylate (syn isomer) mp 184-188 ° C (dec.).

IC (nujol):

3400-3100, 1770, 1670, 1610, 1520 СПГ ¹

NMR (d6 -DMSO) δ:

1.17 (3H, t, J = -71-Is),

3.05 and 3.53 (2H, ABq, J = 18 Hz),

4.13 (2H, q, J = 7Hz);

4.70 (2 H, s),

5.08 (1 H, d, J = 5 Hz),

5.17 and 5.70 (2H, ABq, J = 13 Hz),

5.72 (1H, dd, J = 5 and 8Hz),

8.16 (4H, m).

8.62 (1 H, m),

9.50 (3 H, m).

12) N- [7- {2- (2-Cyclohexen-1-yloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido; -3-cephem-3-ylmethyl] pyridinium-4-carboxylate (syn isomer), m.p. 150-155 ^° C (dec.).

IR (nujol):

3300, 3200, 1775, 1660, 1610, 1520 cm ^-1

NMR (d6 -DMSO) δ:

1.5-2.0 (6H, m)

3.13, 3.57 (2H, ABq, J = 17I-Is),

4.6 - 4.7 (1H, m),

5.07 (1 H, d, J = 4Hz),

5.27, 5.60 (2I-I, ABq, J = 14Hz),

5.80 (1H, 2d, J = 4Hz and 8Hz,

5.77 - 6.0 (2H, m),

8.17 (2 H, s),

8.0 - 8.4 (2H, m),

8.43 - 8.80 (1 H, m),

9.4 - 9.5 (2H, m),

9.55 (1 H, d, J = 8 Hz).

13) N- [7- | 2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido} -3-cephem-3-ylmethyl] -4'-carbamoylpyridinium-4-carboxylate (syn isomer), m.p. 175-180 ° C (dec.).

IR (nujol):

3350, 3200, 1775, 1680, 1615, 1565,

1525 cm ¹

14) N- [7- (2-Methoxycarbonylmethoxyimino-2- (5-amino: -1,2,4-thiadiazol-3-yl) acetamido-3-cephem-3-ylmethyl) pyridinium -4-carboxylate ( syn isomer), m.p. 165-170 ° C (dec.).

IR (nujol):

3300 - 3150, 1760, 1670, 1620, 1520 ^cm-1

NMR (D 2 O) δ:

3.17, 3.70 (2H, ABq, J = 18 Hz),

3.80 (3 H, s),

4.93 (2 H, s),

5.30 (1 H, d, I = 5 Hz),

5.44, 5.73 (2H, ABq, J = 14Hz),

5.93 (1H, d, J = -5Hz),

8.10 (2 H, m),

8.60 (1 H, m),

8.98 (2 H, m).

42

15) N- [7- (2- (1-Methyl-1-carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido) -3-cephem-3-ylmethyl Pyridine-4-carboxylate (syn isomer), white powder, mp 176-180 ° C (dec.).

IR (nujol):

3400-3150, 1770, 1670, 1620, 1520 cm

16) N- [7- {2- (1-Methyl-1-tert-butoxycarbonylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-3-ylmethyl 176-180 ° C (with decomposition). Pyridine-4-carboxylate (syn isomer).

IR (nujol):

3300, 3200, 1780, 1730, 1680, 1620, 1520 cm ^-1

NMR (d 6 -DMSO + D; O)

WITH-.

1.40 (15H, bs).

3.08, 3.42 (2H, ABq, f = 18Hz),

5.13 (1 H, d, J = 5 Hz),

5.40 (2 H, m),

5.80 (1 H, d, J = 5 Hz),

817 (211)

8.65 (1 H, m),

9.37 (2 H, m).

17) N- [7- (2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido (-3-cephem-3-ylmethyl) -4'-carbamoylpyrrolidine- 4-carboxylate (syn isomer), m.p. 230-235 ° C (dec.).

IC (nujol):

3300, 3200, 1770, 1680, 1610, 1560, 1520, 1510 cm ^-1

18) N- [7- {2- (2-Cyclopenten-1-yloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetarnido (-3-cefem-3- ylmethyl] -4'-carbamoylpyridinium-4-carboxylate (syn isomer), m.p. 155-160 ° C (dec.).

IR (nujol):

3300, 3150, 1770, 1675, 1610, 1560,

1520 cm

NMR (d6 -DMSO) <5:

2.0-2.4 (4H, m),

3.17 - 3.67 (2H, m),

5.08 (1H, d, (-5Hz)),

5.23 - 6.30 (6H, m),

8.27 (2I-I, broad s),

8.57 (2H, d, J = -7Hz),

9.53 (1 H, d, J = 8 Hz),

9.70 (2H, d, J = 7 Hz).

19) N- [7- | 2- (1-Methyl-1-carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido-3-cephem-3- ylmethyl] -4'-carbamoylpyridinium-4-carboxylate (syn isomer), m.p. 180-185 ° C (dec.).

IC (nujol):

3300, 1770, 1680, 1620, 1560, 1520 cm

NMR (d 6 -DMSO) δ:

1.40 (6 H, s),

3.0 - 3.6 (2H, m),

5.10 (1 H, d, J = 4Hz),

5.3 - 5.7 (2H, m),

5.80 (1H, dd, J = 4 and 8Hz),

9.18 (2H, d, J = 7 Hz),

9.50 (1 H, d, J = 8 Hz),

9.63 (2H, d, J = 7 Hz).

