DK162391B - ANALOGY PROCEDURE FOR PREPARING SYN-ISOMERS OF 3,7-DISUBSTITUTED 3-CEPHEM-4-CARBOXYLIC ACID COMPOUNDS - Google Patents

Description

DK 162391 B

The present invention relates to an analogous method for preparing novel syn isomers of 3,7-disubstituted 3-ce-phem-4-carboxylic acid compounds and pharmaceutically tolerable salts thereof having antibacterial activity with which compounds can be prepared pharmaceutical compositions. which can be used therapeutically in the treatment of infectious diseases in humans and animals. The process according to the invention is characterized by the characterizing part of claim 1.

The present invention therefore relates to a process for the preparation of syn isomers of 3,7-disubstituted 3-cephem-4-carboxylic acid compounds and pharmaceutically tolerable salts thereof, which compounds and salts can be used as active ingredients in pharmaceutical compositions. which can be used in the treatment of infectious diseases caused by pathogenic bacteria in humans and animals.

The present syn isomers of 3,7-disubstituted 3-cephem-4-carboxylic acid compounds are novel and can be illustrated by the following general formula I

R ^ C-CONH -, '8N

Wherein RA represents a group of the general formula wherein R 2 represents amino, C 1-6 alkanoylamino, halogeno-C 1-6 alkanoylamino-25 no, g-alkanesulfonylamino,. g - alkoxycarbonylamino, hydroxy or

Of-alkyl; R 2 represents C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkylthio-C 1-6 alkyl, carboxy C 1-6 alkyl, C 1-6 alkoxycarbonyl-C 1-8 alkyl, phenylthio C 1-6 alkyl, phenyl -C1-8 alkyl, halogen-substituted phenyl-2

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C 1-6 alkyl, halogen and hydroxy-substituted phenyl-g-alkyl, phenyl-C 2 -g alkenyl, (¼ g-alkanoyloxy-g-alkyl, g-alkoxy-C 1-6 alkyl; hydroxy-substituted phenoxy C 1-6 alkyl, thienyl C 1-6 alkyl or isoxazolyl C 1-6 alkyl; represents carboxy or a pharmaceutically tolerable esterified carboxy group; and R 4 represents propionyl oxymethyl; butyryloxymethyl; isobutyryloxymethyl; valeryloxymethyl; isovaleryloxymethyl; pivaloyloxymethyl; carbamoyloxymethyl; phenyl-carbamoyloxymethyl; halogeno-C2-6 alkanoylcarbamoyloxymethyl; , ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, hexyl or cyclohexyl; thiadiazolylthiomethyl, which can bear ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, hexyl or cyclohexyl; triazolylthiomethyl, which can be C1-6 alkyl or C2-6 alkenyl; or benzothiazolylthiometh yl; or R 2 and R 2 are bonded together to form -C00CH 2 -; or pharmaceutically tolerable salts thereof.

From DK-B-147,683 related antibacterial cephemic derivatives are known.

However, it has surprisingly been found that the compounds prepared by the process of the invention exhibit substantially higher antibacterial activity.

In the process of the present invention, the syn isomer is prepared from 3,7-disubstituted 3-cephem-4-carboxylic acid compounds illustrated by the general formula I, and this syn isomer can be represented by the partial formula R 1 -C-CO 25 N-OR 2 in the molecules, while the corresponding anti-isomer is represented by the partial formula R 1 -C-CO-.

R20-f 30 In this specification and claims, the syn isomers of the subject compounds as well as the starting materials are represented by the partial formula /

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3 -C-CO- in their molecules, with the limitation that when it is convenient for the explanation of the invention to express both the syn isomer 5 and the anti-isomer of one general formula, they are illustrated in partial form. · Len -C-CO-

II

N

10 0

The present compounds of formulas I are novel and can be prepared in the ways listed below. The different process variants are elucidated with the following reaction formulas:

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Process variant a): H2N-i-S SN + R ^ C-COOH -> R ^ C-CONH-i- ^ SN | oy ”T r4 l» - ° r2 / - * f ^ 4 R3 O · 3

R R

II III I

or a reactive or a re or a salt thereof derivative thereof by the active derivative amino group or by the carboxy group a salt thereof or a salt thereof

Process variant b):

S

Rla-C-CONH —- {Svl Rlb-C-CONH —- S -v | 1-OR2 ^ -N \ | ^ «R4 * 1-OR2 ^ R3 O R3 elimination of the amino protecting group IVa or a salt thereof or a salt thereof in

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5

Process variant c): elimination of the carboxy protecting group RI-C-CONH - the group RI-C-CONH -, -

Va Ic or a salt thereof or a salt thereof

Method variant d) Elimination of the amino protecting group fS '1 - ^ R ^ -C-CONH-j- |

ii-OR2 ^ -Nv ^ “CH2-OCONH-R4a | .0R2 J

° r3 O 1 CH2'OC: ONH2 R3

Vb Id or a salt thereof or a salt thereof

Process variant e):

R1-C-CONH-i R4c-SH - »R1-C-CONH-j N

N-OR2 ^ J NVsp ~ CH2 “R b + S-OR2 ^ R3 ° R3

Vc Vd le or a salt thereof or a re- or a salt active derivative thereof thereof at znercapto group 6

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Process variant f): R 1 -C-CONH-|-acid R 1 -C-CONH-1 L · -> Lor2Ϊ- * γ- ^ 2 O {^ 3 o CO-0

Ve If or a salt thereof or a salt thereof In the above formulas, R * ·, R ^, R ^ and R ^ have the meaning given above, R * a represents a group of the general formula where R ^ a represents C j_. g - alkanoylamino, halogen-C g -alkanoylamino, C 1-6 alkanesulfonylamino or C 1-6 alkoxycarbonylamino; R 3 represents a group of the general formula s R 2a represents .alpha.-alkoxycarbonyl-.alpha.-alkyl, R3 represents carboxyC1.

g -alkyl, R 1a represents halo-C 2 -g alkanoyl, R 1 represents a group which can be substituted by a group R 2 cS-where R 1 c represents tetrazolyl which may have C 2 -G alkenyl or ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, hexyl or cyclohexyl, thiadiazolyl which may have ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, hexyl or cyclohexyl, triazolyl which may have C Alkyl or C2-6 alkenyl, or benzotriazolyl.

in

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7

A particularly preferred process results in the preparation of a group of syn isomers of formula I, wherein R * is a group of formula 5 wherein nJ is amino and R 1 is carbamoyloxymethyl, hydroxymethyl, thiadiazolylthiomethyl or triazolylthiomethyl which may have C ^ .g-alky 1.

In this group of syn isomers, those where C ^ hvorg C are alkyl are preferred and R ^ is carboxy.

In the latter group, the syn isomers where R 1 is preferred are carbamoyloxymethyl or thiadiazolylthiomethyl, especially those where R 1 is thiadiazolylthiomethyl.

In a particularly preferred group of compounds, thiadiazolylthiomethyl is and is methyl.

Among the starting compounds, the starting compound of formula III, including the corresponding anti-isomer, is novel and can be prepared by the reactions illustrated in the following reaction scheme:

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(1) (i) 8 nitrosation X-CH, -CO-CH, -Z - »XCH.CO-C-Z E7b-C-NH,

2 2 2 8 I

N S

YY. I XXII

<Ν-χ-ς-2

1 7o _ //% II

0H -> R ~ \ B / \

OH

. . .......... ....... ........... XXI XXIII

N - r - C-COOH

elimination ^^^ \ | S ξ

OH

XXIIIa (ii)

N-r-C-Z alkylation w-τ-C-Z

i - ^ H ^ R2e

XXIV XXV

9

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elimination _

N 5T ~ C-COOH

-> '' H ?! 'i »OR ^ e

Wool (2) alkylation halogenation CH, -CO-C-Z _v CH 2 CO-C-Z -> x-ch 2CO-c-z II I '1

I N

Ϊ c 2nd 6R2e

pH. 0R

XXVII

R 7b-C-NH,

II

p

N - v "C-Z N-K" -C-COOH

XXII R7 ^ - ^ elimination ^ y | -> s l2e * s l2e XXIX Ill (3) (i) amino-protecting H2N- ^ ~ yCH2-Z agent r7 £ __ ^ ~ ^ - <Ή2-Ζ

® S

XXX XXXI

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(Ϋ) oxidation hydrolysis

R1C-CH2 -Z v Rlc-CO-Z, R1C-C-Z

2 -> <- ||

N

XXXII XXXIII ς

OH

elimination R20-NH2 or XXIIIb an XIV a salt thereof

Rlc-COC00H Rlc-C-Z

XN

or £ a salt j OR2

thereof / XXXV

/ elimination NH 2 ° h or a salt thereof

RLC-C-C00H

II

V N

le ^ 2 R -C-C00H OR * j Ulf

OH

XXXVI

(4) 11

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H2N tf -C-Z amino-protecting -C-Z

^ \ s / I miaaeX \ s / H

-> l2 (W OR2 XXXIX Illh In the above formulas, and R 1a has the meaning given above, X represents halogen, Z represents protected carboxy, R 5 represents lower alkyl, amino or lower alkoxy, V? c represents lower alkyl, amino or hydroxy, R 1 represents lower alkyl, R 1 represents lower alkyl, R 1 c represents a group of the general formula R 7 - B / 10 wherein B is the above meaning and Za is optionally protected carboxy. *

The other starting compounds of formulas IV, V, Va-Vc and Ve are novel compounds and can be prepared by the methods described above under 1-4.

