CS228149B2 - Preparation of derivatives of 7/2-hydroxyimino or substituted 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-carboxylic 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 cephem compounds and their pharmaceutically acceptable salts are effective against numerous pathogenic microorganisms. They are used as active ingredients of pharmaceutical preparations for the treatment of both human and animal patients.

The present invention provides novel cephem compounds which are derivatives of 7- [2-hydroxyimino- or substituted oxyimimo-2- (amino-substituted-1,2,4-thiadadolyl) ucetamido] -3-substituted methyl-3-ces ( of the compound of formula I

R ¹ an amino group,

R ² is hydrogen, C 1 -C 4 alkyl optionally substituted by carboxy, C 2 -C 5 alkoxycarbonyl, C 2 -C 5 phenylalkoxycarbonyl, C 1 -C 4 alkylthio, phenyl or a halogen atom, furthermore a (C 2 -C 4) alkyl group, a (C 3 -C 6) cycloalkyl group, a (C 3 -C 6) cycloalkenyl group, or an oxo-substituted tetrahydrofuryl group,

R @ ³ group of the formula ·

where it means

where it means

X is hydrogen or carbamoyl; and

R ⁴ is COO or R ^{3 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, wavy line means that both syn and anti isomers are included, provided that R ^{2 is} not a cyclopeininity group, a cyclopentenyl group or a 1-methyl-1-carboxyethyl group when R ³ is a group of the formula

CONU4 and pharmaceutically acceptable salts thereof, by reacting a compound of formula II

a cycloalkyl radical having 1-4 carbon atoms in the alkyl moiety, or of the compound of formula I wherein R ² represents írifenylalkylovou group having 1 to 4 carbon atoms in the alkyl moiety, eliminating a hydroxy protecting group to give a compound of formula I wherein R ² represents a hydrogen atom.

Formula II also includes tautomeric isomers.

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

II l

R ¹ (R ¹ as defined above) contained in the molecule of the preparation and the starting material may also alternatively be present in its tautomeric form

R @ ¹ and R @ ^2, m ^and had the abovementioned meaning,

R ^3a represents a reactive group optionally substituted by a group of formula R ³ , wherein R ³ has the above meaning of a

R ^4a represents a carboxy group when R ^3b represents a compound of the general formula

(R ¹ is imino or a protected imino] Both of these groups are in the state of equilibrium each other and such tautomerism can be represented by the equation:

where

UN-_

X is as defined above, or

R ^4a represents a carboxy group when:

R ^3b represents a compound of the general formula R ^3c -H where is

R ^3c 2-alkyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazinylthio having 1 to 4 carbon atoms in the alkyl moiety, or a salt thereof, with a compound of formula III

R ^3b (ΙΠ) wherein R ^3b is as hereinbefore defined, or a reactive derivative thereof, and optionally from an obtained compound of formula I wherein R ² represents an alkoxycarboinylalkyl group having 2 to 5 carbon atoms in the alkoxy moiety of up to 4 carbon atoms in the alkyl moiety or a phenylalkoxycarbonylalkyl group having 2 to 5 carbon atoms in the alkoxy moiety of up to about 4 carbon atoms in the alkyl moiety, eliminates the carboxy protecting group to give a compound of formula I wherein R ² is carboxyalkyl R ¹ and R ¹ 'are as defined above.

These types of tautomerism between the amino compound and the corresponding amino compound as described above are well known in the literature and are obvious to those skilled in the art that both tautomeric forms of the isomers can readily be 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. Prepared and starting compounds containing a group of such tautomeric isomers are, however, referred to only for the group of the formula

In addition, the compound of formula I and the starting compound of formula II include the prepared compounds and starting materials in the form of the syn isomer and anti isomer, and mixtures thereof. 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 with NOP ² wherein R ¹ and R ² are as defined above and the antisomer is a different geometric ^: somer having a partial structure corresponding to the general formula

Wherein R ¹ and R ² are as defined above.

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, magnesium, ammonium salts, organic base salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicycohexylamine salt, N, N'-dibenzylethylenediamine salt, orgamic acid salts such as stay, maleate, tartrate, methanesulfonate, benzenesulfonate, format, toluenesulfonate, inorganic acid salts such as for example, hydrochloride, hydrobromide, hydroiodide, thiocyanate, sulfate, phosphate, or amino acid salts such as larginine, aspartic acid or glutamic acid salts and the like.

The term "lower" refers to 1 to 4 carbon atoms unless otherwise specified.

A compound of formula I or a salt thereof can be prepared by reacting a compound of formula II or a salt thereof with a compound of formula III or a reactive derivative thereof.

A suitable salt of a compound of formula (II) is 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 or metal. a salt such as a sodium, potassium, calcium, magnesium, and ammonium salt, or an organic amine salt, such as a triethylamine salt, a dicyclohexylamine salt, and the like.

A suitable reactive derivative compound ^; The formula (III) may be a metal salt such as an alkali metal salt, for example a sodium or potassium salt or the like.

The reaction may be carried out in a solvent such as water, phosphate buffer, acetone, chloroform, nitrobenzene, methylene chloride, ethylene chloride, dimethylformamide, methanol, ethanol, ether, tefrahydrofuran, dimethylformamide or any other organic solvent that does not adversely affect the reaction, preferably a strong polarity solvent. If solvents ^{1 are} hydrophilic, they may be < Use in admixture with water.

The reaction is preferably carried out in an approximately neutral environment. When a compound of formula II or a compound of formula III is used in free form, the reaction is preferably carried out in the presence of a base such as an alkali metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, in the presence of an organic base such as trialkylamine or the like . The reaction temperature is not critical, typically the reaction is conducted at a temperature of heat ^l under warming or under moderate heating.

This reaction also includes the case where a protected carboxy group is converted to a free carboxy group during the reaction.

The geometric isomer and / or tautomeric isomer obtained in the reaction may optionally be converted to another geometric isomer and / or itautomeric isomer.

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) has significant anitimicrobial properties and high antimicrobial activity and inhibits the growth of a number of 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 compositions comprising a compound of formula I together with pharmaceutically acceptable carriers such as organic and 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 has proven to be effective. 100 mg, 250 mg, and 500 mg of a compound of formula 2228149 are effective for the treatment of infectious diseases caused by numerous pathogenic bacteria. In general, an amount of a daily dose of 1 mg / individual to 1000 mg / individual or even a larger amount may be administered.

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

Test method

A full loop overnight culture of each test strain in trypticase soy broth (10 ⁸ viable cells per ml) is streaked onto irtfusion agar (HI-agar) containing graduated antibiotic concentrations and expressed as the minimum inhibitory concentration (MIC) as? g / ml after incubation for 20 hours at 37 ° C.

Test compounds

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

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

3) 7- (2- (2-propiinyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido) -3- (1-pyridinomethyl) -3-methyl-4- carboxylate (syn isomer)

4) 7- [2-cyclopentyloxyimino-2- (5-amino-1,2,4-thladiazol-3-yl) acetamido] -3- (1-pyridiiniomethyl) -3-cephem-4-carboxylate (syn isomer )

5) 7- (2- (2-cyclopent-l-yloxyimino) -2- (5-amino-l, ^{2,4-thiadiazol;} azole-3-y1) acetamido] -3- (l-pyridiniomethyl) - 3-cef em -4-carboxylate (syn isomer)

6) 7- [2-methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-pyridimiomethyl) -3-cephem-4-carboxylate (syn isomer)

7) 7- [2-isopropoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl Jaicetamido) -3- (2-meithyl-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-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (4-carbamoyl-1-pyridinomethyl) -3-cef em-4-carboxylate (syn isomer) co

Test results

Test bacteria Test compound Μ. I.C. (µg / ml) to

Ml

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With respect to 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-thiazadol-3-yl) acetamido] -3- (1-pyridinomethyl) -3-cephem-4-carboxylate (syn isomer) or N- {7- [2-methoxyimino-2- (5-amino-1,2,4H-thiadiazol-3-yl) acetamido] -3-chloro-3-ylmethyl] pyrimidin-4-carboxylate (syn isomer) Further, the hydrochloric acid salt of compound (B) is referred to as 1 - [(7-amino-4-carboxy-3-cephem-3-yl) methyl] pyrimidinium chloride or N- [7-amino-3-cephem-3]. -ylmethyl] pyridinium-4-carboxylate hydrochloride.

Other compounds prepared by the process of the invention and within the scope of the invention are referred to accordingly.

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- mo-1,2,4-thiadiazole-3-carboxylate

To a solution of 1-ethoxycarbonylformmiamidine hydrobromide (16.6 g) in absolute methanol (84 mL) was added a solution of sodium (1.93 grams) 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 is filtered through cellulose powder and the filtrate is evaporated to dryness. 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 5-amino-1,2,4-thiadiazole-3-carboxylate (9.0 g), m.p. 202-205 ° C.

IR (nujol):

3400, 3250, 3100, 1710, 1610, 1540 ^cm-first

NMR (d ₆ -DMSO, δ):

3.85 (3H, sj,

8.25 (2H, sj.

Preparation 2

Preparation of m, ethyl-5-formamido-1,2,4-thiole ^; adiazole-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) and then stirred for two days at a temperature of rooms. The reaction mixture was concentrated under reduced pressure and the residue was triturated with a mixture of diethyl ether and n-hexane to give meithyl-5-formamide-1,2,4-thiadiazole-3-carboxylate (7.2 g) at a temperature mp 210-215 ° C.

IR (nujol j:

3100, 1720, 1680 ^cm-first

NMR (d 6 -DMSO, δ):

3.90 (3 H, s).

8.85 (1 H, s).

Preparation 3

Preparation of 5-formamido-3- (2-methylthio -? - methylsullfinylaceityl) -l, ^2,4-th: thiadiazol

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

Company ID (nujolj:

3100, 1680, 1670 ^cm-first

NMR (d ₆ -DMSO, δ '):

2.22  (2H, 2s) 2.28. 2.68 (2H, 2s) 2.85. 5.70  (1H, 2s) 5.80 8.86 (1H, H) Ex a v a 4

Preparation of S-methyl- (5-formamido-1,2,4-thiadiazol-3-yl) thioglyoxylate

A mixture of 5-formamido-3- (2-methylthio-2-methylsulifinylacetyl) -1,2,4-thiadiazole (0.85 g) and sodium periodate (0.2 gj in glacial acetic acid (10 mL)) was stirred for The reaction mixture was evaporated and the residue was dissolved in a mixture of ethyl acetate and water, the mixture was adjusted to pH 7 with aqueous sodium bicarbonate solution and treated with aqueous sodium thiosulphate solution. The residue was triturated with diethyl ether and petroleum ether to give S-methyl- (5-formamido-1,2,4-thiadiazol-3-yl) thoglyoxylate (280 mg) at a temperature mp 186-187 ° C.