20) 7- [2-Allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-pyridiniomethyl) -3-cephem-4-carboxamide (syn 160-165 ° C (dec.).

IR (nujol):

3290, 3180, 1770, 1660, 1610, 1525 cm ^-1

NMR (d6 -DMSO-d6):

3.12, 3.50 (2H, ABq, J = 18 Hz),

4.44 - 4.76 (2H, m),

5.10 (1 H, d, J = 5 Hz),

5.0 - 6.1 (6H, m),

8.0 - 8.4 (2H, m),

8.44 - 8.76 (1 H, m),

9.32 - 9.68 (2H, m).

21) 7- [2- (2-Propinyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-pyridinomethyl) -3-cephem-4-carboxylate syn isomsr), m.p. 145-150 ° C (dec.).

Ic (nujol):

3250, 2100, 1770, 1660, 1630, 1610,

1525 cm ^-1

NMR (d 6 -DMSO) <5:

3.10, 3.55 (2H, ABq, J = 18 Hz),

3.47 (1 H, t, J = 2 Hz),

4.73 (2H, d, J = 2 Hz),

5.08 (1 H, d, J = 5 Hz),

5.25, 5.65 (2H, ABq, J = 14 Hz),

5.60 - 5.93 (1H, m),

8.0 - 8.4 (4H, m),

8.4 - 8.8 (1H, m);

9.3 - 9.7 (3H, m).

22) 7- [2-Hydroxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl Jacetamido) -3- (1-pyridinomethyl) -3-cephem-4-carboxylate (syn isomer) m.p. 170-175 ° C (dec.).

IR (nujol):

3350, 3200, 1780, 1620, 1530, 1490 cm ^-1

23) 7- [2-Methylthiomethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-

- (1-pyridinomethyl) -3-cephem-4-carboxylate (syn isomer), m.p. 195-205 ° C (dec.).

IR (nujol):

3350 - 3150, 1770, 1670, 1620, 1520

1150 cm ⁴

NMR (d 6 -DMSO + D 6) δ:

2.17 (ZN, s),

3.00, 3.67 (2H, ABq, J = 18 Hz),

5.10 (1 H, d, J = 5 Hz),

5.22 (2 H, s),

5.73 (1 H, d, J = 5 Hz),

5.00 - 5.83 (2H, m),

8.13 (2 H, m),

8.53 (1 H, m),

9.33 (2 H, m).

24) 7- [2-Trityloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-pyridimomethyl) -3-cephem-4-carboxylate (syn isomer) mp 165-170 ° C (dec.).

IR (nujol):

'345О, 1780, 1670, 1620, 1530, 1490 cm ^-1

NMR (d6 -DMSO)

5:

3.18, 3.64 (2H, ABq, J = 18 Hz),

5.18 (1 H, d, J = 5 Hz),

5.34, 5.74 (2H, ABq, J = 12 Hz),

5.92 (1H, dd, J 5 and 8Hz),

7.28 (15H, s);

7.94 - 8.30 (4H, m)

8.42 - 8.66 (1H, m),

9.22 - 9.54 (2H, m);

9.78 (1 H, d, J = 8 Hz).

25) 7- (2- (2,2,2-Trifluoroethoxyimino) -2-

- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-pyridinomethyl) -3-cephem-4-carboxylate (syn isomer), m.p. 150-155 ° C (dec.).

IR (nujol):

3300, 1780, 1675, 1630, 1530 cm ^-1

NMR (d ₆ -DMSO + D ₂ O) <5:

3.23, 3.50 (2H, ABq, J = 18Hz),

4.63, 4.93 (2H, ABq, J = 9Hz),

5.17 (1 H, d, J = 5 Hz j,

5.37, 5.73 (2H, ABq, J = 14 Hz),

5.83 (1 H, d, J = 5 Hz),

8.1 - 8.4 (2H, m),

8.5 - 8.8 (1H, m),

9.3 - 9.6 (2H, m).

26) 7- [2-Ethoxy-amino-2- (5-amino-1,2,4-thiadiazol-3-yl) -acetamido] -3- (4-carbamoyl-1-pyridinomethyl) -3-cephem-4- carboxets (syn Isomer), m.p. 160-165 ° C (dec.).

IR (nujol):

3300, 3200, 1780, 1680, 1620, 1570

1530 cm ^-1

27) 7- (2- (2-Oxotetrahydrofuran-3-yloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido) -3- (1-pyridinomethyl) -3- cep-4-carboxylate (syn isomer), m.p. 140-145 ° C (dec.).

IR (nujol):

3350, 1780, 1670, 1620, 1530, 1490 cm ^-1

NMR (d 6 -DMSO + D 6) <5:

2.43 - 2.83 (2H, m),

3.27, 3.63 (2H, ABq, J = 18 Hz),

4.23 - 4.67 (2H, m),

5.17 - 5.37 (1H, m),

5.20 (1H, d, J = 5Hz)

5.38, 5.73 (2H, ABq, J = 13 Hz),

5.87 (1 H, d, J = 5 Hz),

8.07 - 8.43 (2H, m),

8.53 - 8.80 (1 H, m),

9.23- 9.50 [2H, m].