With respect to the compounds of Formula I, Ia and Ic-If and the starting compounds of Formulas III, Ille, Ulf, Illh, IV, Va-Vc, Ve, XXIII-XXIIIb, XXIX-XXXVI and XXXIX, it is clear that these compounds include tautomeric isomers with respect to their thiazole groups.

That is, in the case that the group illustrated by the general formula 12

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(wherein R 5 represents amino, amino or hydroxy) in the formula of the compounds of the present invention and the starting compounds have the general formula, αΛ

R, e S

Alternatively, the group of formula 10 may be represented by its tautomeric formula - (where denotes imino, protected imino or oxo). Ie that the two groups (A) and (B) are in equilibrium state as the so-called tautomeric forms which can be represented by the equilibrium below /

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13 "X? = 7.17- (A) (B) (where β7β and r7 ^ have the meaning given above).

These types of tautomerics between 2-amino and 2-hydroxythiazole compounds and 2-imino or 2-oxo-thiazoline compounds as mentioned above are well known in the literature, and it is clear to those skilled in the art that both of the tautomeric isomers are present in the art. equilibrium and can easily be converted among themselves, which is why it is clear that such isomers fall within the same category as the compound itself. Both the tautomeric forms of the 10 compounds of Formula I, Ia and Ic-If and the starting compounds of Formula III, Ille, Ulf, Illh, IV, Va-Vc, Ve, XXIII-XXIIIb, XXIX-XXXVI and XXXIX are within the scope of the present invention. In this specification, claims and examples, the present compounds and the starting compounds, including the group of such tautomeric isomers, are represented using one of the appropriate terms, i. E. only the formula: 'for convenience.

Suitable pharmaceutically tolerable salts of the subject syn isomers of 3,7-disubstituted 3-cephem-4-carboxylic acid compounds of formula I are usual non-toxic salts which may be inorganic salts, e.g., a metal salt such as an alkali metal salt (e.g., sodium salt). or the potassium salt) or an alkaline earth metal salt (e.g., the calcium or magnesium salt) or an ammonium salt, or an organic salt, e.g., an organic amine salt (e.g., trimethylamine, triethylamine, ethanolamine, diethanolamine,

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the pyridine, picoline, dicyclohexylamine or N, N'-dibenzylethylenediamine salt), an organic acid salt (e.g., acetate, maleate, tartrate, methanesulfonate, benzenesulfonate or toluene sulfonate), an inorganic acid salt (e.g., hydrochloride, hydrobromide, hydrobromide, phosphate) or a salt with an amino acid (e.g., arginine, aspartic acid or glutamic acid).

In the above and in the description given below, suitable examples and illustrations of the various definitions encompassed by the present invention are explained in more detail.

The term "lower", unless otherwise indicated, denotes 1-6 carbon atoms.

"Halogen" may conveniently include chlorine, bromine, fluorine and iodine.

"Alkoxy groups" may include groups which may be branched, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy and hexyloxy, and preferably have 1-4 carbon atoms, especially 1-2 carbon atoms.

Suitable alkyl groups and alkyl moieties in the terms "alkylthio", "carboxy-C1-6 alkyl" and "protected carboxy-C1-6 alkyl" may include groups which may be branched, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl, and such groups preferably contain 1-4 carbon atoms, especially 1-2 carbon atoms.

Suitable protected imino groups may include acylimino groups and imino groups which are substituted by conventional protecting groups other than an acyl group, for example a benzyl group.

Suitable protected carboxy groups and protected carboxy moieties in the term "protected carboxy - C1-6 alkyl" may include esterified carboxy, the ester being, for example, a lower alkyl ester (e.g., a methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert. butyl ester, pentyl ester, tertiary pentyl ester, hexyl ester or 1-cyclopropylethyl ester), wherein the lower alkyl moiety may preferably be one containing 1-4 carbon atoms, a lower alkenyl

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Ester (e.g., a vinyl ester or allyl ester), a lower alkynyl ester (e.g., an ethynyl ester or propynyl ester), or a mono- (or di- or tri) -halo (lower alkyl) ester (e.g., a 2-iodoethyl ester or 2.2, 2-trichloroethyl ester); a lower alkanoyloxy lower alkyl ester (e.g., an acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester or 2-propionyloxyethyl ester); lower alkanesulfonyl-lower alkyl ester (e.g., a mesyl methyl ester or 2-methyl methyl ester); 10-lower alkyl ester, for example, a phenyl-lower alkyl ester which can carry one or more suitable substituents (e.g., a benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenylethyl ester, trityyl ester, diphenylmethyl ester, bis (methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester or 4-hydroxy-3,5-di-tert.butylbenzyl ester); or an aryl ester which may have one or more suitable substituents (e.g., a phenyl ester, tolyl ester, tert.butyl phenyl ester, xylyl ester, mesityl ester or cumenyl ester).

Preferred examples of protected carboxy may be. g -alkoxycarbonyl (e.g. methoxyearbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl, tert.pentyloxycarbonyl or hexyloxycarbonyl) having 2-7 carbon atoms, preferably 2-5 carbon atoms.

Suitable alkenyl groups are groups of 2-6 carbon atoms, which may be, for example, vinyl, allyl, isopropenyl, 1-propenyl, 2-butenyl or 3-pentanyl, preferably with 2-4 carbon atoms.

Suitable alkanoyl groups are, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl or pivaloyl), preferably groups of 1-4 carbon atoms, especially of 1-2 carbon atoms. Alkoxycarbonyl can have from 2 to 7 carbon atoms and is, for example, methoxyearbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxyearbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxy-carbonyl, tert-pentyloxyearbonyl or hexoxyloxycarbonyl Alkanesulfonyl may be, for example, mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl or butanesulfonyl, preferably having from 1 to 4 carbon atoms, especially with 1-2 carbon atoms;

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16

Suitable protecting groups for the amino group R 2a may be halo-C 2-6 alkanoyl (e.g., chloroacetyl, dichloroacetyl, trichloroacetyl or trifluoroacetyl), preferably having 2-3 carbon atoms.

Suitable acid residues may comprise the residue of an acid such as an inorganic acid. 5. Acid (e.g. hydrochloric, hydrobronic, iohydric or sulfuric) or an organic acid (e.g., methanesulfonic, benzenesulfonic or p-toluenesulfonic).

Among the suitable examples of each of the groups of the present compounds as explained and illustrated above are. Preferred examples thereof illustrated below: are preferably amino, - g -alkanesulfonylamino (preferably C 1-4, especially C 1-4), trishalo- C 1-4 g - alkanoylamino (preferably C 1-4, especially C 1-4). ), C1-6 alkoxycarbonylamino (preferably C2.7, especially Cg.g) or g-alkanoylamino (preferably C1-4, especially C2-2).

Hydroxy or C ^gg alkyl (preferably C ^. ^, Especially C ^₂) · R ^ is preferably carboxy.

The various processes for preparing the subject compounds are described in detail below:

Process a): The compound of formula I or a salt thereof can be prepared by reacting the 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 the carboxy group or a salt thereof which process is the fundamental process for preparing the compounds of formula I.

Suitable reactive derivatives at the amino group of the compound of formula II include conventional reactive derivatives used in amidation, for example, silyl derivatives formed by reaction of the compound of formula II and a silyl compound, for example bis (trimethylsilyl) acetamide 30 or trimethylsilylacetamide.

$

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17

Suitable salts of the compound of formula II include acid addition salts, e.g., an organic acid salt (e.g., the acetate, maleate, tartrate, benzenesulfonate or toluene sulfonate) or an inorganic acid salt (e.g., the hydrochloride, hydrobromide, sulfate or phosphate), an inorganic base salt. such as an alkali metal salt (e.g., the sodium or potassium salt), an alkaline earth metal salt (e.g., the calcium or magnesium salt), or the ammonium salt, or a salt with an organic base (e.g., the triethylamine salt or pyridine salt).

Suitable reactive derivatives of the carboxy group of the compound of formula III include conventional derivatives used in the amide ring.

The salts of the compound of formula III may be salts with an inorganic base such as the alkali metal salts (e.g., the sodium or potassium salt) or an alkaline earth metal salt (e.g., the calcium or magnesium salt), an salt having an organic base such as trimethylamine, triethylamine or pyridine or a salt of an acid (e.g. hydrochloric or hydrochloric acid).

The reaction is usually 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 other organic solvent which does not have adversely affecting the reaction. Of these solvents, hydrophilic solvents can be used in admixture with water.

The present reaction is preferably carried out in the presence of a condensing agent such as a so-called Vilsmeier reagent, for example chloromethylene dimethylammonium chloride formed by reaction of dimethylformamide with thionyl chloride or phosgene, or a compound formed by reaction of dimethylformamide with phosphorus .

The reaction may also be carried out in the presence of an inorganic or organic base, for example, an alkaline number hydroxide, an alkali metal hydrogen carbonate, an alkali metal carbonate, an alkali metal acetate, tri (lower alkyl) amine, pyridine, N-lower alkyl morpholine, N, N-di ( lower alkyl) - 18

DK 162391 B

benzylamine or N, N-di (lower alkyl) aniline as set forth below by way of example. When the base or condensing agent is a liquid, it can also be used as a solvent. The reaction temperature is not critical and the reaction is usually carried out under cooling or at room temperature.