IR (nujol):

3100, 1680, 1660 cm ^-1 .

NMR (d 6 -DMSO, δ):

2.55 (3 H, s),

8.95 (111.3).

Preparation 5

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

(1-azol-3-yl) thioglyoxylate (231 mg) in methanol (2 ml) and 1N aqueous potassium hydroxide solution (3.5 ml) were stirred for one hour at ambient temperature. The pH of the mixture was adjusted to 7.6 with 1N hydrochloric acid, then O-methylhydroxylamine hydrochloride (90 mg) was added and stirred for 30 minutes at ambient temperature. The reaction mixture was neutralized with aqueous bicarbonate solution and concentrated to remove methanol. 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. The extract was evaporated to dryness and the residue was triturated with diethyl ether, the product collected by filtration and dried to give 2-methoxyimtao-2- (5-formylamido-1,2,4-thiad; azoi-3-yl) oic acid ( syn isomer) (80 mg], m.p. 185-186 ° C).

IR (nujol):

3150, 1720, 1690 ^cm-first

NMR (d ₆ -DMSO, _δ ):

3.98 (3H, 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) -1,2,4-thiadiazole (3.2 g) and sodium periodate (0.8 g) in glacial acetic acid (32 mL) was stirred. for 45 minutes at 70 ° C. The reaction mixture was evaporated and the residue was washed with n-hexane, then methanol (20 ml) and 1N aqueous potassium hydroxide solution (40 ml) were added and the solution was stirred for one point at ambient temperature. 8N 1N hydrochloric acid was added, 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 pH was adjusted to 10 with 10% hydrochloric acid saturated with sodium chloride and extracted with ethyl acetate, 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.

A mixture of S-methyl- (5-formamido-1,2,4-thia228149)

Preparation 7

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

A solution of 2-mefhoxyimino-2- (5-formamldo-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (1.4 gj in 1N aqueous sodium hydroxide solution (19.1 ml) was maintained at 50-55 ° C for 1 hour Concentrated hydrochloric acid (1.9 ml) was added to the solution while cooling in an ice bath, saturated with sodium chloride and extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated to dryness. . the residue was triturated with d ^f ethyleiíhere «m to give 2-methoxyimino-2- (5-amino-l, 2,4-thiadiazol-3-yl) acetic acid (syn isomer) (0.9 g) mp mp 180-182 ° C (dec.).

IR (nujol):

3450, 3250, 3100, 1715, 1610, 1530 cm ^-1 .

NMR (d -DMSO _fi a):

3.90 (3 H, s),

8.10 (3H, broad s).

Preparation 8

A mixture of 5-formamido-3- (2-methylthio-2-methylsulfanylacetyl) -1,2,4-thladiazole (10 g) and sodium periodate (2.0 g) in glacial acetic acid (50 mL) was stirred for 50 minutes. 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 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, The pH was adjusted to 10 with 10% hydrochloric acid and extracted with ethyl acetate, dried over magnesium sulfate and evaporated to dryness, and the residue triturated with diethyl ether and diisopropyl ether to give 2-ethoxyimino-2-i5-formamido-1,2,4- thiodiazol-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 ^- L

NMR (d6-DMSO, a):

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

4.30 (2H, q, I = 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 (d 6 -DMSO, δ):

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

1.4-1.9 (2 H, m),

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

8.85 (1 H, s).

2. 2-Isopropoxy. ^: Amino-2- (5-formamido-l, 2,4-thiadiazol-3-yl) acetic acid (syn isomer), mp 180 to 182 ° C.

IR (nujol):

3230, 1720, 1690, 1590, 1530 cm ¹ .

NMR (d 6 -DMSO, δ):

1.25 (6H, d, I = 6Hz),

4.2-4.7 (1H, m),

8.85 (1 H, s).

Preparation 10

A mixture of 2-ethoxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (4.4 g) and 1N aqueous sodium hydroxide solution (54 mL) was stirred for for two hours at 50-55 ° C. The mixture was cooled in an ice bath, acidified with hydrochloric acid (5.4 mL) and extracted with ethyl acetate. The extract was dried over magnesium sulphate and evaporated to dryness. The residue was triturated with diethyl acetate to give 2-ethoxyimino-2- (5-amino-1,2,4-thiodiazol-3-yl) acetic acid (syn isomer (2.92 g), m.p. 168-170 ° C ( decomposition).

IR (nujol):

3450, 3370, 3250, 3150, 1665, 1610, 1539 cm ^-1 .

NMR (d 6 -DMSO, δ):

1.22 (3H, f, 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:

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-first

NMR (d ₆ -DMSO, δ):

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

1.3-2.0 (2Ή, m),

4.13 (1H, t, J = 6 Hz),

8.17 (2H, broad s).

2) 2-Isopropoxylamino-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 ^1st

NMR _[G d -DMSO, 5):

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

4.1-4.6 (1 H, m),

8.20 (2H, broad s).

Preparation 12

(1) A mixture of N-hydroxyphthalimide (8.15 g), striethylamine (5.05 g), N, N-dimethylformamide (60 mL) and 1-bromo-2-cyclohexene (8.05 grams) is stirred for 3, 5 hours at room temperature. The reaction mixture was poured into water (300 mL). The precipitated crystals were collected by filtration, washed successively with water and n-hexane and then dried to give N- (2-cyclohexein-1-yloxy) phthalimide (9.8 g), m.p. 87 ° C.

Company ID (nujolj:

1770, 1720, 1610 cnv ¹ .

NMR (d ₆ -DMS0) .delta

1.50-2.17 (6 H, m),

4.60-4.77 (1 H, m),

5.73-6.27 (2 H, m),

7.90 (4 H, s).

(2) A mixture of N-hydroxyphthalimide (58.2 g), 1-chloro-2-cyclopenphene (36.9 g), triethylamine (53.9 g) in acetonitrile (370 mL) was treated as described in paragraph 1. to give N- (2-cyclopentanen-1-yloxy) ifthalimide (56.5 g).

IR (nujol):

1780, 1730, 1610 ^cm-first

NMR (d ₆ -DMSO, δ):

7.92 (3 H, s),

6.28 (1H, mj,

6.00 (1H, mj,

5.42 (1 H, m),

2.9 - 1.98 (4H, inter alia.

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-cyclopenteu-1-yljoxyamine) is added to a solution of sodium 2-S-formamido-1 H-thiadiazol-5-yl] glyoxylate (22.4 g) in water. The pH of the mixture is adjusted to 2 with 10% The mixture was stirred for two hours and then concentrated, adjusted to pH 10 with 10% hydrochloric acid, and the precipitate collected by filtration and dried to give 2- (2-cyclopentan-1-yl) oxyimino-2- ( 5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (20.0 g), m.p. 150 DEG C. (dec.).

IR (nujol):

3400, 3100, 1720, 1690, 1540 cm ¹ .

NMR (d ₆ -DMSO, _δ ):

1.80-2.50 (4 H, m),

5.30-5.50 (1 H, m),

5.83-6.30 (2 H, m),

8.90 (1 H, s).

2) A mixture of N- (2-cyclohexen-1-yloxy) -fitalimide (7.29 g), hydrazine hydrate (1.5 g) in ethanol (40 ml) was maintained at reflux for 5 ml ^. nut. The reaction mixture was cooled and filtered. to obtain a filtrate containing (2-cyclohexen-yljoxyamin (filtrate If Separately, a mixture of S-methyl-1-2- (5-fo.unamldo-l, ^9-4 khiadiazol-3-yl) thioglyoxylátu (6.93 gj in aqueous 1N sodium hydroxide solution (90 ml) was stirred for 30 minutes at room temperature and the reaction mixture containing sodium 2- (5-difluoramido-1,2,4-thiadiazol-3-yl) glyoxylate was adjusted to pH 7% 10% hydrochloric acid was added to the filtrate, and then the pH was adjusted to 3 with 10% hydrochloric acid, the mixture was stirred for three hours at room temperature, the reaction mixture was concentrated and ethyl acetate was added to the concentrate. 1 is set to 10 '% hydrochloric acid. the precipitate was collected by filtration from the typist ^f 2- (2-cyclohexen-1-yl) oxyimtoo-2- (5-formamido-l, 2,4-thiadiazol 3-yl) acetic acid (syn isomorph) (2.5 g) Separate the ethyl acetate layer from the filtrate and evaporate and triturate with diethyl ether. The total yield was 4.0 g. The product had a melting point of 190 DEG-192 DEG C. (with decomposition).

IR (nujol):

3550, 3400, 3200, 2500, 1690, 1590, 1540 cm ^-1 .

NMR (d ₆ -DMSO, <5):

1.5-2.3 (6H, m);

4.73-5.0 (1 H, m),

5.76-6.23 (2 H, m),

8.97 (1 H, s),

13.60 (1H, broad s).

3) To a solution of sodium hydroxide (11.2 grams) in water (140 mL) was added S-methyl-2- (5-formamido-1,2,4-thiadiazol-3-yl) thioglyoxylate (27 g) at 10 ° C and the mixture is stirred for 30 minutes at 20 degrees Celsius. The reaction mixture containing sodium 2- (5-formamido-1,2,4-thiadiiazol-3-yl) glyoxylate is cooled, adjusted to pH 7 with 10% hydrochloric acid, and cyclopentyloxyamine solution (15, 3 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-cyclopemtyloxyimino-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 an amount of 8.1 g. Total yield 12.09 g, mp 180-185 ° C (dec.).

IR (nujol):

3130, 3040 2680 2610 2520 1720 1690

1660, 1550, 1600 ^cm-first

NMR (d 6 -DMSO, SS):

1.33-2.10 (8H, m),

4.67-5.0 (1 H, 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-thiadiazol-3-yl) acetic acid (syn isomer) (20.0 g) -a IN aqueous sodium hydroxide solution (200 mL) was stirred at 50-55 ° C for 1 hour. The reaction mixture was cooled, adjusted to pH 7 with 10% hydrochloric acid, and ethyl acetate was added. The mixture was adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated. The residue was powdered with diisopropyl ether to give 2- (2-cyclopenten-1-yl) oxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer). mp 150 ° C (dec.).