28) 7- [2-Methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (4-carbamoyl-1-pyridin-ethyl) -3-cephem-4- m.p. 165-170 ° C (dec.).

IR (nujol):

3350, 3200, 1780, 1690, 1610, 1570,

1530 СПГ ¹

29) 7- [Propoxyimino-2 (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (4-carbamoyl-1-pyridinomethyl) -3-cephem-4-carboxylate (syn isomer), m.p. 170-175 ° C (dec.).

IR (nujol):

3350, 3200, 1780, 1690, 1610, 1570,

1530 cm ¹

30) 7- [2-Isopropoxylmino-2- (5 amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (4-carbamoyl-1-pyridinomethyl) -3-cefem-4 -carboxylate (syn isomer), m.p. 155-160 ° C (dec.).

IR (nujol):

3350, 3220, 1780, 1680, 1615, 1570,

1530 cm ¹

31) 7- [2-Allyloxyimino-2- (5-amino-1,2,4-1-thiadiazol-3-yl) acetamido] -3- (4-carbamoyl-1-pyridinomethyl) -3-cephem-4- carboxylate (syn isomer), m.p. 161-165 ° C (dec.).

IR (nujol):

3400 - 3150, 1770, 1670, 1610, 1560

1520 cm ¹

32) 7- (2- (2,2,2-Trifluoroethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (4-carbamoyl-1-pyridimomethyl) -3-cep-4-carboxylate (syn isomer), m.p. 160-165 ° C (dec.).

IR (nujol):

3300, 3150, 1780, 1680, 1610, 1580

1520 cm * ¹

33) 7- [2-Methylthiomethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-

(4-carbamoyl-1-pyridinomethyl) -3-cephem-4-carboxylate (syn isomer), m.p. 160-165 ° C (dec.).

IR (nujol):

3300, 3150, 1770, 1680, 1610, 1560,

1520 cm * ¹

34) 7- (2- (2-Propinyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido) -3- (4-carbamoyl-1-pyridinomethyl) -3- cep-4-carboxylate (syn isomer), m.p. 155-160 ° C (dec.).

IR (nujol):

3400, 3250, 3150, 2120, 1770, 1685, 1610, 1560, 1525 cm * ¹

35) 7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (2-methyl-5-oxo-6-hydroxy-2,5-dihydro- 169 DEG-174 DEG C. (dec.), 1,2,4-triazin-3-yl) thiomethyl-3-cephem-4-carboxylate (syn isomer).

IR (nujol):

3600 - 3100, 1760, 1690, 1665, 1640, 1610

1520, 1005 cm @ ^-1

36) 7- [2-Methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (2-methyl-5-oxo-6-oxido-2,5-dihydro Disodium 1,2-triazin-3-yl) thiomethyl-3-cephem-4-carboxylate (syn isomer), m.p. 220-225 ° C (dec.).

IR (nujol):

3400 - 3150, 1760, 1660, 1640 - 1560, 1520, 1040 cm ^-1

37) 7- [2-Ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (2-methyl-5-oxo-6-oxido-2,5- Disodium dihydro-1,2,4-triazin-3-yl) thiomethyl-3-cephem-4-carboxylate (syn isomer), m.p. 155-265 ° C (dec.).

IR (nujol):

3400 - 3150, 1760, 1660, 1600, 1500, 1400, 1030 cm * ¹

38) 7- (2- (2-Cyclopenten-1-yloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido) -3- (2-methyl-5-oxo-) 6-hydroxy-2,5-dihydro-1,2,4-triazin-3-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), m.p. 158-164 ° C (dec.).

IR (nujol):

3450-3150, 1770, 1680, 1630, 1510, 1260, 1180, 1100, 1030, 1010 cm * ¹

NMR (d6 -DMSO)

5:

2.0 - 2.6 (4H, m),

3.2-4.0 (2H, m),

3.62 (3 H, s),

4.13, 4.45 (2H, ABq, J = 13 Hz),

5.13 (1H, d, I = 5Hz)

5.2-5.5 (1H, m),

5.7 - 6.0 (2H, m),

6.0 - 6.2 (1H, m),

8.20 (2H, broad s),

9.50 (1H, d, J = 8 Hz).

39) 7- [2-Isopnopoxyimino-2- (5-amino-1,2,4-thiadlazol-3-yl) acetamido] -3- (2-methyl-5-oxo-6-hydroxy-2,5-dihydro -1,2,4-triazin-3-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), m.p. 160-167 ° C (dec.).

IR (nujol):

3400, 3280, 3180, 1780, 1770, 1630, 1515,

1410, 1240, 1009 cm ¹

NMR (d6 -DMSO + D5O)

WITH:

1.27 (6H, d, J = 6Hz),

3.62 (3 H, s),

3.5-3.9 [(H, m),

4,13,4,44 [(H, ABq, J = 11Ηζ),

4.40 (1H, J J == J> Hz),

5.17 (1H, d, J J = 5 Hz,

5.83 (1H, d, J 1 = 5Hz),

10) 7- [2- (2-Propinyloxyimino), 2- (2-amino-1,1,1-thiadiazol-3-yl) acetamido] -3- (2-methyl- (5 (Xyx-6-hydroxy) -) 2,5-dihydro-1,1,1-tr-a (zin (3-yl) thiomethyl-3-cephem-1 (carboyylic acid (syn isomer)), m.p. 161-16 ° C (dec. .