In this reaction, when the starting compound of formula III is reacted with the compound of formula II or a reactive derivative thereof by the amino group or a salt thereof in the presence of, for example, phosphorus pentachloride or thionyl chloride, only the corresponding anti-isomer of the compound of formula I or a mixture of the corresponding anti-isomer and syn-isomer as the final product, although the compound of formula III, i. the syn isomer, is used as starting material. It is to be understood that the reaction of the corresponding anti-isomer to the starting material of formula III and compound XI can never lead to the formation of the desired compound of formula I, i.e. syn isomer. Obviously, such a trend and uniformity in the reaction as stated above is due to the tendency of the less stable syn isomer to partially or completely isomerize to the corresponding more stable anti-isomer during the reaction, e.g. in the so-called activation step. of the compound of formula III such that the isomerized compound, i.e. the anti-isomer corresponding to the desired compound of formula I is obtained as the final product.

To obtain the desired compound of formula I, i. the syn isomer, selectively and in high yield, it is necessary to use the starting compound of formula III, i. the syn isomer, and to select appropriate reaction conditions. The desired compound of formula I, i. the syn isomer, can be obtained selectively and in high yield by carrying out the reaction, for example, in the presence of a Vilsmeier reagent as stated above, and under approximately neutral conditions.

In the case where the starting material of formula III wherein R 1 is a group of the general formula *

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19 / H2N - may be used, the desired compound of formula I, i. the syn isomer is obtained selectively and in high yield by carrying out the reaction of the corresponding starting compound of formula XII, i.e. the syn isomer, and the compound of formula II, for example, in the presence of a Vils-meier reagent prepared by the reaction of dimethylformamide and phosphorus oxychloride, and under approximately neutral conditions. In this case, particularly good results can be obtained by carrying out the reaction in the presence of more than two molar equivalents of phosphorus oxychloride relative to the amount of the starting compound of formula III, i. the syn isomer, and dimethylformamide as set forth in the exemplary embodiments. Furthermore, good results can be obtained by performing an activation step with the starting compound of formula III, i. the syn isomer, in the vicinity of a silyl compound (e.g., bis (trimethylsilyl) acetamide or trimethylsilylacetamide).

Regarding the reaction between the compound of formula II and the compound of formula III, it should be noted that: when the compound of formula II, which is a carbamoyloxymethyl group with an acyl group, is used as starting material, either the desired compound of the formula can be obtained I, where is a carbamoyl oxymethyl group having an acyl group or a free carbamoyloxymethyl group, depending on the reaction conditions, when a compound of formula II, which is a hydroxymethyl group, is used as starting material, the desired compound of formula I may optionally be obtained. wherein R 3 and R 2 are bonded together to form a -COOCH 2 group, and further, the protected carboxy group or salts of the compound of formula II can be converted to a free carboxy group either during the reaction or by post-treatment. These cases are also within the scope of the invention.

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20

As can be seen from the above described, process a) is a superior method which is particularly advantageous in preparing the desired compound of formula I, i. syn isomer.

Process b): The compound of formula Ia or a salt thereof can be prepared by subjecting the compound of formula IV or a salt thereof to an elimination reaction for the amino or imino protecting group. A suitable salt of the compound of formula IV may comprise a metal salt, an ammonium salt or an organic amine salt, as set forth above.

The elimination reaction is carried out according to conventional methods, for example, by hydrolysis, reduction or by reacting a compound of formula IV, wherein the protecting group is an acyl group, with an imino halogenating agent and then with an imino etherifying agent, and, if necessary, hydrolysis of the resulting connection.

The hydrolysis can be carried out using, for example, an acid, a base or hydrazine. These methods can be selected depending on the nature of the protecting group to be eliminated.

Of these methods, hydrolysis using acid is a common and preferred method for eliminating protecting groups 20 such as, for example, substituted or unsubstituted alkoxycarbonyl (e.g., tert.-pentyloxycarbonyl), alkanoyl (e.g., formyl), cycloalkoxycarbonyl, substituted or unsubstitutedxyl (unsubstituted or unsubstituted) benzyloxycarbonyl), substituted phenylthio, substituted aralkylidene, substituted alkylidene or substituted cycloalkylidene. A suitable acid may be an organic or inorganic acid, for example formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or hydrochloric acid, and a preferred acid is an acid which can be easily removed from the reaction mixture in the usual manner, for example by distillation under reduced pressure. , for example formic acid, trifluoroacetic acid or hydrochloric acid. An acid suitable for the reaction can be selected according to the nature of the protecting group to be eliminated. When the elimination reaction is carried out with an acid, it can be carried out in the presence of

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Or the absence of a solvent. Suitable solvents may include an organic solvent, water or a mixed solvent thereof. When trifluoroacetic acid is used, the elimination reaction can preferably be carried out in the presence of anisole.

Hydrolysis using hydrazine is commonly used to eliminate a protecting group such as succinyl or phthaloyl.

Preferably, hydrolysis with a base is used to eliminate an acyl group, e.g., haloalkanoyl (e.g., trifluoroacetyl). A suitable base may be, for example, an inorganic base such as an alkali metal hydroxide (e.g., sodium hydroxide or potassium hydroxide), an alkaline earth metal hydroxide (e.g., magnesium hydroxide or calcium hydroxide), an alkali metal carbonate (e.g., sodium carbonate or potassium carbonate), an alkaline earth metal ( alkali metal hydrogen carbonate (e.g., sodium bicarbonate or potassium hydrogen carbonate), an alkali metal acetate (e.g., sodium acetate or potassium acetate), an alkaline earth metal phosphate (e.g., magnesium phosphate or calcium phosphate), an alkali metal hydrogen phosphate, and the like, trialkylamine (e.g. trimethylamine or triethylamine), picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4,3,0] non-5-ene, 1,4-diazabicyclo [2,2,2octane or 1 , 5-diazabicyclo [5,4,0] undecene-fifth Hydrolysis using a base is often carried out in water or in a hydrophilic organic solvent or a mixed solvent thereof.

Of the protecting groups, the acyl group can generally be eliminated by hydrolysis as indicated above or by another conventional hydrolysis method. In case the acyl group is halo-substituted alkoxycarbonyl or 8-quinolyloxycarbonyl, these groups are eliminated by treatment with a heavy metal such as copper or zinc.

The reductive elimination is commonly used to eliminate a protecting group such as, for example, haloalkoxycarbonyl (e.g., trichloroethoxycarbonyl), substituted or unsubstituted aralkoxycarbonyl (e.g., benzyloxycarbonyl, or substituted benzyloxycarbonyl) or 2-

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22 pyridylmethoxycarbonyl. A suitable reduction may include, for example, reduction with an alkali metal borohydride (e.g., sodium ohydride).

Suitable imino halogenating agents used in a method as mentioned above may include phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride or phosgene. The reaction temperature is not critical and the reaction is usually carried out at room temperature or under cooling. Suitable imino-etherifying agents which can be reacted with the reaction products thus obtained may be, for example, an alcohol or a metal alkoxide. A suitable alcohol may be, for example, an alkanol (e.g., methanol, ethanol, propanol, isopropanol, butanol or tert-butanol) which may be substituted by alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy or butoxy). Suitable metal alkoxides may include alkali metal alkoxides (e.g., sodium alkoxide or potassium alkoxide) or alkaline earth metal alkoxides (e.g., calcium alkoxide or barium alkoxide). The reaction temperature is not critical and the reaction is usually carried out under cooling or at room temperature.

The product thus obtained is subjected, if necessary, to hydrolysis.

The hydrolysis can be easily carried out by pouring the obtained reaction mixture 20 into water, but a hydrophilic solvent (e.g. methanol or ethanol), a base (e.g. an alkali metal hydrogen carbonate or trialkylamine) or an acid (e.g. dilute hydrochloric acid) may be added in advance. or acetic acid) to the water.

The reaction temperature is not critical, and it can conveniently be selected according to the nature of the amino protecting group and the elimination method used, and the reaction is preferably carried out under mild conditions, for example under cooling, at room temperature or at slightly elevated temperature.

It is within the scope of the present invention to convert a protected carboxy group to a free carboxy group. When the compound of formula IV wherein R 1 is carbamoyloxymethyl with an acyl group is used as starting material, either the desired compound of formula Ia wherein R 1 is a carbamoyloxymethyl group having an acyl group or a free carbamoyloxymethyl group, depending on DK 162391 kan, can be obtained. 23 reaction conditions. When using a compound of formula IV wherein R 1 is an acyloxymethyl group as starting material, optionally the desired compound of formula Ia wherein R 1 and R 2 are bonded together to form a -COOCH 2 depending on the reaction conditions, during the reaction or after treatment.

Process c):

The compound of formula Ic or a salt thereof can be prepared by subjecting the compound of formula Va or a salt thereof to an elimination reaction for the carboxy protecting group.

A suitable salt of the compound of formula Va may be as exemplified for the compound of formula IV.

This elimination reaction is carried out in the usual manner, for example, by hydrolysis. The hydrolysis may be a method in which an acid or base is used. These methods can be selected depending on the nature of the protecting group to be removed.