IR (nujol):

3300, 3150, 1710, 1620, 1520 cm ^-1 .

NMR (d ₆ -DMSO, _δ ):

1.80-2.50 (4H, m),

5.30-5.50 (1 H, m),

5.83-6.30 (2 H, m),

8.20 (2 H, 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.

IR (nujol):

3400, 3300, 3200, 1720, 1620, 1600, 1520 ^cm-first

NMR (d 6 ₎ -DMSO, δ:

1.50-2.17 (6H, m),

4.53-4.83 (1 H, m),

5.57-6.13 (2 H, 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 ^1st

NMR (d -DMSO _G TS):

1.17-2.10 (8H, m),

4.60-4.97 (1 H, m),

8.22 (2 H, s).

Preparation 16

A mixture of 5-formamido-3- (2-methylthio-2-methylsulfinylacetyl) -1,2,4-thiadiazole (10 g) and sodium periodate (2.0 g) in glacial acetic acid (50 mL) was stirred 50 min at 70 ° C. The solvent was evaporated and the residue was washed with n-hexane. To the residue was added 1N aqueous sodium hydroxide solution (160 mL), and the mixture was stirred for one hour at ambient temperature. O-allylhydroxylamine hydrochloride (4.31 g) was added to the reaction mixture and the pH of the solution was adjusted to 3-4 with 10% hydrochloric acid and then stirred for one hour at ambient temperature. The insoluble material was then filtered off, the filtrate was washed with ethyl acetate and the pH was adjusted to 1 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 a mixture of diethyl ether and diisopropylether to give 2-allyloxyimino-2- (5-formamido-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (5.6 g), temperature mp 169-172 ° C (dec.).

IR (nujol):

3130, 2500, 1720, 1690, 1590, 1550 cm ¹ .

NMR (d ₆ -DMSO, _δ ):

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

5.1-5.6 (2 H, m),

5.8-6.4 (1 H, 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-propynyloxyimino) -2- (5-formamido-1,2,4-triazol-3-yl) acetic acid (syn isomer), m.p. 150-155 ° C (dec.).

IR (nujol):

3570, 3360, 3260, 1720, 1670, 3120, 1550,

1530 cm ^1st

NMR (d ₆ -DMSO, δ):

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

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

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 . Preparation 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 pH 8 with 10% hydrochloric acid, 5 and stirred for 30 minutes at ambient temperature. Separately, a mixture of N- (2,2,2-triifluoroethoxy) phthalimide (8.78 g) and hydrazine hydrate (1.7 g) in ethanol (40 mL) was refluxed for 5 minutes and then cooled. in an ice bath. The resulting precipitate was filtered off and washed with ethainol. The filtrate and wash solution were combined and this combined solution containing O- (2,2,2-trifluoroethyl) hydroxylamine was 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 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- (2,2,2-trifluoroethoxyimino-2- (5-aminamido-1,2,4-thiadiazol-3-yl) acetic acid). (syn isomer) (2.46 g), m.p. 180-185 ° C (dec.).

NMR (d6-DMSO, a):

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

IR (nujol):

3300, 2600, 2550, 1730, 1705, 1680, 1600

1530 cm ^-1 .

NMR (d ₆ -DMSO, _δ ):

2.23 (3H, s).

5.40 (2 H, s),

8.87 (1 H, s).

Preparation 20

A mixture of S-methyl- (5-formamido-1,2,4-thiadiazol-3-yl) thioglyoxylate (6 g) and an aqueous solution (50 ml) of sodium hydroxide (4.2 g) was stirred for 1 hour at a temperature of Mp 50-55 ° C. The mixture was cooled to ambient temperature and the pH was adjusted to 10 with 10% hydrochloric acid. Separately, a mixture of N- (epoxycarbonylmethoxy) phthalimide (12.9 g) and hydrazine hydrate (2.08 g) in ethanol (60 ml) was maintained at The filtrate and wash solution were combined and the combined solution containing O- (ethoxycarbonylmeithyl) hydroxylamine was added to the above aqueous solution. The pH of the mixture was adjusted to 3-4 with 10% hydrochloric acid, stirred for one and a half hours at ambient temperature, neutralized with aqueous sodium bicarbonate solution, concentrated to half volume in vacuo and washed with ethyl acetate. The extract was dried over magnesium sulphate, evaporated to dryness and the residue triturated with diisopropylether. m to give 2-ethoxycarbonylmethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (1.8 grams), m.p. 135-140 ° C ( decomposition).

IR (nujol):

3500, 3330, 3210, 2670, 2550, 1740, 1610,

1540 cm ^1st

NMR (d -DMSO _fi, 5):

1.24 (3H, <t, J = 7Hz);

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

4.80 (2 H, s),

8.15 (2H, broad s).

Preparation 21

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

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

Company ID (nujolj:

3450, 3350, 3240, 1750, 1730, 1630, 1530 cm ^1st

NMR (d -DMSO _G, DJ:

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

1.50 (6H, sj,

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

8.23 (2H, broad sj.

Preparation 22

The following compounds were prepared in a similar manner to that described in Preparation 14.

Ij 2-Allyloxyimino-2- (5-amino-l, 2,4-thiadiazol-3-yl) acetic acid (syn isomer), m.p. 93-95 ^Q C (decomposition).

IR (nujol):

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

NMR (d ₆ -DMSO, δ):

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

5.1-5.5 (2 H, m),

5.7-6.3 (1 H, m),

8.17 (1H, broad s).

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

IR (nujol):

3500, 3310, 3160, 2600, 2480, 1745, 1610,

1535 cm ^1st

NMR (d ₆ -DMSO, d):

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

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

8.23 (2H, broad s).

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

IR (nujol):

3450, 3350, 3260, 1745, 1670, 1645, 1615,

1515 cm ^-1 .

NMR (d 6 -DMSO, d):

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 (dec.).

IR (nuiol):

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

1605, 1530 cm ^-1 .

NMR (d 6 -DMSO, d):

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.). IR (nujol):

3450, 1735, 1620, 1540 cm ^-1 .

NMR (d -DMSO _fi, d):

7.35 (15H, s);

8.22 (2 H, s).

Preparation 23

To a mixture of 2-hydroxyimino-2- (5-formamido-1,2,4-thiodiazol-3-yl [acetic acid (syn isomer) (9.5 g) and dimethylformamide (80 ml) was added under stirring at ambient temperature. trityl chloride (22.8 g) and trlethylamine (4.1 g) were then added sequentially after stirring for 3 minutes, followed by stirring for 10 minutes, then ethyl acetate (250 ml) was added, and the mixture was washed three times with water and saturated aqueous solution. NaCl, dried (MgSO4) and concentrated to an aqueous sodium bicarbonate solution (50 mL) and diisopropyl ether (100 mL). The mixture was adjusted to 2 with 10% hydrochloric acid, then extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo. 2-trityloxyimino-2- (5-formamido-l, 2,4-thiadiazol-3-yl) acetic acid (syn isomer) (17.1 g), mp 175-176 ° C (dec).

IR (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).

N- (1-it-Butoxycarbonylethoxy goalimide, m.p. 80-82 ° C).

NMR _(d, DMSO, Aj:

1.42 (1H), s,

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

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

7.86 (4H, s.

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

NMR (d -DMSO _fi, 5):

1.42 (9H, sj,

1.48 (6H, sj,

7.87 (4H, sj.

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

Company ID (nujoll:

1790, 1740, 1450, 1210, 1199, 1110, 1080,

980, 880, 735, 700 cm ^-1 .

4) N- (2-oxo-3-itetrahydrofuryloxy) -phthalimide, m.p. 140-142 ° C;

IR (nujol):

1785 1760 1720 1605 1215 1185 870

G95 cm ^-1 .

Preparation 25

The following compounds were obtained in a similar manner to that described in Preparation 20.

2- (tert-butoxycarbonylmethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer), m.p. 150 DEG-155 DEG C. (dec.).

IR (nujol):

3420, 3230, 3100, 1725, 16.10, 1530 cm ^-1 ,

NMR (d -DMSO _fi, A)

1.45 (9H, s);

4.70 (2H, sj,

8.12 (2H, broad s).

2) 2- (1-tert-butoxycarbonylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn Isomer j, m.p. 155-156 ° C (dec.) .

IR (nujol):

3400, 3300, 3200, 1720, 1710, 1620, 1520 cm ^-1 ,

NMR (d ₆ -DMSO, _δ ):

1.2-1.7 (12H, t),

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

8.2 (2H, broad s).

J 2- (1-tert-butoxycarbonyl-l-methylethoxy imino j -2- (5-amino-3-2,4dhiadiazol -acetic acid methyl ester acid (syn isomer), mp 180 to 181 ^Q C (decomposition) .

IR (nujol):

3400, 3300, 3200, 1745, 1715, 1630, 1530 cm ^-1 .

NMR (d 6 -DMSO, δ):

1.38 (9H, sj,

1.43 (6H, sj,

8,15 2H, broad sj.

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

IR (nujol):

3300, 3200, 1720, 1620, 1530 cm ^-1 .

NMR (DMSO-d6, δ):

1.45 (3 H, d, j = 6 Hzj 4.97 (1 H, q, J = 6 Hzj 5.18 (2H, sj, 7.31 (SH, s) 8.17 (2H, broad with ) ·

Preparation 26

S-methyl- (5-formamiamido-1,2,4-thiadiazol-3-yl) thioglyoxylate (64.8 g) and 1-carboxy-3-hydroxypropoxyamine, which was prepared by maintaining the reflux temperature of a mixture of N- (2-oxo-3). - (tetrahydrofuryloxy) phthalimide (65 g), concentrated hydrochloric acid (50 ml) and water (200 ml) for one hour is 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.) .

IR (nujol):

3400, 3250, 3100, 1710, 1620, 1540 cm ^-1 .

NMR (DMSO-d6, <5):

1.73-2.10 (2H, mj,

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

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

8.13 (2H, sj.

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 and the mixture was stirred at ambient temperature for 30 minutes, filtered, and the filtrate was evaporated to dryness. 1 liter) was added to the mixture, the mixture was stirred at ambient temperature for one hour and the precipitate was collected by filtration and washed with ethyl acetate.