IC (nujol):

3260, 3180, 1770, 1670, 1620, 1520,

1335 cm

NMR (d 6 -DMSO + D 6) δ:

3.48 (1 H, s),

3.61 (3 H, s),

3.3-3.9 (2H, m),

4.10, 4.38 (2H, ABq, J = 14 Hz),

4.77 (2 H, s),

5.12 (1 H, d, J = 5 Hz),

5.78 (1 H, d, J = 5 Hz).

41] 7- [З-ДПо 4-amino-2 - ((-amino-1,2,4 (thiadiazolOpyl) ace tamido) -3- (2-methyl-5 - ((O-O-6-hydroyy-2,5-dihydro- 1,1,1-triazine (3 (-yl) thiomethyl-3-cephem-4-carboyylic acid (syn isomer), m.p. 169-173 ° C (dec.).

IC (nujol):

3360, 3210, 1775, 1670, 1625, 1560, 1520,

1250, 1175, 1100, 1020 cm ¹

NMR (d6 -DMSO) δ:

3.3-4.0 (2H, m),

3.58 (3 H, s),

C-COHN

COO lad 6

O-C-COOC-CH

I I

CСП

4.0 - 4.6 (2H, m);

4.5 - 4.8 (2H, m),

5.13 (1H, d, J = 5 Hz),

5.0 - 5.6 (3H, m),

5.81 (1H, dd, J = 5 and 9Hz),

8.18 (2H, broad s),

9.53 (1H, d, J = 9 Hz).

Example 5

To a solution of N- [7- (2-tert-butoxycarbonylmethylamino) -2- (5-amino) (1,1,1-th-adazol (3 (yl) acetamido-3-piperidin-3-trimethyl) ] pyrimidine ((1-carboxylate (syn (1.8 g) in formic acid (18 ml)) was added concentrated hydrochloric acid (0.5 ml) and the mixture was stirred for one hour at room temperature. under reduced pressure, the residue is taken up in acetone powder, collected by filtration, washed with acetone and diisopropyl ether to give a powder, and the powder is dissolved in water (5 ml) and subjected to column chromatography on a non-oily resin by adsorption D 2. iaion HP-20 (trademark of Mitsubishi Chemica! Industries] (50 mL). The column was washed with water (500 mL) and eluted with 40% aqueous methanol. The eluates containing the compound prepared were collected, evaporated to remove methanol. under reduced pressure and lyophilized to give a white powder of N- [7- [1-2]-akabo Xymethoxyxy-no-2 ((5 (am-nO (-0,2,1-thiadiazo-3-yl) acetamido-3-chloro-3-ylmethyl) pyrimidine-1-carboxylate (syn isomer) (800 mg) ] m.p. 150-155 ° C (dec.).

IC (nujol):

3350, 3200, 1780, 1680, 1530 cm ' ¹

NMR (D 6 O + NaHCO 3) δ:

3.27 and 1.63 [dl, ABq, J ==111-Izz,

4.70 (^ 1 ^, s),

5.30 (1H, d, J = 4Hzz,

5.40 and 1.66 [(H, = Bq, J = 11 Hz),

5.93 (1 H, d, J = 4Hzz,

8.0-9.1 (5H, m).

C-COHN

O-C-COO228145

To a cold mixture of trifluoroacetic acid (22 mL) and anisole (4.4 mL) was added N- [7- (2- (1-methyl-1-butoxycarbonylethoxyimino) -2- (5-amino-1,2,4-) -). thiadiazol-3-yl) acetamide-3-ephemylmethyl] pyridinium-4-carboxylate (3.18 g) and the mixture was stirred for 40 minutes at room temperature.

The mixture was evaporated to remove trifluoroacetic acid and the residue triturated with isopropyl ether to give a yellow powder. The powder was dissolved in aqueous sodium bicarbonate, adjusted to pH 1 with 6N hydrochloric acid, and washed with ethyl acetate. The aqueous solution was subjected to column chromatography using Diaion HP-20 nonionic adsorption resin (140 mL). The column was washed with water and eluted with 5% and 10% aqueous isopropyl alcohol. The eluates containing the prepared compound were collected, evaporated to remove isopropyl alcohol under reduced pressure, and lyophilized to give N- [7-) 2- (1-methyl-1-carboxyethoxyimino) -2- (5-amino-1, 2-carboxylic acid). 2,4-thiadiazol-3-yl) acetamido-3-cephem-3-ylmethyl pyridinium-4-carboxylate (syn isomer) (2.20 g) as a white powder, m.p. 176-180 ° C (dec.) ).

IR (nujol):

3400 to 3100, 1770, 1670, 1620, 1520 and

NMR (d 6 -DMSO + D 2 O) <5:

1.48 (6H, s);

3.10, 3.62 (2H, ABq, J = 18 Hz),

5.12 (1 H, d, I = 5 Hz),

5.45 (2 H, m),

5.78 (1 H, d, J = 5 Hz),

8.13 (2 H, m),

8.58 (1 H, m),

9.38 (2 H, m).

Example 7

The following compounds were prepared in a similar manner as described in Examples 10 and 11.