Hydrolysis using an acid is the most common and preferred method of eliminating protecting groups such as phenyl-lower alkyl, substituted phenyl-lower alkyl, lower alkyl or substituted lower alkyl. A suitable acid may be, for example, an inorganic or organic acid, for example formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or hydrochloric acid. This reaction can be carried out in the presence of anisole. A suitable acid for this reaction can be selected depending on the protecting group to be removed and other factors.

Hydrolysis using an acid may be carried out in the presence of a solvent, for example an organic solvent, water or a mixed solvent thereof.

The reaction temperature is not critical and it can be selected depending on the nature of the protecting group and the elimination method, and

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The reaction is preferably carried out under mild conditions, for example, under cooling, at room temperature or lightly heated.

It is within the scope of the invention to convert the protected carboxy group to a free carboxy group, to convert the protected 5 amino group to a free amino group, to convert a protected imino group to a free imino group, to convert the acyloxy group to a hydroxy group, and / or to convert it. the carbamoyloxymethyl group having an acyl group to a free carbamoyloxymethyl group during the reaction or after treatment.

Method d):

The compound of formula Id or a salt thereof can be prepared by subjecting the compound of formula Vb or a salt thereof to the amino protecting group elimination reaction.

Suitable salts of the compound of formula Vb are as indicated for the compound of formula IV.

This elimination reaction may be, for example, an elimination method using a base, for example, an inorganic base such as an alkali metal hydroxide (e.g., sodium hydroxide or potassium hydroxide), an alkali metal hydrogen carbonate (e.g., sodium bicarbonate or potassium hydrogen carbonate) or alkali metal carbonate ( carbonate), an organic base such as an alkali metal alkoxide (e.g. sodium methoxide or sodium ethoxide), a trialkylamine (e.g. trimethylamine or triethylamine), triethanolamine, Ν, Ν-dimethylaniline, N, N-dimethylbenzylamine, N-methylmorpholine or pyridine, or an elimination reaction using basic alumina, a basic ion exchange resin, an acid (e.g. trifluoroacetic acid or trifluoroacetic anisole). This elimination reaction is usually carried out in water, a hydrophilic solvent or a mixture thereof. The reaction temperature is not critical and the reaction is preferably carried out at room temperature or under cooling.

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25

It is within the scope of the invention to convert the protected carboxy group or salts of the compound of formula Vb to a free carboxy group and to convert a protected amino and / or imino group respectively to a free amino and / or imino group during reaction 5 or by post-treatment.

Method e):

The compound of formula Ie or a salt thereof can be prepared by reacting the compound of formula Vc or a salt thereof with a compound of formula Vd or a reactive derivative thereof at the mercapto group.

Suitable salts of the compound of formula Vc may be as exemplified for the compound of formula IV.

Suitable reactive derivatives of the mercapto group of the compound of formula Vd may be a metal salt such as an alkali metal salt (e.g., a sodium or potassium salt).

This reaction can be carried out in a solvent such as water, acetone, chloroform, nitrobenzene, methylene chloride, ethylene chloride, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran or dimethylsulfoxide or any other solvent which does not adversely affect the reaction, preferably a solvent of strong polarity. Among the solvents, hydrophilic solvents can be used in admixture with water. The reaction is preferably carried out under weakly basic or approximately neutral conditions.

When the compound of formula Vc and / or thiol of formula Vd 25 is used in free form, the reaction is preferably carried out in the presence of a base, for example, an inorganic base such as an alkali metal hydroxide, an alkali metal carbonate or an alkali metal hydrogen carbonate or an organic base such as a trialkylamine. or pyridine. The reaction temperature is not critical and the reaction is usually carried out at room temperature or under heating. The reaction product can be isolated from the reaction mixture in the usual manner.

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26

The reaction between the compound of formula Vc and the compound of formula Vd comprises those cases where the protected carboxy group or salts of the compound of formula Vc are converted to a free carboxy group where the protected amino and / or imino group is converted to a free amino and / or imino group and wherein the acyloxy group is converted to a hydroxy group, either during the reaction or after treatment.

Method f):

The compound of formula If or a salt thereof can be prepared by treating the compound of formula Ve or a salt thereof with an acid.

Suitable salts of the compound of formula Ve are as exemplified for the compound of formula IV.

A suitable acid for use in this reaction may be, for example, an inorganic acid (e.g., hydrochloric, hydrobromic or sulfuric) or an organic acid (e.g., formic or acetic).

This reaction is usually carried out in a solvent such as water, acetone, acetic acid or any other solvent which does not adversely affect the reaction. Of these 20 solvents, hydrophilic solvents can be used in admixture with water.

The reaction temperature is not critical and the reaction is preferably carried out under cooling or heating.

Methods for preparing the starting material of formula III, i.e. The syn-isomer and its anti-isomer, cited as examples, are explained in detail below:

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27 A.) Turnover of XXXII -> XXXIII (Schedule (3) (ii)).

The compound of formula XXXIII can be prepared by oxidation of compound XXXII.

This oxidation reaction is carried out in the usual manner, which is used to convert a so-called activated methylene group to a carbonyl group. Ie the oxidation is carried out in the usual manner, for example oxidation using a conventional oxidizing agent such as selenium dioxide or potassium permanganate. This oxidation is usually carried out in a solvent which does not adversely affect the reaction, for example 10 water, dioxane, pyridine or tetrahydrofuran.

The reaction temperature is not critical and the reaction is preferably carried out under heating.

B) Turnover of XXXIII + XIV - + XXXV (Schedule (3) (ii)) and XXXIV + XIV - + Ulf (Schedule (3) (ii)).

The compounds of formulas XXXV and Ulf can be prepared by reacting the compounds of formulas XXXIII and XXXIV respectively with the compound of formula XIV or a salt thereof.

A suitable salt of the compound of formula XIV may be an inorganic acid salt (e.g., the hydrochloride, hydrobromide or sulfate) or an organic acid salt (e.g., the acetate or p-toluenesulfonate).

This reaction is usually carried out in a solvent such as water, an alcohol (e.g., methanol or ethanol), a mixture thereof, or any other solvent which does not adversely affect the reaction.

This reaction is carried out when the compound of formula XIV is used in salt form, preferably in the presence of a base, e.g., an inorganic base such as an alkali metal (e.g., sodium or potassium), an alkaline earth metal (e.g., magnesium or calcium) or a hydroxide or carbonate or hydrogen carbonate. thereof, or an organic base such as an alkali metal alkoxide (e.g., sodium methoxide or sodium ethoxide), a trialkylamine 28

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(e.g. trimethylamine or triethylamine), Ν, Ν-dialkylamine (e.g., Ν, Ν-dimethylaniline), N, N-dialkylbenzylamine (e.g., Ν, Ν-dimethylbenzylamine) or pyrldine.

The reaction temperature is not critical and the reaction is usually carried out under cooling or heating.

In this reaction, a mixture of syn and anti-isomers of the compounds of formulas XXXV or Ulf can be obtained depending on the reaction conditions, and in such cases the isomers can be cleaved in the usual manner. For example, the mixture is first esterified and the resulting 10 esters are cleaved, for example, by chromatography to give each isomer separately. Each of the cleaved isomers of esters is hydrolyzed in the usual manner to give the corresponding syncytic or anti-carboxylic acid.

To prepare the syn-isomer of the compounds of formula XXXV 15 or Ulf selectively and in high yield, the reaction is preferably carried out under approximately neutral conditions.

C) Revenue of XXXIV · + XXXVI (Schedule (3) (ii)).

The compound of formula XXXVI can be prepared by reacting the compound XXXIV with hydroxylamine or a salt thereof.

Suitable salts of hydroxylamine are those salts listed for compound of formula XIV.

The reaction conditions for this reaction are as given for the procedure XXXIII + XIV - * · XXXV and XXXIV + XIV - * Ulf, as stated in trader B).

25 D) Turnover of XXIV - * XXV (Schedule 1) (ii)) and XXVI - * · XXVII (Schedule (2)).

The compounds of formulas XXV and XXVII can be prepared by alkylating the compounds XXIV and XXVI, respectively.

in

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29

The alkylating agent used in this alkylation reaction may be, for example, di-lower alkyl sulfate (e.g., dimethyl sulfate or diethyl sulfate), diazo-lower alkane (e.g., diazomethane or diazoethane), lower alkyl halide (e.g., methyl iodide or ethyl iodide) or lower alkyl sulfonate. (e.g., methyl p-toluenesulfonate).

The reaction using di-lower alkyl sulfate, lower alkyl halide or lower alkyl sulfonate is usually carried out in a solvent such as water, acetone, ethanol, ether, dimethylformamide or any other solvent which does not adversely affect the reaction.

This reaction is preferably carried out in the presence of a base, for example an inorganic base or an organic base as stated above.

The reaction temperature is not critical and the reaction is usually carried out under cooling or heating to the boiling point of the approximate solvent.

The reaction using diazoalkane is usually carried out in a solvent such as ether or tetrahydrofuran.

The reaction temperature is not critical and the reaction is usually carried out under cooling or at room temperature.

E) Turnover of XX - 'XXI (Schedule (1) (i)).

The compound of formula XXI can be prepared by nitrosating the compound of formula XX.

The nitrosating agent used for this reaction can be any conventional agent which leads to the formation of a C-nitro compound by reaction with an activated methylene group, e.g. .butylnitrit).

When a salt of a nitric acid is used as a nitrosating agent, the reaction is usually carried out in the presence of an acid, e.g.

DK 162391 B

Inorganic acid or an organic acid (e.g. hydrochloric or acetic acid).