Dissolve the precipitate in water (200 mL) and then add ethyl acetate (500 mL), acetone (200 mL) and 6N hydrochloric acid (40 mL). 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 diethylleither, filtered and washed with diisopropyl ether to give 2- (2-oxo-3-tetrahydrofuryloxyimino) -2- (5-amtoo-1,2,4-thiadiazol-3-yl) acetic acid ( syn isomer (265 g), m.p. 185-187 ° C (dec.).

IR (nujol):

3400, 3300, 3200, 1775, 1730, 1640, 1605,

1535 cm ^1st

NMR (d ₆ -DMSO, δ):

2.27-2.70 (2H, m),

4.17-4.50 (2H, m)

5.27 (lH, it, J = 8Hz),

8.22 (2 H, s),

Preparation 28

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

2-Methoxycarbonylmethoxyimino-2- (5-amino-1,2,4-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 _(DMSO-d6) .delta

3.73 (s),

4.87 (2 H, s),

8.2 (2 H, bs).

Preparation 29

The following compound was obtained in a similar manner to that described in Preparation 30.

7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] cep alosporenic acid (syn isomer), m.p. 140-145 ° C (dec.).

IR (nujol):

3480, 3370, 3250, 1785, 1730, 1680, 1630,

1530 cm ^1st

NMR (d ₆ -DMSO, SS):

1.33-2.17 (8H, m),

2.03 (3 H, s),

3.57 (2H, broad s),

4.60-4.90 (1 H, m),

4.73 and 4.97 (2H, ABq, J = 13 Hz),

5.15 (1 H, d, J = 5 Hz),

5.80 (1H, dd, J = 5 and 8 Hz),

8.10 (2H, broad s),

9.47 (1H, d, J = 8Hz).

Preparation 30

To a cold solution of phosphorus pentachloride (10.4 g) in meithylene chloride (250 mL) was added 2-cyclopenityloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetic acid (syn isomer) (12.8 g) at -18 ° C and stirred for 15 minutes at -13 to -10 ^and C. Separately heat the 7-amino-3-acetoacetoxymethyl-3-cofem-4 mixture. -carboxylic acids (15.7 g) and trimethylsilyl acetamide (50 g) in methylleichloride (250 mL) to give a clear solution and cool to -10 ° C.

The cold solution was added to the above mixture and the mixture was stirred for 25 minutes at -10 ° C. The reaction mixture was poured into an aqueous solution (500 mL) of sodium bicarbonate (29.5 g) and stirred for 15 minutes at room temperature. The aqueous layer was separated, adjusted to pH 2 with 6N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with diethyl ether to give a powder

7- [2-cyclopentyloxyimino-2- [5-amino-1,2,4-thiadiazol-3-yl] acetamido] -3-acetacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer (13,5) g), m.p. 130-135 ° C (dec.).

IR (nujol):

3300, 1780, 1720, 1680, 1620, 1525 cm ^-1 .

NMR (DMSO-d ₆ , _δ ):

1.3-2.0 (8H, m),

2.15 (3 H, s),

3.52 (2 H, bs),

3.60 (2 H, s),

4.5-4.7 (1 H, m),

4.77, 5.00 (2H, ABq, J = 14Hz),

5.13 (1 H, d, J = 4 Hz),

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

8.10 (2 H, s),

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

Preparation 31

To a solution of 7- [2- (1-tert-butoxycarbonylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-acetoacetoxymethyl-3-cephem-4-carboxylic acid ( syn isomer) (5.16 g) in formic acid (50 ml) was added concentrated hydrochloric acid (1.7 ml) and the mixture was stirred for 30 minutes at room temperature. The solvent was distilled off under reduced pressure and the residue was powdered with diethyl ether and collected by filtration to give a brownish powder. The powder was dissolved in a mixture of ethyl acetate and water and the pH was adjusted to 7 with a saturated aqueous sodium bicarbonate solution with stirring. The aqueous layer was separated and ethyl acetate was added. The mixture was adjusted to pH 1 with 6N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was powdered with diethyl ether, collected by filtration, washed with the same solvent, and dried over anhydrous phosphorus pentoxide to give a brownish powder of 7- (2- (1-carboxyethoxyimino) -2- (5-amino-1,2-diene). 3,4-thiadiazol-3-yl] acetamido-3-acotoacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer) (3.7 g), m.p. 95-100 ° C (dec.).

IR (nujol):

3450, 3350, 3230, 1780, 1720, 1630, 1525 cm ^1st

NMR (d ₆ -DMSO, _δ ):

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

2.20 (3H, s).

3.58 (2H, broad s),

3.67 (2 H, s),

4.65-5.30 (3H. M),

5.22 (1H, d, j = 5 Hz),

5.77-6.10 (1 H, m),

8.23 (2H, broad s),

9.40-9.68 (1 H, m).

Preparations and 3 2

The following compounds were obtained in a similar manner as described in Preparations 30 and 31.

1) 7- (2- (2-Cyclopentan-1-yloxyimino) -2- (5-amino-1,2,4-hiadiazol-3-yl) acetamido] -3-aceitoacetoxymethyl-3-cephe-4-carboxylic acid ( syn isomer), m.p. 135-140 ° C (dec.).

IR (nujol j:

3400, 3300, 3200, 1775, 1735, 1710, 1675,

1620, 1525 cm ¹ .

NMR (d ₆ -DMSO, δ):

1.93-2.47 (4 H, m),

2.18 (3 H, s),

3.55 (2 H, bs),

3.65 (2 H, s),

4.80, 5.07 (2H, ABq, J = 13Hz),

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

5.23-5.53 (1 H, m),

5.70 - 6.23 (3H, m),

8.12 (2 H, bs),

9.50 (1.11, d, 1H).

2) 7- (2-karboxymethoxyimiino-2- (5-amino-l, 2,4-thiadiazol-3-yl) aceiiamido] -3-acetoacetoxymeťhyl-3-cephem-4-carboxylic kyse28 ¹ Lina (syn isomer), mp 95-100 ^° C (dec.).

IR (nujol):

3400, 3290, 3190, 1770, 1720, 1615, 1520 cm ^{@ -1} .

NMR (d 6 -DMSO, SS):

2.17 (3 H, s),

3.53 (2 H, bs),

3.63 (2 H, s),

4.67 (2 H, s),

4.80, 5.07 (2H, ABq, J = 13 Hz),

5.15 (lH, d, j = 5Hz),

5.87 (1H, 2d, J = 5 and 8 Hz),

8.15 (2 H, bs),

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

3) 7- [2-tert-Buxycarbonylmethoxyimimo-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-acetoacetoxymethyl-3-cep-4-carboxylic acid (syn isomer mp 105-110 ° C (dec.).

IR (nujol):

3350, 3250, 1780, 1720, 1620, 1525 cm ¹ .

NMR (d6-DMSO, a):

1.43 (9H, s);

2.17 (3 H, s),

3.53 (2 H, bs),

3.63 (2 H, s),

4.63 (2 H, s),

4.82, 5.05 (2H, ABq, J = 13 Hz),

5.15 (lH, d, J = 5Hz),

5.85 (1H, 2d, J = 5 and 8 Hz),

8.15 (2 H, bs),

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

4) 7- (2- (1-tert-Butoxycarbonylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido) -3-acetoacetoxymethyl-3-cephem-4- carboxylic acid (syn isomer), brownish powder, mp 11.0-115 ° C with decomposition).

IR (nujol):

3400, 3300, 3200, 1780, 1720, 1620, .1525 cm ¹ .

NMR (d6-DMSO, <$):

1.40 (3H, d, J = 7Hz),

1.42 (9H, s);

2.17 (3 H, s),

3.57 (2 H, bs),

3.63 (2 H, s),

4.58 - 5.22 (3H, m),

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

5.73-5.97 (1 H, m),

8.10 (2H, bs),

9.33-9.57 (1 H, m).

5) 7- (2- (1-Methyl-1-carboxyethoxy) amino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-aceitoacetoxymethyl-3-cephem-4-carboxylic acid acid (syn isomer), mp 180-185 ° C (dec.).

IR (nujol):

3350, 3230, 1730, 1720, 1625, 1525 cm ¹ .

NMR (cl ₆ -DMS0, 0):

1.47 (6H, sl,

2.17 (3H, s,

3.55 (2 H, bs),

3.62 (2 H, s),

4.80, 5.03 (2H, ABq, J = 14 Hz),

5.17 (1H, d, J = 4Hz);

5.87 (1H, 2d, J = 4 and 8 Hz),

8.13 (2 H, s),

9.47 (1H, d, J = 8 @ 1 -Is).

6) 7- (2- (1-Methyl-1-tert-butoxycarbonylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido) -3-acetoacetoxymethyl-3-ceifem- 4-carboxylic acid (syn isomer), m.p. 140-145 ° C (dec.).

IR (nujol):

3350, 3250, 1785, 1720, 1620, 1530 cm ¹ .

NMR (d ₆ -DMSO, 0):

1.47 (6H, s).

1.50 (9H, s).

2.17 (3 H, s),

3.57 (2H, bs), [lambda] &lt; 2H &gt;

4.80, 5.07 (2H, ABq, J 14 Hz),

5.17 (1H, d, J = 4Hz);

5.86 (1H, 2d, J = 4 and 8Hz),

8.13 (2 H, s),

9.43 (1H, d, J = 8);

7) Sodium 7- [2-Ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-acetoacetoxymethyl-3-cephem-4-carboxylate (syn isomer), m.p. 175-180 ° C (dec.).

Company ID (inujol):

3450, 3300, 3100, 1790, 1720, 1670, 1640,

1610, 1550 ^cm-first

NMR (D ₂ O) 0:

1.38 (3H, t, J = 6Hz),

2.34 (3 H, s),

3.44, 3.66 (2H, ABq, J = 18Hz),

4.40 (2H, q, J = 6Hz);

5.05, 5.86 (2H, ABq, J = 12 Hz),

5.26 (1H, d, J = 4 Hz),

5.90 (1H, d, J = 4Hz).

8) 7- [2-Methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-acetoacetoxymethyl-3-cep-4-carboxylic acid (syn isomer), mp 120-125 ° C (dec.).