1) N- [7- (2- (1-Carboxyethoxyimino) -2- (5-amino'-1,2,4-thiadiazol-3-yl) acetamide} -3-chloro-3-ylmethyl) -4 170 DEG-175 DEG C. (with decomposition), n-carbamoylpyridine-4-carboxylate (syn isomer).

IR (nujol):

3300, 3160, 1770, 1680, 1610, 1560,

1520 cm2) N- [7-) 2- (1-carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido} -3-chloro-4-ylmethyl-pyridinium-4- carboxylate (syn isomer), m.p. 175-180 ° C (dec.).

IR (nujol):

3300, 3200, 1775, 1670, 1620, 1520 cmNMR (D 2 O + NaHCO 3) δ:

1.50 (3 H, d, J = 7 Hz),

3.25 and 3.67 (2H, ABq, J = 18Hz),

4.40 - 4.90 (1H, m),

5.32 (1 H, d, J = 5 Hz),

5.42 and 5.60 (2H, ABq, J = 15Hz),

5.83 - 6.00 (1H, m),

7.9 - 9.1 (5H, m).

3) N- [7- (2-Carbhoxymethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido) -3-cephem-3-ylmethyl-4'-carbamioylpyridinium-4 -carboxylate (syn isomer), m.p. 175-180 ° C (dec.).

IC (nujol):

3350, 3200, 1775, 1680, 1615, 1505,

1525 cm ⁴

4) N- [7- (2- (1-Methyl-1-carboxyethoxyinino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamide} -3-methyl-3-ylmethyl)] 4'-carbanoylpyridinium-4-carboxylate (syn isomer), m.p. 180-185 ° C (dec.).

IR (nujol):

3300, 1770, 1680, 1620, 1560, 1520 cm ⁴

Example 8

A mixture of 7- [2-trityloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido) -3- (1-pyridinionethyl) -3-cephem-4-carboxylate (syn isomer) ( 5.55 g) and concentrated hydrochloric acid (2.3 mL) in formic acid (60 mL) was stirred at room temperature for two hours.

The aqueous, insoluble material was filtered off, the filtrate was evaporated to dryness and the residue was pulverized with acetone and collected by filtration. The powder was dissolved in water (13 mL) and subjected to column chromatography on Diaion HP-20 nonionic adsorption resin (commercial name from Mitsubishi Chemical Industries) (100 mL) using water as the eluent. The eluates containing the compound to be prepared are collected and lyophilized to give a yellowish-white powder of 7- [2-hydroxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido-3- (1- -3- [eta] &lt; 4 &gt; -4-carboxylate (syn isomer) (675 mg), temperature m.p. 170-175 ° C (dec.).

IR (nujol):

3350, 3200, 1780, 1610, 1530, 1490 cm ^-1

NMR (d 6 -DMSO + D 2 O) δ:

3.14, 3.54 (2Η, ABq, J = 18Hz),

5.08 (8H, d, J = 5 Hz),

5.28, 5,, 2 J2H, ABq, J = 18Hz),

5.86. (1H, d, J 1 = 5/2),

7.92 - 8.24 (2H, m),

8.40 - 8.68 (8H, m),

9.16 - 9.42 (2H, m).

Example 9

N

c-cooh

To a cold solution of phosphorus pentachloride (20.8 g) in methylene chloride (375 mL) was added 2- (2-cyclopenten-1-yloxyimino) -2 (5-amino-1,2,4-thiadiazole-3). -yl) acetic acid (syn isomer) (25.4 g) at -88 ° C and the mixture is stirred for 40 minutes at -82 to -80 ° C. Diisopropyl ether (8.2 L) is added to the reaction mixture. ) at -80 ° C with stirring, which is continued until the mixture is warmed to room temperature, the precipitate is filtered off, washed with diisopropyl ether and kept in a desiccator for several minutes.

Separately, a mixture of 1 - [(7-amino-4-carboxy-3-cephem-3-yl) methyl] pyridinium chloride hydrochloride dihydrate (30.77 g) and trimethylsilyl acetamide (854.5 g) in methylene chloride (800 mL) was heated to 35 ° C to dissolve, then cool to -88 ° C. The above precipitate was added to the cold solution and the mixture was stirred for 30 minutes at -82 to -80 ° C. A solution of sodium bicarbonate (22 g) in water (400 ml) was added to the reaction mixture and the aqueous layer was separated, adjusted to pH 8.5 with 2N hydrochloric acid and washed with ethyl acetate. The aqueous solution was adjusted to 4 with aqueous sodium bicarbonate solution and passed through a column filled with acidic alumina (7 g). Potassium throcyanate (56.2 g) and sodium chloride (878.5 g) were added to the eluate (8.2 L) and then the pH of the mixture was adjusted to 2.2 with 1N hydrochloric acid while cooling in an ice bath. Sodium chloride (878.5 grams) was added to the filtrate and the pH of the solution was adjusted to 1N with hydrochloric acid.

8.2 with stirring and cooling in an ice bath. The resulting precipitate was filtered off, washed with cold water (850 ml twice) and dried to give 1- [7-- {2- (2-cyclo-penten-1-yloxyimino) -2- (5-amino-1)]. (2,4-thiadiazol-3-yl) acetamido-4-carboxy-3-cephem-3-yl / methyl] pyridinium thiocyanate (syn isomer) (28.8 g), m.p. 858-852 ° C ( decomposition).