When an ester of nitric acid is used, the reaction is preferably carried out in the presence of a strong base such as an alkali metal alkoxide.

This reaction is usually carried out in a solvent such as water, acetic acid, benzene, alcohol (e.g. ethanol or methanol) or any other solvent which does not adversely affect the reaction.

The reaction temperature is not critical and the reaction is usually carried out under cooling or at room temperature.

F) Turnover of XXI + XXII + XXIII (Schedule (1) (i)) and XXVIII + XXII -> XXIX (Schedule (2)).

The compounds of formulas XXIII and XXIX can be prepared by reacting the compounds of formulas XXI and XXVIII respectively with a compound of formula XXII.

This reaction is usually carried out in a solvent such as water, an alcohol (e.g., methanol or ethanol), benzene, dimethylacetamide, dimethylformamide, tetrahydrofuran, a mixture thereof, or any other solvent which does not adversely affect the reaction.

The reaction temperature is not critical and the reaction is usually carried out at a temperature between room temperature and the approximate solvent boiling temperature.

To prepare the syn isomer of the compound of formula XXIII or XXIX selectively and in high yield, it is necessary to use the syn isomer of the starting compound of formula XXI or XXVIII, and this reaction is preferably carried out under approximately neutral conditions in the presence of a base which above. Preferred examples of bases may be a weak base such as an alkali metal acetate (e.g., sodium acetate or potassium acetate), alkali metal hydrogen carbonate (e.g.

DK 162391 B

31 sodium bicarbonate or potassium hydrogen carbonate) or an alkali metal carbonate (e.g., sodium carbonate or potassium carbonate).

G) Turnover of XXIII - »XXIIIa (Schedule (1) (i)), XXV -» Wool (Schedule (1) (ii)), 5 XXIX -v Ille (Schedule (2)), XXXIII * ♦ XXXIV (Schedule (3) (ii)) and XXXV- Ulf (Scheme (3) (ii)).

The compounds of formulas XXIIIa, Wool, Ille, XXXIV and Ulf can be prepared by subjecting compounds XXIII, XXV, 10 XXIX, XXXIII and XXXV to elimination reactions of the carboxy protecting group, respectively.

In this elimination reaction, conventional methods used in the elimination of protected carboxy, e.g., hydrolysis, can be used. When the protecting group is an ester, it can be eliminated by hydrolysis.

The hydrolysis is preferably carried out in the presence of a base or an acid.

Suitable bases may be, for example, an inorganic base or organic base such as an alkali metal (e.g., sodium or potassium), an alkaline earth metal (e.g., magnesium or calcium), a hydroxide or carbonate or hydrogen carbonate thereof, a trialkylamine (e.g., trimethylamine or triethylamine). amine), picoline, 1,5-diazabicyclo [4,3,0] non-5-ene, 1,4-diazabicyclo- [2,2,2] octane or 1,5-diazabicyclo [5,4,0} undecen 5th

Suitable acids are, for example, an organic acid (e.g. formic acid, acetic acid, propionic acid or trifluoroacetic acid) or an inorganic acid (e.g. hydrochloric acid, hydrochloric acid or sulfuric acid).

The reaction is usually carried out in a solvent such as water, an alcohol (e.g., methanol or ethanol), a mixture thereof, or any other solvent which does not adversely affect the reaction. A liquid base or acid can also be used as a solvent.

The reaction temperature is not critical and the reaction is usually carried out under cooling or heating.

DK 162391 B

32 H) Turnover of XXVII · * XXVIII (Schedule (5)).

The compound of formula XXVIII can be prepared by halogenating the compound of formula XXVII.

The halogenating agent used in this reaction may be a conventional halogenating agent used in the halogenation of so-called activated methylene groups, for example halogen (e.g., bromine or chlorine), sulfuryl halide (e.g., sulfuryl chloride), hypohalogenite (e.g. imides (e.g., N-bromosuccinimide, N-bromophthalimide or N-10 chlorosuccinimide).

This reaction is usually carried out in a solvent such as an organic acid (e.g. formic acid, acetic acid or propionic acid), carbon tetrachloride or any other solvent which does not adversely affect the reaction.

The reaction temperature is not critical and the reaction is usually carried out under cooling, at room temperature or under heating.

I) Turnover of XXX - + XXXI (Schedule (3) (i)) and XXXIX f Illh (Schedule (4)).

The compound of formula XXXI may be prepared by reacting the compound ice of formula XXX or a reactive derivative thereof with the amino group or a salt thereof with an amino protecting agent, and the compound of formula IIIl may be prepared by reacting the compound of formula XXXIX or a reactive one. derivative thereof by the amino group or a salt thereof with an amino protecting agent.

Suitable reactive derivatives at the amino group of the compound of formula XXX or XXXIX and suitable salts of the compound of formula XXX or XXXIX are the same as explained in connection with the reactive derivatives for the amino group of the compound of formula II and salts of the compound of formula II, respectively.

i i 33

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Suitable amino protecting agents may be acylating agents which may be an aliphatic, aromatic or heterocyclic carboxylic acid and the corresponding sulfonic acid, haloic acid ester, isocyanic acid ester and carbamic acid and the corresponding thioic acid thereof, and the reactive derivatives of the acids listed above.

Suitable reactive derivatives of the acids listed above may be acid halides, acid anhydrides, activated amides or activated esters. Examples of protecting groups (e.g., acyl groups) to be introduced into the amino group of the compound of formula XXX or XXXIX of the above-mentioned amino protecting agent (e.g., acylating agent) may be the same protecting group (e.g., acyl group) as explained in connection with the protecting moiety (e.g., acyl moiety). in the term "acyl-amino".

This amino protecting reaction is carried out in a similar manner as illustrated in connection with reaction of the compound of formula II and the compound of formula III (process a).

J) Turnover of XXIIIb + XXXIII (Schedule (3) (ii >>).

The compound of formula XXXIII can be prepared by hydrolyzing the compound of formula XXIIIb.

This hydrolysis is carried out in the presence of alkali metal bisulfite (e.g., sodium bisulfite), titanium trichloride, an inorganic or organic acid such as hydrogen halide acid (e.g., hydrochloric or hydrochloric acid), formic acid or nitric acid. Hydrogen halide acid is preferably used in combination with an aldehyde (e.g., formaldehyde).

This reaction is usually carried out in a solvent such as water, aqueous alcohol (e.g., aqueous methanol or aqueous ethanol), water-acetic acid, or any other solvent which does not adversely affect the reaction.

The reaction temperature is not critical and the reaction is usually carried out at room temperature or under heating. In this reaction, a protected carboxy group may optionally be converted to a free carboxylic acid.

DK 162391 B

34 group. This case is also within the scope of the present invention.

In the above reactions and / or post-treatment after the reactions of the present invention, the above-mentioned tautomeric isomers may optionally be converted to other tautomeric isomers, and such cases are also within the scope of the invention.

If the compound of formula I is obtained in the form of the free acid in the 4-position and / or if the compound of formula I contains a free amino group can. it is converted into a pharmaceutically tolerable salt 10 as set forth above by a conventional method.

The compound of formula I and pharmaceutically tolerable salts thereof are all novel compounds having potent antibacterial activity, inhibiting the growth of a wide range of pathogenic microorganisms, including gram positive and gram negative bacteria, and they are valuable as antibacterial agents. In particular, the compound of formula I, i. the syn isomer, much stronger antibacterial effect than the corresponding anti-isomer corresponding to the compound of formula I, therefore the compound of formula I, i. the syn isomer is peculiar in being the corresponding anti-isomer superior in terms of therapeutic effect.

In order to demonstrate the useful effect of the subject compounds of formula I, illustrated by some representative compounds, experimental data on antibacterial activity in vitro, experimental data on the protective effect against experimental infections in vivo, and acute toxicity are listed below. ment. Comparative experimental data on the antibacterial effect in vitro relative to the corresponding anti-isomer of the compound of formula I for comparison are also provided.

DK 162391 B

35

Test compounds: 1) 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamido] -3-carbamoyloxy-methyl-3-cephem-4-carboxylic acid (syn isomer), 2) 7- [2-methoxyimino-2 - (3-hydroxyphenyl) acetamido] -3- (1-methyl-1H-5-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), 3) 7- [2-methoxyimino-2 - (3-hydroxyphenyl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (anti-isomer), 4) 7- [2-methoxyimino-2- (3-hydroxyphenyl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), 5) 7- [2-methoxyimino 2- (3-acetoxyphenyl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), 6) 7- [2-methoxyimino 2- (2-Amino-1,3-thiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) 7) 7- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1- methyl-1H-tetrazol-5-yl) thiomethyl-3- cephem-4-carboxylic acid (anti-isomer), 8) 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] ceph alo-sporanoic acid (syn isomer), 9) 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] cephalo-sporanoic acid (anti-isomer), 10) 7 - [2-methoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), 11) 7- [2-methoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) ) thiomethyl-3-cephem-4-carboxylic acid (anti-isomer), 12) 7- [2-methoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -cephalosporanoic acid (syn-isomer) 13) 7- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) , 14) 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem -4-carboxylic acid (syn isomer), 15) 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-hydroxymethyl-3-cephem 4-carboxylic acid (syn-isomer),

DK 162391 B

36) 7- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl -3-cephem-4-carboxylic acid (syn-isomer), 17) 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (4-methyl) -4H-1,2,4-triazol-3-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) and 18) 7- [2-methoxyimino-2- (2- (2,2,2) (trifluoroacetamido) -1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

1. In vitro antibacterial activity:

Experimental method.