IR (nujol):

3350, 3250, 1780, 1710, 1680, 1630, 1530 ^cm-first

NMR (D ₂ O + NaHCO 3, O):

2.32 (3 H, s),

3.40, 3.62 (2H, ABq, J = 18Hz),

4.10 (3 H, s),

4.84, 5.04 (2H, ABq, J = 14Hz),

5.22 (H-d, d, J = 4Hz),

5.86 (1H, d, I = 4Hz).

9) 7- [2-Propoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-acetoacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer), temperature mp 125-130 ° C (dec.).

IR (nujol):

3350, 3250, 1780, 1710, 1680, 1620, 1530 cm ^1st

NMR (D ₂ O + NaHCO 3, O):

0.94 (3 H, t, J = Hz),

1.5-1.9 (2H, m)

2.30 (3 H, s),

3.40, 3.62 (2H, ABq, J = 18Hz),

4.26 (2H, t, J = 6Hz),

4.84, 5.04 (2H, ABq, J = 12Hz),

5.22 (1H, d, J = 4 Hz),

5.86 (1H, d, J = 4Hz).

10) 7- [2-Isopropoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-acetoacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer), m.p. 95 to 100 degrees Celsius (with decomposition).

IR (nujol):

3400, 3300, 3200, 1775, 1740, 1710, 1670,

1620, 1525 ^cm-first

NMR (d -DMSO _B, 0)

1.28 (6H, d, I = 6Hz),

2.18 (3 H, s),

3.48, 3.60 (2H, ABq, J = 18Hz),

3.62 (2 H, s),

4.24-4.54 (1 H, m),

4.78, 5.02 (2H, ABq, J = 13 Hz),

5.14 (1H, d, J = 5Hz),

5.80 (1H, dd, J = 5 and 8 Hz),

8.06 (2H, broad s),

9.44 (1H, d J = 8Hz).

11) Sodium 7- [2-Allyloxyimiino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-acetoacetoxymethyl-3-cephem-4-carboxylate (syn isomer), iteplota mp 160-170 ° C (dec.

IR (nujol):

3450, 3300, 3100, 1790, 1720, 1670, 1550 cm ^-1 .

NMR (D ₂ O) 0:

2.31 (3 H, s),

3.33, 3.64 (2H, ABq, J = 18Hz),

4.6- 5.1 (4H, m);

5.1-5.5 (2 H, m),

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

5.8-6.3 (1 H, m),

5.84 (1H, d, J = 5Hz).

12) 7- (2- (2,2,2-Trifluoroethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido) -3-acetoacetoxymethyl-3-cephem-4-carboxylate sodium (syn isomer), m.p. 128-132 ° C (dec.).

IR (nujol):

3300, 1780, 1710, 1670, 1600, 1530 ^cm-first

NMR (D ₂ O) δ:

2.32 (3 H, s),

3.50, 3.63 (2H, ABq, J = 17Hz),

4.60-5.07 (4H, m),

5.23 (1H, d, J = 4Hz),

5.87 (1H, d, J = -4Hz).

13) 7- [2-Methylithiomethoxylmino-2- (5-amino-l, 2,4 ^j thiadiazol-3-yl) acetamido] -3-acetoacetoxymethyl-3-cephem-4-carboxylate (syn isomer), m.p. 180 to 190 degrees Celsius (with decomposition).

IR (nujol):

3500, 3200, 1770, 1670, 1620, 1530 ^cm-first

NMR (d -DMSO _fi, 5):

2.18 (3 H, s),

2.20 (3H, s).

3.16, 3.48 (2Ή, ABq, J = 18 Hz),

3.58 (2 H, s),

4.84, 5.08 (2H, ABq, J = 12 Hz),

4.86 (1 H, d, J = 5 Hz),

5.22 (2 H, s),

5.62 (1 H, dd, J = 5 and 8 Hz),

8.14 (2H, broad s),

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

14) 7- (2- (2-Propinyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido) -3-acetoacetoxymethyl-3-acetam-4-carboxylic acid (syn isomer), mp 90-95 ° C (dec.).

IR (nujol):

3400, 3280, 3200, 2100, 1770, 1740, 1710,

1670, 1620 ^cm-first

NMR (d6-DMSO, <5):

2.18 (3H s),

3.46 (1H, t, J = 2Hz),

3.46, 3.58 (2H, ABq, J = 18Hz),

3.62 (2 H, s),

4.76 (2H, d, J = 2Hz),

4.78, 5.02 (2H, ABq, J = 14 Hz),

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

5.80 (1H, dd, J = 5 and 8 Hz),

8.10 (2H, broad s),

9.60 (1 H, d, J = 8 Hz).

Preparation 33

The following compound was obtained in a similar manner to that described in Preparation 30.

7- [2-ethoxyimino-2- (5'-amino-1,2,4-thiadiazol-3-yl) acetamido] sodium disalosporanate (syn isomer), m.p. 180-185 ° C (dec.).

IR (nujol):

3480, 3430, 3250, 1780, 1730, 1665, 1635,

1610, 1540, 1515, 1400, 1280, 1240 1040 cm ^-1 .

Example 1

A mixture of 7- [2-cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] ceiphalosporanic acid (syn isomer) (5.1 g), sodium bicarbonate (840 g) , water (50 mL), potassium thiocyanate (24.3 g) and isonicotinamide (1.83 g) were stirred at 50-55 ° C for 22 hours. The reaction mixture was cooled and added to ethyl acetate. The pH of the mixture was adjusted to 2 using 10% hydrochloric acid and the mixture was filtered. The aqueous layer was separated from the filtrate, washed with ethyl acetate and evaporated. The residue was subjected to column chromatography (non-ionic adsorption resin, Diaion HP20 from Mitsubishi Chemical Industries) and the column was washed with water (0.7 L) and then eluted with 30% aqueous methanol (0.7 L). The eluates containing the compound to be prepared are collected, washed with ethyl acetate and then evaporated. The residue was lyophilized to give N- (7- [2-cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-3-ylmethyl} 4'-carbamoylpyridine-l-4-carboxylate (sy isomer) (1.0 g), m.p. 230-235 ° C (dec.).

IR (nujol):

3300, 3200, 1770, 1680, 1610, 1560, 1520,

1510 cm ¹ .

NMR (d ₆ -DMSO, δ):

1.30-1.95 (8H, m),

3.15 and 3.50 (2H, ABq, J = 18 Hz),

5.60 - 5.75 (1H, m),

5.06 (1 H, d, J = 4 Hz),

5.30 and 5.65 (2H, ABq, H, J = 14Hz),

5.70 (1H, dd, J = 4 and 8 Hz),

8.12 (2 H, s),

8.45 (2H, d, J = 6Hz);

9.42 (2H, d, I = 6Hz),

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

Example 2

N

H, ^N = COCH 0 O

CH ^OCOCH ^COC H ~ Í p

-5 »N

H, S

N ¹¹

Z N

0 ° c <z

A mixture of 7- [2-cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazazol-3-yl) acetamido] -3-aceitoacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer) (2,8 g) sodium bicarbonate (420 mg), potassium iodide (28 grams) and pyridine (590 mg) in water (28 ml) were stirred at 55 ° C for one hour.

After cooling, ethyl acetate (20 ml) of 1N hydrochloric acid (5.5 ml) and acetone (10 ml) were added to the mixture with stirring. The aqueous layer was separated, washed with ethyl acetate, and concentrated to 30 mL under reduced pressure. Insoluble matter was filtered off and the filtrate was subjected to column chromatography on a nonionic adsorption resin Diaion HP20 (100 mL).

After washing the column with water (500 mL), elution was performed with 30% aqueous methanol. The aqueous eluates containing the prepared material were collected, evaporated to remove methanol under reduced pressure, and lyophilized to give N- {7- [2-cyclopentyloxyimiino-2- {5-amino-1,2,4-thiadiazol-3-yl " (acetamido) -3-cephem-3-ylmethyl) pyridinium 4-carboxylate (syn isomer) (620 mg) as a white powder, m.p. 180-185 ° C (dec.).

Company ID (mujol):

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

NMR (DMSO-d6, <S):

1.4-2.0 (8H, m);

3.17-3.53 (2H, ABq, J = 18Hz),

4.60-4.83 (1 H, m),

5.10 (III, d, J = 4Hz),

5.30, 5.83 (2H, ABq, J = 14Hz),

5.87 (1H, 2d, J = 4 and 8 Hz),

8.17 (2 H, s),

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

8.0-9.7 (5 H, m).

Example 3

The following compounds were prepared in a similar manner as described in Examples 1 and 2.

1) N- {7- [2- (2-Cyclopenten-1-yloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem 3-ylmethyl] pyridinium-4-carboxylate (syn isomer), m.p. 190-195 degrees C (dec.).

IR (nujol):

3350, 3200, 1780, 1660, 1620, 1530 cm ^-1 .

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

IR (nujol):

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

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

IR (nujol):

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

4) N- {7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-3-ylmethyl} pyridinium-4-carboxylate (syn isomer mp 180-185 ° C (dec.).

IR (nujol):

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

NMR (d ₆ -DMSO, _δ ):

1.4-2.0 (8H, m);

3.17, 3.53 (2H, ABq, J = 18Hz),

4.60-4.83 (1 H, m),

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

5.30 and 5.83 (2H, ABq, J = 14 Hz),

5.87 (1H, dd, J = 4 and 8 Hz),

8.17 (2 H, s),

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

8.0-9.7 (5 H, m).

5) N- {7- [2- (1-Carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-3-ylmethyl] -4'- k ^l arbamoylpyridi228149 nium-4-carboxylate (syn isomer, mp 170-175 ° C (dec).

IR (nujol):

3300, 3160, 1770, 1680, 1610, 1560, 1520 cm ¹ .

NMR (d -DMSO _c, 5):

1.38 (3H, d, J = 7Hz),

3.10-3.60 (2H, m),

4.40-4.83 (1 H, m),

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

5.28-6.00 (3H, m),

8.22 (2H, broad s),

8.48 (2H, d, J = 6Hz)

9.48 (2H, d, J = 6Hz)

9.32-9.65 (1H, inter alia).

6) N- {7- [2- (1-tert-Butoxycarbonyleithoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem-3- 160 DEG-165 DEG C. (dec.), methylmethylpyridinium-4-carboxylate (syn Isomer).

IR (nujol):

3290, 3160, 1770, 1725, 1670, 1620, 1525 cm ^{@ -1} .