1P (nujol):

2050, 8780, 8270, 8230, 8280, 8530 cm

NMR (d 6 -DMSO + D 6) δ:

8.2-2.7 (4H, m),

3.33 - 3.22 (2H, ABq, J = 88 Hz),

5.20 (8H, d, J = 5 Hz),

4.9 - 2.3 (5H, ia,

5.82 (8H, d, J = 5 Hz),

8.2 (2H, m).

8.7 (8H, m).

9.85 (2 H, m).

Example 80

8- [1- [2- (5-Amino-1,2,4-thiadiazol-3-yl) acetamido] -4-carboxy-3-carboxamide; 3-yl / methyl] pyridinium iodide (syn isomer) was obtained in a similar manner as described in Example 84 using sodium iodide instead of potassium thiocyanate.

1C (nujol):

3400-3800, 8775, 8270, 8220, 8520 cm

NMR (d 6 -DMSO + D 6)

5:

8.2 - 2.8 (4H, m),

3.35, 3.80 (2H, ABq, J = 19 Hz),

5.31 (1 H, d, J = 5 Hz),

5.93 (1 H, d, J = 5 Hz),

5.0 - 6.4 (5H, m),

8.28 (2 H, m),

8.74 [m 111]

9.15 (2 H, m).

Example 11

To a solution of 1- [η 7 - [2- (2-cyclopenten-1-yloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamide] -4-carboxy-3- cef em-3-yl] methyl] pyridinium thiocyanate (syn isomer) (11.7 grams) in dimethylformamide (30 mL) was added a solution of lithium chloride [1.7 g] in methanol (20 mL) with stirring in which continue for 10 minutes at ambient temperature. The insoluble material was filtered off, washed with dimethylformamide (6 ml) and then the filtrate and wash solution were combined. The combined solution was added to acetone (300 mL) with stirring, which was continued for 5 minutes at room temperature. The resulting precipitates were filtered off, washed with acetone (3 x 40 mL each) and dried in vacuo to give 1- [(7--2-2-yloxy-enen-1-yloxy-ylamino) -2-5-] - amino-1,2,4-thiadiazol-3-yl) acetamido} -4-carboxy-3-methyl-3-ylmethyl] pyridinium chloride (syn isomer) (11.0 g).

IR (nujol):

3400 - 3100, 1780, 1660, 1530, 1530 cm -1

NMR (d 6 -DMSO) (δ:

1.6 - 2.6 (4H, m)

3.39, 3.61 (2H, ABq, J = 18 Hz),

5.19 (1 H, d, J = 5 Hz),

4.9 - 5.6 (2H, m),

5.64 (1H, broad s),

5.81 (1H, dd, J = 5 and 8Hz),

5.7 - 6.2 (2H, m),

8.20 (2H, mj,

8.64 (1 H, m),

9.22 (2 H, m),

9.48 (1H, d, J = 8Hz).

Example 12

Purification of the prepared compound

Powder (0.2 g) 7- [2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-31-trimethyl-3-yl) The 4-carboxylate (syn isomer) was dissolved in water (0.8 mL), acetone (1.6 mL) was added dropwise and stirred at ambient temperature. After five minutes, stirring was stopped and the solution was allowed to stand for 1 min. The resulting colorless needles were filtered, washed with 90% aqueous acetone (2 x 1 mL each) and acetone (3 x 1 mL each), and dried for 9 hours under reduced pressure to give colorless needles. 7- [2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yilacetamido) -3- (1-pyridinomethyl) -3-cephem-4-carboxylate acetone adduct as monohydrate ( syn isomer) (120 mg), m.p. &gt; 155 DEG C. (dec.).

IR (nujol):

3430 - 3120, 1760, 1700, 1680, 1615, 1531 cm ^-1

NMR (D 2 O) <5:

1.32 (3H, t, J = 7 Hz),

2.26 (6 H, s),

3.20 and 3.72 (2H, ABq, J = 17Hz),

4.37 (2H, q, J = 7Hz),

5.30 (1 H, d, J = 5 Hz),

5.35 and 5.66 (2H, ABq, J = 14 Hz),

5.91 (1H, d, J = 5Hz),

8.12 (2 H, m),

8.61 (1 H, m),

8.98 (2 H, m).

Analysis for:

C19H19N7O5SS. CsHsO. H2O calculated:

46.72 C, 4.81 H, 1.073 ^ 4 N, 3.18 H2O found:

46.79 C, 4.79 H, 16.72 N, 3.24 H2O Example 13

Purification of the prepared compound

2-Ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (11.4 g) and 1 - [(7-amino-4-carboxk-3)] -cephem-3-yl) methylpyridinium chloride hydrochloride dihydrate (24 g) was reacted in a similar manner to that described in Example 1.