The in vitro antibacterial effect is determined by the double agar plate dilution method as described below.

One eye of a culture of each test strain grown overnight in 15 Trypticase soy culture fluid (10® viable cells / ml) is irradiated on cardiac infusion agar (Hi-agar) containing graduated antibiotic concentrations and the minimum inhibitory concentration (MIC) expressed in µg / ml after incubation at 37 ° C for 20 hours.

DK 162391 B

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DK 162391 B

38

It is clear from the test results that the compounds of formula I, i.e. the syn isomers, have much higher antibacterial effect than the corresponding anti-isomers.

2. In Vitro Antibacterial Effect - Comparative Experiment 5 Using the test procedure described in Test 1, the antibacterial activity of test compounds 13, 14, 15 and 17 above against different organisms was compared to the action of two compounds A and B known from DK-B-147,683, namely (A) 7- [2-Methoxyimino-2- (2-furyl) acetamido] -3-carbamoyloxymethyl-3-10 cephem-4-carboxylic acid (syn isomer) (commercially available under the name Cefuroxime ).

(B) 7- (2-Methoxyimino-2-phenylacetamido) -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

The results set forth in the following table were obtained which clearly show that the compounds of the present invention have a substantially higher antibacterial effect than the known compounds.

Test results

Experimental Bacteria MIC (/ µg / ml) 20 (13) (14) (17) (15) (A) (B) E. coli NIHJ JC-2 1.56 0.10 0.20 0.78 6.25 6 , 25 E. coli 351 0.10 0.20 0.20 0.78 6.25 25.0

Kleb. pneumoniae 418 0.10 0.20 0.39 0.39 6.25 12.5 25 Pr. mirabilis 501 <0.025 0.20 0.20 0.20 6.25 6.25

Pr. mirabilis 520 <0.025 0.05 0.10 0.10 1.56 6.25

Pr. vulgaris 616 0.05 0.20 0.20 0.78 6.25> 100

DK 162391 B

39 3. Protective effect against experimental infections in mice:

Experimental method: 4 week old male mice of the strain ICR, each weighing 20-23 g, are divided into groups of 8 mice each. The test bacterium is grown overnight at 37 ° C on Hi-agar and then suspended in 2.5-5% mucin solution to give a cell suspension for each administration. The mice are administered intraperitoneally 0.5 ml of the suspension. A solution containing the test compound is administered subcutaneously to the mice at various doses 1 hour after administration. The ED50 values are calculated from 10 numbers of surviving mice for each dose after 1 week of observation time. The results are summarized in the tables below:

DK 162391B

40

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DK 162391 B

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DK 162391 B

42 4. Acute toxicity in mice.

The same strain of mice as in the above experimental experiment against experimental infections is used in groups of every 10 mice. The test compound (8) (2 g) is administered intravenously to these mice.

5 All mice survived without but after 1 week of observation.

For therapeutic administration, the compound of formula I was used in the form of a conventional pharmaceutical composition containing this compound as an active ingredient in admixture with pharmaceutically tolerable carriers, for example an organic or inorganic solid 10 or liquid excipient suitable for oral, parenteral or exothermic administration. The pharmaceutical compositions may be in solid form, for example, as capsules, tablets or dragees, as ointment or as a suppository or in liquid form, for example as solution, suspension or emulsion. If necessary, auxiliaries, stabilizers, wetting or emulsifying agents, buffers and other commonly used additives may be iricorated in said compositions.

While the dosage of the compounds may vary and also depends on the patient's age and condition, the nature of the disease and the nature of the compound of formula I used, an average single dose of about 20 50 mg, 100 mg, 250 mg and 500 mg of the compound of formula I have been shown to be effective in the treatment of pathogenic bacteria.

Generally, amounts between 1 mg and approx. 1000 mg or even more is administered to a patient.

The process of the invention is illustrated in more detail by the following examples, and preparations of some starting materials are illustrated in the "Preparations" below:

DK 162391 B

EXAMPLE 1

The compounds listed below are prepared in a similar manner as described in Examples 12-16.

1) 7- [2-Methoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -3-5 (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem -4-carboxylic acid (syn isomer), mp 145-147 ° C (dec.).

IR Spectrum (nujol): 3150-3400, 1780, 1725, 1680 and 1640 cm cm ".

NMR Spectrum (d6-DMSO): δ - 12.58 (1H, broad s), 9.70 (1H, d, J -8Hz), 9.58 (1H, s), 8.50 (1H, s) ), 7.40 (1H, s), 5.82 (1H, dd, J - 5, 10 8Hz), 5.17 (1H, d, J - 5Hz), 4.43 (2H, ABq, J - 13Hz), 3.88 (3H, s) and 3.70 (2H, broad s) ppm.

2) 7- [2-Methoxyimino-2- (2- (2,2,2-trifluoroacetamido) -1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn -isomer).

IR Spectrum (nujol): 3500, 3200, 1785, 1700 and 1660 cm -1.

NMR Spectrum (d 6 -DMSO): δ - 9.75 (1H, d, J = 8Hz), 8.4 (2H, m), 7.53 (1H, s), 6.6 (1H, m) , 6.20 (1H, d, J - 5Hz), 5.83 (1H, m), 4.77 (2H, ABq, J = 14Hz), 3.91 (3H, s) and 3.55 (2H , m) ppm.

3) 7- [2-Methoxyimino-2- (2- (2,2,2-trifluoroacetamido) -1,3-thiazol-4-yl) acetamido] -3- (1,3,4-thiadiazole-2) -yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3200, 1780, 1720 and 1650 cm

NMR Spectrum (d6-DMSO): δ - 9.81 (1H, d, J - 8Hz), 9.6 (1H, m), 9.57 (1H, s), 7.56 (1H, s) , 5.83 (1H, dd, J - 5.8Hz), 5.20 (1H, d, J - 25Hz), 4.47 (2H, ABq, J - 14Hz), 3.96 (3H, s ) and 3.72 (2H, ABq, J - = 18Hz) ppm.

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44) 7 - [2-Me thoxy imino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-hydroxymethyl-3-cephem-4-carboxylic acid (syn isomer) , m.p. 260-270 ° C (dec.).

IR Spectrum (nujol): 3370, 3270, 1765, 1660, 1610, 1590 and 1550 cm

NMR Spectrum (d 6 -DMSO): S - 9.58 (1H, d, J - 8Hz), 6.76 (1H, s), 5.75 (1H, dd, J - 5, 8 Hz), 5.12 (1H, d, J - 5Hz), 4.27 (2H, broad s), 3.85 (3H, s) and 3.57 (2H, wide s) ppm.

5) 7- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer), m.p. 210-220eC (decomposition).

IR Spectrum (nujol): 3250, 1765 and 1650 cm

NMR Spectrum (d6-DMSO): S = 9.64 (1H, d, J = 8Hz), 7.4 (2H, m), 6.79 (1H, s), 6.60 (2H, m) , 5.77 (1H, dd, J = 5.8Hz), 5.16 (1H, d, J = 5Hz), 4.75 (2H, ABq, J * = 12Hz), 3.87 (3H, s ) and 3.53 (2H, ABq, J -15 18Hz) ppm.

6) 7- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem 4-carboxylic acid (syn isomer), mp 172-175 ° C (dec.).

IR Spectrum (nujol): 3300, 1770 and 1665 cm

NMR Spectrum (d 6 -DMSO): S - 9.80 (1H, d, J = 8Hz), 9.63 (1H, s), 6.95 (1H, s), 6.8 (2H, m ), 5.82 (1H, dd, J = 5, 8Hz), 5.22 (1H, d, J = 5Hz), 4.48 (2H, ABq, J - 15Hz), 3.97 (3H, s) ) and 3.76 (2H, ABq, J - = 18Hz) ppm.

7) 7- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (4- methyl-4H-1,2,4-triazol-3-yl) ) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), m.p. 185 ° C (dec.).

IR Spectrum (nujol): 3150-3350, 1770, 1710, 1660 and 1630 cm cm ".

DK 162391B

NMR Spectrum (d6-DMSO): δ 9.61 (1H, d, J - 8Hz), 8.69 (1H, s), 6.73 (1H, s), 5.72 (1H, dd) , J - 4, 8Hz), 5.1 (1H, d, J - 4Hz), 4.1 (2H, ABq, J - 13Hz), 3.87 (3H, s), 3.65 (2H, wide s) and 3.59 (3H, s) ppm.

8) 7- [2-Methoxyimino-2- (2- (2,2,2-trifluoroacetamido) -1,3-thiazol-4-yl) acetamido] -3-hydroxymethyl-3-cephem-4-carboxylic acid ( syn isomer), mp 155-160 "G (decomposition).

IR Spectrum (nujol): 3250, 1780, 1730, 1660, 1585, and 1520 cm -1, NMR Spectrum (d6-DMSO): S IH, s), 5.80 (1H, dd, J - 4, 8Hz), 5.15 (1H, d, J - 4Hz), 4.29 (2H, s), 3.93 (3H, 10 s) ) and 3.60 (2H, s) ppm.