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

IR (nujol):

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

j N- (7- [2- (1-Benzyloxycarbonylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-chloro-3-ylmethyl) pyridinium carboxylate (syn isomer ), mp 178 to 182 ^Q C (decomposition).

IR (nujol):

3250, 3150, 1770, 1670, 1620, 1520 cm ¹ .

9) N- (7- [2-Butoxycarbonylmethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-chloro-3-ylmethylamino} pyridinium-4-carboxylate (syn mp 184-188 ° C (dec.).

IR (nujol):

3400—3100, 1770, 1670, 1610, 1520 cm ¹ .

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

IR (nujol):

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

11) N- {7- [2-Carboxymethoxyimino-2- (5-amino-1,2,4-thiadlazol-3-yl) acetamido] -3-methyl-3-ylmethyl} -4'-carbamoylpyridinium 36

4-carboxylate (syn isomer), m.p. 175-180 ° C (dec.).

IR (nujol):

3350, 3200, 1775, 1680, 1615, 1565, 1525 cm ¹ .

NMR (d ₆ -DMSO-D ₂ O, α):

3.23, 3.55 (2H, ABq, J = 18Hz),

4.67 (2 H, s),

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

5.35, 5.72 (2H, ABq, J = 15 Hz),

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

8.43 (2H, d, J = 6Hz);

9.38 (2H, d, J = 6Hz).

12) N- {7- [2-Methoxycarbonylmethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-methyl-3-ylmethyl] pyridinium-4-carboxylate (syn isomer 165 DEG-170 DEG C. (with decomposition).

IR (nujol):

3300—3150, 1760, 1670, 1620, 1520 cm ¹ .

13) N- {7- (2- (1-Methyl-1-carboxyethoxyimino) -2- (5-amino-1,2,4-phiadiazol-3-ylacetamido) -3-cephem-3-ylmethyl) ( pyridinium 4-carboxylate (syn isomer), white powder, m.p. 176-189 ° C (dec.).

IR (nujol):

3400—3150, 1770, 1670, 1620, 1520 cm ¹ .

] N- {7- [2- (1-Methyl-1-ethoxycarbonylethoxyimino) -2- (5-amino-1,2,4-thiadlazol-3-yl) acetamido] -3-cephem-3-ylmethyl] pyridinium-4 -carboxylate (syn isomer), white powder, m.p. 164-168 ° C (dec.).

IR (nujol):

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

15) N- {7- [2- (1-Methyl-1-tert-butoxycarbonylethoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-cephem- 3-ylmethyl} pyridinium-4-carboxylate (syn isomer), m.p. 176-180 ° C (dec.).

IR (nujol):

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

16) N- {7- [2- (2-Cyclopesruten-2-yloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-formol-3-ylmethyl} 4'-carbamoylpyridinium-4-carboxylate (syn isomer), m.p. 155-160 ° C (dec.).

IR (nujol):

3300, 3150, 1770, 1675, 1610, 1560, 1520 cm &^lt; -1 ^&gt;.

NMR (d ₆ -DMSO, δ):

2.0-2.4 (4H, m);

3.17-3.67 (2H, m),

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

5.23-6.30 (6H, m),

8.27 (2H, broad s),

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

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

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

17) N- {7- [2- (1-Methyl-1-carboxyethoxyiminio) -2- (5-amino-1,2,4-hiadiazol-3-yl) acetamido] -3-cefem-3-y 180 DEG-185 DEG C. (with decomposition) IR (nujol): &lt; tb &gt;

3300, 1770, 1680, 1620, 1560, 1520 cm ^-1 .

18) 7- [2-Ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-pyridinomethyl) -3-acetyl-4-carboxylate (syn) 155 DEG-165 DEG C. (with decomposition). IR (nujol):

3400—3150, 1770, 1660, 1610, 1530 cm ^-1 .

7- [2-Propoxy-imino-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 .

20) 7- [2-Methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-pyridinomethyl) -3-methyl-4-carboxylate (syn isomer), mp 250 to 260 ^Q C (decomposition).

IR (nujol):

3400—3100, 1770, 1650, 1610, 1520 cm ¹ .

21) 7- [2- (Isopropoxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-pyridinomethyl) -3-cephem-d-carboxylate (syn isomeir), m.p. 160-165 ° C (dec.).

IR (nujol):

3270, 3180, 1770, 1660, 1610, 1525 cm ^-1 .

22) 7- [2-Allyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-pyridinomethyl) -3-cephem-4-carboxylate (syn isomer), temperature m.p. 160-165 (dec.).

IR (nujol):

3290, 3180, 1770, 1660, 1610, 1525 cm ¹ .

23) 7- (2- (2-Propinyloxyimino) -2- (5-amino-1,2,4-hiadiazol-3-yl Jacetamido) -3- (1-pyridinomeithyl) -3-cephem-4- carboxylate (syn isomer), m.p. 145-150 ° C (dec.).

IR (nujol):

3250, 2100, 1770, 1660, 1630, 1610, 1525 cm ^{@ -1} .

24) 7- [2-Hydroxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl Jacetamido) -3- (1-pyridinomethyl) -3-cephem-4-carboxylate (syn isomer) mp 170-175 ° C (dec.) IR (nujol):

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

25) 7- [2-Methylthiomethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl Jacetamido) -3 (1-pyridinomethyl) -3-cephem-4-carboxamide (syn isomer) m.p. 195-205 ° C (dec.).

IR (nujol):

3350 - 3150, 1770, 1670, 1620, 1520, 1150 cm ^-1 .

26) 7- [2-Trityloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl Jacetamido) -3- (1-pyridinomethyl) -3-cephem-4-carboxylate (syn isomer), mp 165-170 ° C (dec.).

IR (nujol):

3450, 1780, 1670, 1620, 1530, 1490 cm ^-1 .

27) 7- (2- (2,2,2-Trifluoroethoxyimino) -2- (5-aminio-1,2,4-thiadiazol-3-yl) acetamido) -3- (1-pyridinomethyl) -3-cef em-4-carboxylate (syn isomer), m.p. 150-155 ° C (dec.).

IR (nujol):

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

28) 7- [2-Ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (4-carbamoyl-1-pyridiniomethyl) -3-cephem-4-carboxylate (syn isomer), m.p. 160-165 ° C (dec.).

IR (nujol):

3300, 3200, 1780, 1680, 1620, 1570, 1530 cm ^-1 .

NMR (d ₆ -DMSO + D ₂ O, δ):

1.33 (3H, t, J = 7Hz),

3.33, 3.67 (2H, ABq, J = 18Hz),

4.35 (2H, q, J = 7Hz);

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

5.47, 5.67 (2H, ABq, J = 14 Hz),

5.90 (1 H, d, J = 4 Hz),

8.40 (2H, d, J = 7Hz);

9.17 (2H, d, J = 7Hz).

29) 7- (2- (2-Oxotetrahydro-furan-3-yloxyimino) -2- (5-aminio-1,2,4-thiadlazol-3-yl) acetamino) -3- (1-pyridinomethyl) -3-cephem 4-carboxylate (syn isomer), m.p. 140-145 ° C (dec.).

IR (nujol):

3350, 1780, 1670, 1620, 1530, 1490 cm ¹ .

30) 7- (2-Methoxy-imino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (4-carbamoyl-1-pyridinomethyl) -3-cephem- 4-carboxylate (syn isomer), m.p. 165-170 ° C (dec.).

IR (nujol):

3350, 3200, 1780, 1690, 1610, 1570, 1530 cm

NMR (D, O, .delta.):

3.33, 3.67 (2H, ABq, J = 18 Hz),

4.07 (3 H, s),

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

5.47 (5.67 (2H, ABq, J = 14Hz))

5.90 (1H, d, J = 4 Hz),

8.40 (2H, d, J = -7Hz),

9.17 (2H, d, J = 7 Hz).

31) 7- [2-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 degrees C (dec.).

IR (nujol):

3350, 3200, 1780, 1090, 1610, 1570, 1530 cm ^1st

NMR (D ₂ O, δ):

0.95 (3H, t, J = 7I-Is),

1.5-2.0 (2 H, m),

3.33, 3.68 (2H, ABq, J = 17Hz),

4.28 (2H, t, J = 7Hz),

5.33 (1 H, d, J = 4 Hz),

5.47, 5.70 (2H, ABq, J = 14Hz),

5.92 (1 H, d, J = 4 Hz),

8.42 (2H, d, J = 7Hz);

9.17 (2H, d, J 7 Hz).

32) 7- [2-Isopropoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (4-carbamoyl-1-pyridinylmethyl) -3-cephem-4- 155 DEG-160 DEG C. (dec.).

IR (nujol):

3350, 3220, 1780, 1680, 1615, 1570, 1530 cm ^{@ -1} .

NMR _{δ 6} -DMSO + D ₂ O, δ):

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

3.17, 3.48 (2H, ABq, J = 18Hz),

4.1-4.6 (1 H, m),

5.03 (1H, d, I = 5Hz),

5.25-5.63 (2H, ABq, J = 14Hz),

5.70 (1H, cl, j = 5Hz),

8.40 (2H, d, J = 6Hz);

9.45 (2H, d, J ₌ 6 Hz).

33) 7- [2-Allyloxyimino-2- (5-amino-1,2,4-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 .

NMR (d 6 -DMSO + D ₂ O, δ):

3.09, 3.50 (2H, ABq, J = 18Hz),

4.5-4.7 (2H, m),

4.9-5.4 (4H, m),

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

5.6-6.1 (1 H, m),

5.71 (1 H, d, J = 5 Hz),

8.43 (2H, d, J = 6Hz),

9.50 (2H, d, J = 6Hz).

34) 7- (2- (2,2,2-Trifluoroethoxyimino) -2- (5-amino-1,2,4-thiadiadol-3-yl) acetamido) -3- (4-carbamoyl-1-pyridiniomethyl) M.p. 160 DEG-165 DEG C. (dec.), -3-cephem-4-carboxylate (syn isomer).

IR (nujol):

3300, 3150, 1780, 1680, 1610, 1580, 1520 cm ^-1 .

NMR (D ₂ O, δ):

3.30, 3.67 (2H, ABq, J = 17Hz),

4.73, 4.97 (2H, ABq, J = 8Hz),

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

5.47, 5.67 (2H, ABq, j = 14 Hz),

5.92 (1 H, d, J = 4 Hz),

8.40 (2H, d, J = 7Hz),

9.20 (2H, d, J = 7Hz).