Water (300 mL) was added to the reaction mixture, and the pH of the mixture was adjusted to 1.5 with aqueous sodium hydroxide, and the mixture was subjected to column chromatography on Diaion HP-20 nonionic adsorption resin (960 mL). The column was washed with water (3.6 L) and eluted with 30% aqueous methanol (1.26 L). The eluates were collected, concentrated under reduced pressure to a volume of 110 mL. The solution was subjected to column chromatography on alumina (120 g) and eluted with water. Eluates containing 7- [2-ethoxyquino-2- (5-amino) -11- (2-methyl-2-carboxylic acid) -3- ( 1-Pyridinyl ethyl) -3-cephem-4-carboxylate (syn isomer) (310 mL) was collected and acetone (1.1 L) was added with stirring at ambient temperature for 5 minutes. The mixture was stirred for 1.5 hours under ice-cooling and the precipitates were collected by filtration, washed with 90% aqueous acetone (80 mL) and acetone (240 mL) and dried under reduced pressure to give crystals (20 g). 7- [2-ethoxyimino-2- (5-amino-1,2,4-thiodiazol-3-yl) acetamido] -3- (1- (1-fluorophenyl) -3-cephem-4-carboxylate acetone) adduct (syn isomer). Dissolve the crystals in water (40 mL) and pass the solution through a column filled with acidic alumina (40 g). Elute with water and collect the eluates (140 mL). Acetone (300 mL) was added to the solution at ambient temperature and stirring was terminated in a minute. The mixture was allowed to stand for 20 minutes at ambient temperature and for 1.5 hours in a refrigerator. The resulting colorless needles were filtered off, washed with 90% aqueous acetone (25 mL) and acetone (25 mL), each with aqueous acetone and acetone three times, dried for 3.5 hours under reduced pressure to give pure , colorless needles 7- [2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-pyridiniomethyl) -3cephem-4-carboxylateocetone adduct (syn isomer melting point greater than 157 ° C.

Example 14

Purification of the prepared compound

A solution of 7- [2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-pyridinomethyl) -3-cephem-4-carboxylateocetone adduct (syn isomer) (1.0 g) in water (1 ml) was allowed to stand for 5 days in a freezer at -20 ° C. The ice-precipitate mixture is allowed to stand at ambient temperature until the ice melts. The resulting precipitate was collected by filtration, washed with water (0.3 mL) and dried in vacuo to give 7- [2-ethoxyimino-2- (5-omino-1,2,4-thiadiazol-3-yl)]. ocetamidoyl-3- (1-pyridinomethyl) 3-cephem-4-carboxylate (syn isomer) (0.52 g) as colorless needles, m.p. 165-170 ° C (dec.).

IR (nujol):

3450 - 3200, 3070, 1765, 1665, 1630, 1600, 1530, 1485 cm ^-1

NMR (D 6) δ:

• 1.32 (3H, t, J = 7 Hz),

3.20 o 3.72 (2H, ABq, J = 17 Hz),

4.33 (2H, q, J = 7Hz); 5.27 (1H, d, J = 5Hz);

5.34 o 5.65 (2H, ABq, J = 14Hz),

5.89 (1 H, d, J = 5 Hz),

8.10 (2 H, m),

8.60 (1 H, m),

8.97 (2 H, m).

Example 1 and d 15

Purification of the prepared compound

To a solution of 7- [2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-pyridinomethyl) -3-cephem-4-carboxylic acid lactone adduct ( syn isomer) (40 g) in water (50 ml) was added a molar amount of colorless needles 7- [2-ethoxyimino-2- (5-omino-1,2,4-thiodiozol-3-yl) acetamido] -3 - (1-pyridinomethyl) -3-cephem-4-carboxylate (syn isomer) was stirred for 1 hour in an ice bath. The resulting precipitate was collected by filtration, washed with cold water (33 mL) and dried in vacuo for 10 hours to give 7- [2-ethoxyimino-2- (5-amino-1,2,4-thiodiazole-3). -yl) acetomido] -3- (1-pyridinomethyl) -3-cephem-4-carboxylate dihydrate (syn isomer) (24.7 g), as colorless needles, m.p. 170-175 ^° C (dec.).

Water content (KF method) calculated:

6.72 o / o found:

6.20%

Example 16

Purification of the prepared compound

7- [2-Methoxyimino-2- (5-omino-1,2,4-thiadiazol-3-yl) acetamido) -3- (1-pyridinomethyl) -3-cephem-4-carboxylate powder (syn isomer) (7.7 g) was dissolved in water (15.4 ml) and the solution was allowed to stand overnight in the refrigerator. The precipitate was filtered off and washed with 80% isopropyl alcohol (5 ml) and isopropyl alcohol (5 ml), air dried for one hour and dried in vacuo for two hours to give the needles 7- [2]. -methoxyimino-2- (5-amino-1,2,4-thiodiazol-3-yl) ocetamido] -3- (1-pyridinomethyl) -3-cephem-4- (4-carbonyl) ethyl (syn isomer) ( 4.2 g), m.p. 165-170 ° C (dec.).

IR (nujol):

3300, 3200, 1765, 1670, 1630, 1605,

1550 - 1520 cm ^-1

NMR (D 2 O) δ:

3.24, 3.70 (2H, ABq, J = 18 Hz),

4.06 (3 H, s),

5.28 (1 H, d, J = 5 Hz),

5.36, 5.60 (2H, ABq, J = 14 Hz),

5.87 (1 H, d, J = 5 Hz),

8.06 (2 H, m),

8.54 (1 H, m),

8.95 (2 H, m).