9) 6- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -5a, 6-dihydro-3H, 7H-azeto [2,1-b] furo [3 , 4-d] [1,3] thiazine-1,7 (4H) -dione (syn isomer), m.p. 210-215 ° C (dec.).

IR spectrum (nujol); 3270, 1780, 1740, 1655, 1610 and 1525 cm

NMR Spectrum (d6-DMSO): δ - 9.70 (1H, d, J - 8Hz), 7.26 (2H, broad s), 6.77 (1H, s), 5.93 (1H, dd, J - 5, 8Hz), 5.16 (1H, d, J - 5Hz), 5.05 (2H, wide s), 3.85 (3H, s) and 3.81 (2H, wide s) ppm.

10) 7- [2-Methoxyimino-2- (2-ethoxycarbonylamino-1,3-thiazol-4-yl) acetamide] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3200, 1775, 1720, 1680 and 1660 cm -1.

NMR Spectrum (dg-DMSO): δ - 11.9 (1H, m), 9.70 (1H, d, J - 10Hz), 9.55 (1H, s), 7.31 (1H, s) , 5.80 (1H, dd, J - 5, 10Hz), 5.18 (1H, d, J - 5Hz), 4.44 (2H, ABq, J - 16Hz), 4.22 (2H, q, J -7Hz), 3.89 (3H, 25 s), 3.72 (2H, ABq, J - 16Hz) and 1.23 (3H, t, J - 7Hz) ppm.

11) 7- [2-Methoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido) -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

DK 162391 B

46 IR Spectrum (nujol): 3300, 1780, 1705 and 1680 cm cm ".

NMR Spectrum (d 6 -DMSO): δ -12.50 (1H, broad s), 9.67 (1H, d, J - 8Hz), 8.50 (1H, s), 7.43 (1H, s) ), 6.58 (2H, broad s), 5.80 (1H, dd, J - 5.8Hz), 5.16 (1H, d, J - 5Hz), 4.78 (2H, ABq, J - 14Hz), 3.95 (3H, s), and 3.57 (2H, ABq, J - 18Hz) ppm.

Example 2 23 g of 7- [2-methoxyimino-2- (2- (2,2,2-trifluoroacetamido) -1,3-thiazol-4-yl) acetamido] -3- (1,3,4-thiadiazole) 2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) is suspended in a solution of 74.8 g of sodium 10 acetate trihydrate in 230 ml of water and the suspension is stirred for 15 hours at room temperature. The reaction mixture is adjusted to pH 5.0 with concentrated hydrochloric acid and the insoluble material is filtered off.

The filtrate is adjusted to pH 2.5 and precipitated crystals are isolated by filtration and dried to give 14 g of 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido ] -3- (1,3,4-Thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 172-175 ° C (dec.).

IR Spectrum (nujol): 3300, 1770 and 1665 cm

NMR Spectrum (dg-DMSO): S - 9.80 (1H, d, J - 8Hz), 9.63 (1H, s), 6.95 (1H, s), 6.8 (2H, m ), 5.82 (1H, dd, J = 5, 8Hz), 5.22 (1H, d, J -5Hz), 4.48 (2H, ABq, J - 15Hz), 3.97 (3H, s) ) and 3.76 (2H, ABq, J -18Hz) ppm.

EXAMPLE 3 3.5 g of 7- [2-methoxyimino-2- (2- (2,2,2-trifluoroacetamido) -1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem 4-carboxylic acid (syn isomer) is suspended in a solution of 12.2 g of sodium acetate trihydrate in 30 ml of water. The mixture is stirred for 15 hours at room temperature. The reaction mixture is saturated with sodium chloride and adjusted to pH 5.0 with concentrated hydrochloric acid with stirring and ice-cooling.

47

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Precipitated insoluble material is filtered off. The filtrate is adjusted to pH 3.0 with concentrated hydrochloric acid and further adjusted to pH 1.5 with 10% hydrochloric acid. Precipitated material is isolated by filtration and dried to give 2.1 g of 7- [2-methoxyimino-2- (2-5 amino-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem -4-carboxylic acid (syn isomer), mp 210-220 ° C (dec.).

IR Spectrum (nujol): 3250, 1765 and 1650 cm

NMR Spectrum (d 6 -DMSO): 6 - 9.64 (1H, d, J = 8Hz), 7.4 (2H, m), 6.79 (1H, s), 6.60 (2H, m) , 5.77 (1H, dd, J - 5.8Hz), 5.16 (1H, d, J -10.5Hz), 4.75 (2H, ABq, J - 12Hz), 3.87 (3H, s ) and 3.53 (2H, ABq, J -18Hz) ppm.

EXAMPLE 4 10.4 ml of concentrated hydrochloric acid are added under stirring at room temperature to a suspension of 48.35 g of 7- (2-methoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] cephalosporanoic acid ( syn isomer) in 725 ml of methanol, After stirring for 3 hours at room temperature, the reaction mixture is adjusted to pH 4.5 with an aqueous solution of ammonia and the methanol is distilled off. To the residue is added 100 ml of water. The mixture is adjusted to pH 6 5 with an aqueous solution of sodium hydrogen carbonate and insoluble material is isolated by filtration to give 6.5 g of 6- [2-methoxyimino-2- (2-amino-1,3-thlazol-4-yl) acetamido] -5a, 6-dihydro-3H, 7H-azeto [2,1b] furo [3,4-d] - [1,3] thiazine-1,7 (4H) dione (syn isomer) The filtrate is adjusted to pH value 4.5 with acetic acid, adsorbed on 600 ml of "Diaion" ® HP-20-Resin 25 (manufactured by Mitsubishi Chemical Industries Ltd.), washed with 2 liters of water and then eluted with a 25% aqueous solution of isopropyl alcohol Eluates inside holding the desired compounds are isolated and cooled after the addition of isopropyl alcohol (1/3 volume of the eluates). The precipitate is isolated by filtration, washed with 30 isopropyl alcohol and dried to give 10.4 g of 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] cephalosporanoic acid (syn -isomer).

The mother liquor is evaporated under reduced pressure until crystals begin to precipitate. Isopropyl alcohol (2/3) is added to the residue

DK 162391 B

48 volume of the residue). The mixture is cooled and the precipitate is isolated by filtration to give 5.8 g of the same desired compound. Total yield 16.2 g. This compound is identified by IR and NMR spectra to be the same compound prepared in the previous examples.

Example 5 10.8 g of 7- [2-methoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl 3-cephem-4-carboxylic acid (syn-isomer) is added to 200 ml of methanol, to which is added dropwise 7.2 g of 10 phosphorus oxychloride with stirring, and ice-cooling to 2-9eG. After stirring for 1 1/2 hours at the same temperature, the reaction mixture is evaporated under reduced pressure to a volume of 100 ml on a water bath at 25-28 ° C. To the residue is added 300 ml of ether with stirring and under ice-cooling. The precipitate is isolated by filtration and dried to give 12.3 g of 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1,3, 4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer). This powder (12.3 g) is suspended in 100 ml of water and dissolved by adjusting the pH of the suspension to 7.5 by adding a saturated aqueous solution of sodium hydrogen carbonate. To the solution is added 100 ml of ethyl acetate and the mixture is adjusted to pH 2.5 with 10% hydrochloric acid. The precipitate is isolated by filtration, washed with cold water and dried to give 6.1 g of 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3 - (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer). The aqueous phase of the mother liquor is separated and stirred under cooling after addition of sodium chloride. The precipitated substance is isolated by filtration to give 3.8 g of the same compound. Total yield 9.9 g. This compound is identified by IR and NMR spectra to be the same compound prepared in the previous examples.

EXAMPLE 6 49

DK 162391 B

The compounds listed below are prepared in a similar manner as described in Examples 2-5: 1) 7- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-hy-5 droxymethyl-3-cephem-4-carboxylic acid (syn-isomer), m.p. 260-270 ° C (dec.).

IR Spectrum (nujol): 3370, 3270, 1765, 1660, 1610, 1590 and 1550 cm -1 · 1 ·.

NMR Spectrum (dg-DMSO): 8 - 9.58 (1H, d, J - 8Hz), 6.76 (1H, s), 5.75 (1H, dd, J - 5, 8Hz), δ, 12 (1H, d, J - 5Hz), 4.27 (2H, broad s), 3.85 (3H, s) and 3.57 (2H, broad s) ppm.

2) 7- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer), m.p. 210-220 ° C (dec.).

IR Spectrum (nujol): 3250, 1765 and 1650 cm cm -.

NMR Spectrum (d6-DMSO): 8 - 9.64 (1H, d, J - 8Hz), 7.4 (2H, m), 6.79 (1H, s), 6.60 (2H, m) ), 5.77 (1H, dd, J = 5, 8Hz), 5.16 (1H, d, J - 5Hz), 4.75 (2H, ABq, J = 12Hz), 3.87 (3H, s) ) and 3.53 (2H, ABq, J -18Hz) ppm.

3) 7- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (4- methyl-4H-1,2,4-triazol-3-yl) ) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer), mp 185 ° C (dec.).

IR Spectrum (nujol): 3150-3350, 1770, 1710, 1660 and 1630 cm

NMR Spectrum (d 6 -DMSO): δ = 9.61 (1H, d, J - 8Hz), 8.69 (1H, s), 6.73 (1H, s), 5.72 (1H, dd, J - 4, 8Hz), 5.1 (1H, d, J - 4Hz), 4.1 (2H, ABq, J - 13Hz), 3.87 (3H, s), 3.65 (2H, wide s) and 3.59 (3H, s) ppm.