35) 7- [2-Methylthiomethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (4-carbamoyl-1-pyridiniorneithyl) -3-cephem-4-carboxylate ( syn isomer), m.p. 160-165 ° C (dec.).

IR (nujol):

3300, 3150, 1770, 1680, 1610, 1560, 1520 cm ^&lt; -1 ^&gt;.

NMR (d ₆ -DMSO + D ₂ O, δ):

2.23 (3 H, s),

3.15, 3.67 (2H, ABq, J = 18Hz),

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

5.32 (2 H, s),

5.00 - 5.57 (2H, m),

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

8.68 (2H, d, J = 6Hz);

9.50 (2H, d, J = 6Hz).

36) 7- [2- (2-Pfimyloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (4-carbanioyl-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 ,

22S143

NMR (d 6 -DMSO + D ₂ O, α):

3.23, 3.58 (2H, ABq, J = 18Hz),

3.45 (1 H, t, J = 2 Hz),

4.80 (2H, d, J = 2Hz)

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

5.35, 5.72 (2H, ABq, J = 14Hz),

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

8.47 (2H, d, J = 7Hz);

9.50 (2H, d, J = 7Hz).

Example 4

7- [2-Cyclopentyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-aceitoacetoxymethyl-3-carboxylic-4-carboxylic acid (syn isomer) reacted with 2-methyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazin-3-thiol in a manner similar to that described in Examples 1 and 2 to give

7- [2-cyclopentyloxyimino-2- (5-amino-1,2,4-thiadlazol-3-yl) acetamido] -3- (2-methyl-54Oxo-6-hydroxy-2,5-dihydro-1, 2-cyclopentyloxyimino-2- (5-amino-1,2,4-thiadlazol-3-yl) acetamido) 2,4-triazin-3-yl) ithiomethyl-3-ce fem ^{l-4-carboxylate} (syn isomer), mp 169 aIZ 174 ° C (dec).

Company ID (inujol):

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

1520, 1005 cm ^-1 .

NMR (D ₉ O + NaHCO 3, δ):

1.3-2.1 (8H, m);

3.63 (3 H, s),

3.4-3.9 (2H, m),

4.08, 4.40 (2H, ABq, J = 14Hz),

4.7-5.1 (1 H, m),

5.22 (1 H, d, J = 5 Hz),

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

Example 5

The following compounds were prepared in a similar manner as described in Examples 1, 2 and 4.

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

Company ID (nujoll:

3400—3150, 1760, 1660, 1640—1560, 1520,

1040 cm ^-1 .

NMR (D, O, δ):

3.64 (3 H, s),

3.48, 3.78 (2H, ABq, J = 18Hz),

4.08 (3 H, s),

4.00-4.56 (2 H, m),

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

5.82 (1H, d, J = 5Hz).

2) 7- [2-Ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (2-methyl-542)

Disodium oxo-6-oxido-2,5-dihydro-1,2,4-triazin-3-yl) thiomethyl-3-cephem-4-carboxylate (syn isomer), m.p. 255-265 ° C (dec.) ).

IR (nujol):

3400—3150, 1760, 1660, 1600, 1500, 1400, 1030 cm ^-1 .

NMR (D ₂ O, A):

1.35 (3H, t, J = 7Hz),

3.42, 3.80 (2H, ABq, J = 18Hz),

3.65 (3 H, s),

4.07, 4.43 (2H, ABq, J = 13 Hz),

4.38 (2H, q, J = 7Hz),

5.22 (1 H, d, J = 5 Hz),

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

3) 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) lithium-3-cephem-4-carboxylic acid (syn isomer), m.p. 158-164 ° C (dec.).

IR (nujol):

3450 - 3150, 1770, 1680, 1630, 1510, 126, 1180, 1100, 1030, 1010 cm ^-1 .

4) 7- (2-Isopropoxyimino-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) trifluoromethyl-3-cephem-4-carboxylic acid (syn isomer), m.p. 160 DEG-167 DEG C. (dec.).

IR (nujol):

3400, 3280, 3180, 1780, 1770, 1630, 1515, 1410, 1240, 1009 cm &^lt; -1 ^&gt;.

5) 7- (2- (2-Propinyloxyimino) -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. 161-166 ° C (dec.).

IR (nujol):

3260, 3180, 1770, 1670, 1620, 1520, 1335 cm @ ^-1 .

6) 7- [2-Allyloxyimino-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-cofem-4-carboxylic acid (syn isomer), m.p. 169 DEG-173 DEG C. (dec.).

IR (nujol):

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

1250, 1175, 1100, 1020 ^cm-first

Example 6

To a solution of N- {7- [2-tert-butoxycarbonyl228143 methoxy-amino-1- (5-amino-1,2,4-thiadiazol) -3-yl) acetamido] -3-tert-3-ylmethyl} pyridinium- 4-Carboxylate (syn isomer) (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. The solvent was distilled off under reduced pressure and the residue was pulverized with acetone, collected by filtration, washed with acetone and diisopropylether to give a powder.

The powder was dissolved in water (5 ml) and subjected to column ehromatography on a nonionic resin with Diaion HP 20 adsorption (trademark of Mitsubishi Chemical Industries) (50 ml).

The column was washed with water (500 mL) and eluted with 40% aqueous methanol. The eluates containing the prepared compound were collected, evaporated to remove methanol under reduced pressure, and lyophilized to yield a white powder of N- {7- [2-carbonyloxymethoxyimino-2- (5-amino-1,2,4-thiadiazole) 3-yl) acetamido] -3-chloro-3-ylmethyl-pyridinium-4-carboxylate (syn isomer) (800 mg), m.p. 150-155 ° C (dec.).

IR (nujol):

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

NMR (D ₂ O + NaHCO 3, SS):

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

4.70 (2 H, s),

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

5.40 and 5.60 (2H, ABq, J = 14Hz),

5.93 (1 H, d, J = 4 Hz),

8.0-9.1 (5 H, m).

Example 7

O-C-COOC-Ch 2

CH, ^CH 2

° »

N!

W,

C-COHN-N-N-N-

CH 2 O

O ~ C ~ COHOH

CH, coo

CH 2 N

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) acetamido] -3-chloro-3-ylmethyl] pyridinium-4-carboxylate (3.18 g) and 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 a nonionic adsorption resin Diaion HP-20 (140 mL).

The column is washed with water and eluted with 5% and 10% aqueous isopropyl alcohol. The eluates containing the compound to be prepared are collected. Evaporate to remove isopropyl alcohol under reduced pressure and lyophilize to give N- {7- [2- (1-methyl-1-carboxyethoxyimino) -2- (5-amino-1,2,4-thiadiazole-3- yl) acetamido] -3-chloro-3-ylmethyl-pyridinium-4-carboxylate (syn isomer) (2.20 g) as a white powder, m.p. 176-180 ° C (dec.).

IR (nujol):

3400 to 3150, 1770, 1670, 1620, 1520 cm ^-1 .

NMR (DMSO-d ₆ + D ₂ O, 5):

1.48 (6H, s);

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

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

5.45 (211, m),

5.78 (lH, d, J = 5Hz),

8.13 (2 H, m),

8.58 (1 H, m),

9.38 (2 H, m).

Example 8

The following compounds were prepared in a similar manner to that of ponsano in Examples 6 and 7.

1) N- {7- [2- (1-Carboxyethoxyimino) -2- (5-amino-1,2,4-triazol-3-yl) acetamido] -3-cephem-3-ylmethyl} -4 ' 4-carboxylate (syn isomer), m.p. 170-175 ° C (dec.).

IR (nujol):

3300, 3160, 1770, J680, 1610, 1560, 1520 cm ^-1 .

2) 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.).

IR (nujol):

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

NMR _(D? O! - _{NaHCO 5):

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

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

4.40-4.90 (1 H, m),

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

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

5.83-6.00 (1H, m),

7.9-9.1 (5 H, m).

3) 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 .

4) N- {7- [2- (1-Methyl-1-carboxyethoxylamino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3-chloro-3-ylmethyl] 4'-carbamoylpyridinium-4-carboxylate (syn isomer), m.p. 180-185 ° C (dec.). IR (nujol):

3300, 1770, 1680, 1620, 1560, 1520 ^cm-first Example 9

A mixture of 7- [2-tritytoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-pyridinlomethyl) -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 is filtered off, the filtrate is evaporated to dryness and the residue is taken up in powder with acetone and collected by filtration. The powder was dissolved in water (13 mL) and subjected to column chromatography on a nonionic adsorption resin Diaion HP 20 (100 mL) using water as eluent. The eluates containing the compound to be prepared are collected and lyophilized to give a yellowish-white powder

7- [2-hydroxyimimo-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-pyridinomeithyl) -3-cephem-4-carboxylate (syn isomer) (675 170 DEG-175 DEG C. (with decomposition).

IR (nujol):

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

NMR (DMSO-d ₆ + D ₂ O, <5)

3.14, 3.54 (2H, ABq, J = 18Hz),

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

5.28, 5.62 (2H, ABq, J = 12 Hz),

5.86 (1H, d, J = 5Hz),

7.96-8.24 (2 H, m),

8.40 - 8.68 (1 H, m),

9.16-9.42 (2 H, m).

Example 10

To a solution of 1 - {[7- (2- / 2-cyclopemitem-1-yloxyimino) -2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido) -4-carboxy-3-cep -3-yl] meithyl] 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, which was continued for 10 minutes at temperature Surroundings. The insoluble material was filtered off, washed with DMF (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, washed with acetone (3 x 40 mL each) and dried in vacuo to give 1 - {[7- (2- / 2-cyclopenten-1-yloxyimino) -2- (5-amino-1)]. 2,4-thiadiazol-3-yl / acetamido) -4-carboxy-3-cephem-3-yl] methyl] pyridinium chloride (syn isomer) (11.0 g).

IR (nujol):

3400—3100, 1780, 1660, 1630, 1530 cm ¹ .