Claims (9)

OBJECT OF THE INVENTION A process for the preparation of 7- [2-hydroxyimino- or substituted-oxyimino-2- [amino-substituted-1,2,4-thiadiazolyl] acetamido-] -3-substituted-methyl-3-methyl-3-methoxy-4- derivatives carboxylate or 7- (2-hydroxyimino) or substituted oxyimino-2- (amino-substituted-1,2,4-thiadiazolyl) acetamido] -3-substituted methyl-3-cephem-4-carboxylic acid of formula I wherein: means R1 is amino R ² is hydrogen, C 1 -C 4 alkyl optionally substituted by carboxy, C 2 -C 5 alkoxycarbonyl, phenylalkoxycarbonyl C 2 -C 5 alkoxy, C 1 -C 4 alkylthio, phenyl or halogen, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, cycloalkyl (C 3 -C 6), (C 3 -C 6) cycloalkenyl, or oxo-substituted tetrahydrofuryl, R 3 is a group of the general formula where R is X is hydrogen or carbamoyl; and R 4 is COO- or is R3 is 2-alkyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazinylthio having 1 to 4 carbon atoms in the alkyl moiety and, R 4 carboxy, a wavy line means that both syn and anti isomers are included, provided that R ^{2 is} not a cyclopentyl group, a cyclopentenyl group, or: 1-methyl-1-carboxyethyl group when R 3 is a group of the formula CONH _Z and pharmaceutically acceptable salts and adducts thereof, characterized in that a compound of formula II is reacted wherein: R 3 and R 4 are as defined above, or an amino-reactive derivative thereof, or a salt thereof - with a compound of formula III wherein: R ¹ and R ² are as defined above, or with a reactive derivative thereof on the carboxy group or a salt thereof, and optionally from a compound of formula I wherein R ² is C 2 -C 5 alkoxycarbonylalkyl and 1 to 4 or C 2 -C 5 phenylalkoxycarbonylalkyl having 1 to 4 carbon atoms in the alkyl moiety eliminates the carboxy-protecting group to form a compound of formula I wherein R 2 is C 1 -C 4 carboxyalkyl or a hydroxy protecting group is eliminated from the compound of formula (I) in which R @ ² represents a triphenyl alkyl group having 1 to 4 carbon atoms in the alkyl moiety to give a compound of formula (I) in which R @ ² is hydrogen. 2. The process of item 1, for preparing a compound of formula I, wherein R1 and R2 are as defined in item 1, and wherein R3 is a group of formula wherein: X is hydrogen or carbamoyl; and R ^{4 is a} group of formula COO-, characterized in that a compound of formula II is reacted with a compound of formula III, wherein the symbols are as defined above. 3. The method of claim 1, py preparing a compound of, formula I, wherein R ¹ has in point 1 above, R ² represents an alkyl group having 1 to 4 carbon atoms, R3 is a group of the formula wherein ....... .. ..... X is hydrogen and R 4 is a group of formula COO -, characterized in that a compound of formula II is reacted with a compound of formula III, wherein the symbols are as defined above. 4. The process of item 1, for the preparation of a compound of formula I wherein R1 and R2 are as defined in item 1, R3 is 2-alkyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4 C1 -C4 -triazinylthio and R4 carboxy, characterized in that a compound of formula (II) is reacted with a compound of formula (III), the symbols being as defined above. 5. Method according to claim 1 for preparing a compound of formula I, wherein R ¹ has in point 1 above, R2 represents an ethyl, propyl or iso.přopylovou, R3 is a group of formula wherein X is hydrogen and R4 is a COO- group, characterized in that a compound of the formula II is reacted with a compound of the formula III, the symbols being as defined above. 6. The process of item 5, for preparing a compound of formula I, wherein the moiety has the formula R 2 is ethyl and R 1, R 3, R 4 are as defined in item 5, in the form of a synisomer, characterized in that a compound of formula II is reacted with a compound of formula III, wherein the symbols are as defined above and they are in the form of syn isomers. 7. The process of item 1, for preparing a compound of formula I, wherein R ¹ , R 2, R 3 and R 4 are as defined in item 1, provided that R 2 is not a C 1 -C 4 alkyl group when R 3 is a group of the formula wherein * X is as defined in item 1, characterized in that a compound of formula II is reacted with a compound of formula III, wherein the symbols are as defined above. 8. The method of item 2 for preparing a compound of formula I wherein R1 is as defined in item 1, R2 is 1-methyl-1-ethoxycarbonylethyl, carboxymethyl, methoxycarbonylmethyl, cyclohexenyl, 1-methyl-1-carboxyethyl or 1- methyl-1-tert-butoxycarbonylethyl and the other symbols have at point A compound of formula (I) as defined above II with a compound of formula (III), wherein the symbols are as defined above. 9. The process of clause 3, for preparing colorless needles of the syn isomer of 7- (2-ethoxyimino-2-) -5-amino-1,2,4-thiadiazol-3-yl (acetamido) -3- (1-pyridinomethyl) 3-Cephem-4-carboxylate, its acetone addition product, its acetone addition product monohydrate or dihydrate or colorless needles syn isomer of 7- (2-methoxyimino-2-) -5-amino-1,2,4-thiadiazo 3-yl (acetamido) -3- (1-pyridinomethyl) -3-cephem-4-carboxylate, characterized in that a compound of formula II is reacted with a compound of formula III, wherein the individual symbols have the corresponding importance.