NMR (DMSO-d 6):

1.6-2.6 (4H, m)

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

5.19 (lH, d, J = 5Hz),

4.9-5.6 (2 H, m),

5.64 (1H, broad s),

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

5.7 - 6.2 (2H, m),

8.20 (2 H, m),

8.64 (1 H, m),

9.22 (2 H, m),

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

Example 11

To a solution of sodium iodide (10 g) and pyridine (1.28 g) in formamide (8 mL) was added 7- [2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido ] sodium cephalosporanate (syn isomer) (4.0 g) at 75 ° C with stirring continued for

1.5 hours at 80-85 ° C. The mixture was cooled to ambient temperature and poured into ethanol (100 mL). The resulting precipitate was collected by filtration and another precipitate was obtained from the filtrate by addition of diisopropyl ether (100 mL). The aqueous solution was subjected to column chromatography on Diaion HP-20 nonionic adsorption resin (160 mL), the column was washed with water and eluted with 30% aqueous methanol.

The eluates containing the compound are collected, evaporated to remove methanol under reduced pressure, and lyophilized to give 7- [2-ethoxy-imino-2- (5-amino-1,2,4-thiadiazole-3) as a white powder. -yl] acetamido] -3- (1-pyridininyl) -3-cephem-4-carboxylate (syn isomer) (1.52 g), m.p. 155-165 ° C (dec.).

IR (nujol):

3400—3150, 1770, 1660, 1610, 1530 cm ^-1 . Example 12

Purification of the prepared compound

Powder (0.2 g) of 7- [2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-pyridinomethyl) -3-cefern-4- The carboxylate (syn isomer) is dissolved in water (0.8 ml), acetone (1.6 ml) is added dropwise and stirred at ambient temperature.

1.5 hours at ambient temperature to redry. The resulting colorless needles were filtered off, 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 7- [2-ethoxyimino-2 needles. - (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-pyridinomethyl) -3-cephem-4-carboxylate acetone adduct as monohydrate (syn isomer) (120 mg) o melting point greater than 155 degrees Celsius (with decomposition).

IR (nujol):

3430—3120, 1760, 1700, 1680, 1615, 1530 cm ^-1 .

NMR (D ₂ O, <S):

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

2.26 (6H, s,

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

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

5.30 (1 H, d, I = 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 C _l9 H _J9 N ₇ O5S _second C ₃ H ₆ O. H ₂ O calculated:

46.72% C 4.81% I H, 17.34% N, 3.18% H ₂ O; found:

46.79% C, 4.79% H, 16.72% N, 3.24% H ₂ O. Example 13

Purification of the prepared compound

A solution of 7- [2-ethoxy-amino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-pyridinomethyl) -3-cephem-4-carboxylate adduct with acetone (syn. isomer) (1.0 g) in water (1 ml) was allowed to stand for 5 days in a freezer at -20 ° C. The mixture of ice and precipitate 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-amino-1,2,4-thiadiazol-3-yl)]. acetamido] -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-first

NMR (D ₂ O, δ):

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

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

4.33 (2H, q, J = 7Hz)

5.27 (1 H, d, J = 5 Hz),

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

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

8.10 (2 H, m),

8.60 (1 H, m),

8.97 (2 H, m).

Example 14

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-carboxylate adduct with acetone (syn isomer) (40 g) in water (50 mL) was added a small amount of colorless needles of 7- [2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-pyridinomethyl) -3-cephem-4-carboxylate (syn isomer) was added and the mixture was stirred for 1 hour in an ice bath.The precipitate formed 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-thiadiazol-3-yl) acetamido] -3- (1-pyridiniummethyl) -3-cephem- 4-carboxylate wire (syn isomer) (24.7 g) as colorless needles, m.p. 170-175 ° C (dec.).

Water content (KF method) calculated:

6,72%, found:

6.20%

Example 15

Purification of the prepared compound

7- [2-methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-pyridinium-ethyl) -3-cephem-4-carboxylate powder (syn isomer (7.7 g) was dissolved in water (15.4 ml) and the solution was allowed to stand in a refrigerator overnight. The precipitate was filtered off and washed with 80% isopropyl alcohol (5 mL) and isopropyl alcohol (5 mL), air dried for one hour, and then dried in vacuo for two hours to give colorless needles. methoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (1-pyrrole-28,149 diniomethyl) -3-cephem-4-carboxylate (syn isomer) (4,2 g) m.p. 165-170 ° C (dec.).

IR (nujol):

3300, 3200, 1765, 1670, 1630, 1605, 1550- -1520 cm ^1st

NMR:

3.24, 3.70 (2H, ABq, J = 18Hz), 4.06 (3H, s),

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

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

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

8.06 (2 H, m),

8.54 (1 H, m),

8.95, (2 H, m).

Claims (8)

OBJECT OF THE INVENTION A process for the preparation of 7- [2-hydroxyiniino or substituted oxyimino-2- (amino-substituted-1,2,4-thiadiazolyl) acetamido] -3-substituted methyl-3-cephem-4-carboxylate derivatives or 7- [ 2-hydroxyiminoor substituted oxyimino-2- (amino-substituted-1,2,4-thiadiazolyl) acetamido] -3-substituted methyl-3-cephem-4-carboxylic acid of general formula (I) in the case where R ³ is a group formulas CONH 4 _R 14 U + 1 -? - CONH jj N wavy line means that both syn and anti isomers and their pharmaceutically acceptable salts are included, characterized in that a compound of formula II is reacted OF STEED 2. Method according to claim 1 for preparing a compound of formula I wherein R ² has in point 1 above, R ³ represents a group of formula in claim 1 above, R ² represents an ethyl, propyl or isopropyl group, R ³ represents a group of wherein X is hydrogen, R ⁴ is COO-, characterized in that a compound of formula II wherein R ^4a is carboxy and the other symbols are as defined in point 1 is reacted with a compound of formula III wherein R ^3b represents a compound of the formula wherein X is as defined above. 2. RbN (I) where is R ¹ an amino group, R ³ is hydrogen, C 1 -C 4 alkyl optionally substituted by carboxy, C 2 -C 5 alkoxycarbonyl, C 2 -C 5 phenylalkoxycarbonyl, C 1 -C 4 alkylthio, phenyl or a halogen atom, furthermore a C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl or tetrahydrofuryl substituted oxo group, R ^{3 is a} group of the formula · -C-CONH κ li S / v OR ^á where R ¹ and R ² are as defined above, R ^3a is a reactive group optionally substituted with a group of formula R ³ , wherein R ³ is as defined above, and R ^4a represents a carboxy group when R ^3b represents a compound of the formula wherein ± N X is as defined above, or R ^4a represents a carboxy group when R ^3b represents a compound of the general formula X is hydrogen or carbamoyl; and R ^{4 is a} group of formula COO ^- or is R ^{3 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, provided that R ^{2 is} not cyclopenityl, cyclopentenyl or 1-methyl-1-carr ^3c -H where R ^3c 2-alkyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazinylthio having 1 to 4 carbon atoms in the alkyl moiety, or a salt thereof with a compound of formula III R ^3b (III) wherein R ^3b is as hereinbefore defined, or with a reactive derivative thereof, and optionally from a compound of formula I, wherein R ² is C 2 -C 5 alkoxycarbonylalkyl of up to 4 carbon atoms in the alkyl group share or. phenylalkoxycarbonylalkyl having 2 to 5 carbon atoms in the alkoxy moiety and having 1 to 4 carbon atoms in the alkyl moiety, eliminates the carboxy-protecting group to form a compound of formula I wherein R- is C1-C4 carboxyalkyl in the alkyl moiety, or the obtained compounds of formula I wherein R ² is a triphenylalkyl group having 1 to 4 carbon atoms in the alkyl moiety eliminates the hydroxy protecting group to give a compound of formula I wherein R ² is hydrogen. 3. Process according to claim 1 for preparing a compound of formula I wherein R ² has in point 1 above. R ³ is 2-alkyl-5-oxo-6-hydroxy-2,5-dihydro-2,4 -triazinylthio having 1 to 4 carbon atoms in the alkyl moiety, R ⁴ carboxy and R ¹ are as defined in item 1, characterized in that a compound of formula II is reacted, wherein R ^4a is carboxy and the other symbols have the same of formula III, wherein R ^3b is a compound of formula R ^3c -H and R ^3c are 2-alkyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazinylthio having 1 to 4 carbon atoms in the alkyl moiety. 4. Method according to claim 1 for preparing a compound of formula I, wherein R ¹ has the syn isomer, characterized by reacting a compound of formula II wherein R ³ is acetoxy or acetacetoxyskupinu a compound of formula III, the other symbols being as defined in point 4. 5. A method according to claim 4 for preparing a compound of formula I, wherein R ¹ has in point 1 above, R ² is ethyl and wherein the proportion of X is hydrogen or carbamoyl, R ⁴ represents a group of formula -COO and other symbols as defined in claim 1, characterized in that a compound of formula II wherein R ^4a is carboxy and the other symbols in point 1 is reacted with a compound of formula III wherein R ^3b is wherein X is as defined above . 6. The process of item 1, for the preparation of a compound of formula I wherein R ¹ , R ² , R ³ and R ⁴ are as defined in item 1, but R ^{2 is} not C 1 -C 4 alkyl when R ³ is wherein X is as defined in item 1, characterized in that a compound of formula II wherein R ^3a and R ^4a is as defined in point 1 is reacted with a compound of formula III, wherein R ^3b is as defined in point 1 importance. 7. The process of Claim 2 for preparing a compound of formula I wherein R ² známe228149 L-mothyl-l-ethoxycarbonylethyl, carboxymethyl, meíhoxykarbonylmethylovou, cyclohexenyl, 1-methyl-carboxyethyl or 1-methyl- 1-tert-butoxycarbonylethyl and the other symbols have the meanings given in point 2, characterized in that a compound of formula II wherein R ² is as defined above is reacted with a compound of formula III wherein R ^3b is as defined in point 2 the other symbols have the meaning given in point 2. 8. The method of item 1, for preparing: 14 colorless needles 7- (2-ethoxyimino-2) -5-aino-1,2,4-thiadiazol-3-yl (acetamido) -3- (1-pyridinomethyl) -3-cep-4-carboxylate (syn isomer), its acetone adduct, its acetone adduct monohydrate or dihydrate, or the colorless needles of Ί- (2-methoxyimino) -2- (5-amino-1,2,4-thiadiazole) -3-yl (-acetamido] -3- (1-pyridinomethyl) -3-cephem-4-carboxylate (syn isomer), characterized in that a compound of formula II is reacted with a compound of formula III, where each symbol has a corresponding meaning.