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4) 6 - [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -5a, 6-dihydro-3H, 7H-azeto [2,1-b] furo [ 3,4-d] [1,3] thiazine-1,7- (4H) -dione (syn isomer), mp 210-215 ° C (dec.).

IR Spectrum (nujol): 3270, 1780, 1740, 1655, 1610 and 1525 cm -1.

NMR Spectrum (d 6 -DMSO): S - 9.70 (1H, d, J = 8Hz), 7.26 (2H, broad s), 6.77 (1H, s), 5.93 (1H, dd, J - 5, 8Hz), 5.16 (1H, d, J - 5Hz), 5.05 (2H, wide s), 3.85 (3H, s) and 3.81 (2H, wide s) ppm.

EXAMPLE 7

A suspension of 2.76 g of 7- [2-methoxyimino-2- (2- (2,2,2-trifluoroacetamido) -1,3-thiazol-4-yl) acetamido] cephalosporanoic acid (syn isomer) and 0.63 g of 4-methyl-4H-1,2,4-triazole-3-thiol in 50 ml of pH 6.4 phosphate buffer solution are adjusted to pH 6.4 with sodium hydrogen carbonate and stirred for 5 minutes. 6 hours at 65-70 ° C. The mixture is cooled and ethyl acetate is added. The mixture is adjusted to pH 5 with 10% hydrochloric acid and washed with ethyl acetate. The aqueous phase is treated with activated charcoal and adjusted to pH 2.7 with 10% hydrochloric acid with stirring and ice-cooling. Precipitated crystals are isolated by filtration, washed with cold water and dried to give 0.7 g of 7- [2-methoxy-imino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3 - (4-methyl-4H-1,2,4-20 triazol-3-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 185 ° C (dec.).

IR Spectrum (nujol): 3150-3350, 1770, 1710, 1660 and 1630 cm cm 1.

NMR Spectrum (d6-DMSO): δ = 9.61 (1H, d, J = 8Hz), 8.69 (1H, s), 6.73 (1H, s), 5.72 (1H, dd, J = 4, 8Hz), 5.1 (1H, d-, J - 4Hz), 4.1 (2H, ABq, J - 13Hz), 3.87 (3H, s), 3.59 (3H, s) and 3.65 (2H, broad s) ppm.

EXAMPLE 8

The compounds listed below are prepared in a similar manner as described in Example 7:

DK 162391 B

51 1) 7- [2-Methoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn-isomer), mp 145-147 ° C (dec.).

IR Spectrum (nujol): 3150-3400, 1780, 1725, 1680 and 1640 cm cm ".

NMR Spectrum (d 6 -DMSO): δ = 12.58 (1H, broad s), 9.70 (1H, d, J-8Hz), 9.58 (1H, s), 8.50 (1H, s), 7.40 (1H, s), 5.82 (1H, dd, J - 5.8Hz), 5.17 (1H, d, J - 5Hz), 4.43 (2H, ABq, J - 13Hz), 3.88 (3H, s) and 3.70 (2H, broad s) ppm.

2) 7- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem -4-carboxylic acid (syn isomer), mp 172-175 ° C (dec.).

IR Spectrum (nujol): 3300, 1770 and 1665 cm -1.

NMR Spectrum (dg-DMSO): 8 - 9.80 (1H, d, J - 8Hz), 9.63 (1H, s), 6.95 (1H, s), 6.8 (2H, m) , 5.82 (1H, dd, J - 5.8Hz), 5.22 (1H, d, J -15.5Hz), 4.48 (2H, ABq, J - 15Hz), 3.97 (3H, s ) and 3.76 (2H, ABq, J -18Hz) ppm.

3) 7- [2-Methoxyimino-2- (2-ethoxycarbonylamino-1,3-thiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3- cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3200, 1775, 1720, 1680 and 1660 cm -1.

NMR Spectrum (dg-DMSO): S - 11.9 (1H, m), 9.70 (1H, d, J - 10Hz), 9.55 (1H, s), 7.31 (1H, s) , 5.80 (1H, dd, J - 5, 10Hz), 4.44 (2H, ABq, J - 16Hz), 4.22 (2H, q, J - 7Hz), 3.89 (3H, s) , 3.72 (2H, ABq, J - 16Hz) and 1.23 (3H, t, J - 7Hz) ppm.

EXAMPLE 9 52

DK 162391 B

A solution of 0.3 g of 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-hydroxymethyl-3-cephem-4-carboxylic acid (syn isomer) in a mixture of 3 ml of acetone and 1.5 ml of water is adjusted to pH 2.5 with 6N hydrochloric acid and stirred for 4 hours at room temperature. After distilling off the acetone, 1 ml of water is added to the residue. The mixture is adjusted to pH 7 with a saturated aqueous solution of sodium hydrogen carbonate and ice-cooled for 1 hour. Precipitated crystals are isolated by filtration, washed with water and dried to give 0.23 g of 6-10 [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -5a, 6 -dihydro-3H, 7H-azeto [2,1-b] furo [3,4-d] [1,3] thiazine-1,7 (4H) -dione (syn isomer), m.p. 210-215 ° C (dec. ).

IR Spectrum (nujol): 3270, 1780, 1740, 1655, 1610 and 1525 cm -1.

NMR Spectrum (d6-DMSO): S = 9.70 (1H, d, J * 8Hz), 7.26 (2H, broad s), 6.77 (1H, s), 5.93 (1H, dd, J = 5, 8Hz), 5.16 (1H, d, J = 5Hz), 5.05 (2H, wide s), 3.85 (3H, s) and 3.81 (2H, wide s) ppm.

EXAMPLE 10

The compound listed below is prepared in a similar manner as described in Example 9: 6- [2-Methoxyimino-2- (3-hydroxyphenyl) acetamido] -5α, 6-dihydro-3H, 7H-azeto [2,1b] furo [ 3,4-d] [1,3] thiazine-1,7 (4H) -dione (syn-isomer).

IR Spectrum (nujol): 3250, 1785, 1755, 1660, 1600, 1570 and 1540 cm -1.

NMR Spectrum (d 5 -DMSO): δ - 9.83 (1H, d, J = 8Hz), 7.5-6.75 (4H, m), 6.02 (1H, dd, J = 5, 8Hz) ), 5.21 (1H, d, J = 5Hz), 5.07 (2H, broad s), 3.95 (3H, s), and 3.84 (2H, broad s) ppm.

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EXAMPLE 11 53

The compounds listed below are prepared by elimination reaction of the protecting group for the amino group in the carbamoyl group: 5 1) 7- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer), mp 210-220 ° C (dec.).

IR Spectrum (nujol): 3250, 1765 and 1650 cm cm '.

NMR Spectrum (d6-DMSO): S - 9.64 (1H, d, J - 8Hz), 7.4 (2H, m), 6.79 (1H, s), 6.60 (2H, m) ), 5.77 (1H, dd, J - 5.8Hz), 5.16 (1H, d, J - 5Hz), 4.75 (2H, ABq, J - 12Hz), 3.87 (3H, s) ) and 3.53 (2H, ABq, J = 18Hz) ppm.

2) 7- [2-Methoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3300, 1780, 1705 and 1680 cm

NMR Spectrum (d6-DMSO): δ * = 12.50 (1H, broad s), 9.67 (1H, d, J -8Hz), 8.50 (1H, s), 7.43 (1H, s), 6.58 (2H, broad s), 5.80 (1H, dd, J - 5.8Hz), 5.16 (1H, d, J - 5Hz), 4.78 (2H, ABq, J - 14Hz), 3.95 (3H, s) and 3.57 (2H, ABq, J - 18Hz) ppm.

EXAMPLE 12 3.0 g of 2-ethoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer) and 40 ml of dry ethyl acetate are added at 0-5 ° C with stirring to a suspension of a Vilsmeier reagent prepared on usual manner from 1.0 g of dry dimethylformamide and 2.1 g of phosphorus oxychloride in 4.0 ml of dry ethyl acetate, and the resulting mixture is stirred for 30 minutes at the same temperature. The solution is added at -10 ° C with stirring to a solution of 3.7 g of 7-amino-3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid, 10.3 g trimethylsilylacetamide and 6.8 g bis

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54 (trimethylsilyl) acetamide in 80 ml of dry ethyl acetate and the mixture is stirred for 1.5 hours at the same temperature. After adding 50 ml of water to the reaction mixture, an insoluble material is filtered off and the ethyl acetate phase of the filtrate is separated and extracted with 50 ml of aqueous sodium bicarbonate solution. The aqueous extract is washed with ethyl acetate and acidified to pH 2.0 with concentrated hydrochloric acid. The precipitated material is isolated by filtration, washed with water and dried to give 2.3 g of 7- [2-ethoxyimino-2- (2-formamidothiazol-4-yl) -acetamido] -3- (1,3,4- thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) in the form of a powder.

IR Spectrum (nujol): 3250, 1780 and 1680 cm

NMR Spectrum (d6-DMSO): δ (ppm) - 1.31 (3H, t, J - 7.0Hz), 3.77 (2H, m), 4.28 (2H, q, J = 7, 0Hz), 4.43 (2H, ABq, J - 13.0Hz), 5.18 (1H, d, J - 5.4Hz), 5.84 (1H, d, d, J * = 5.4 and 9.8Hz), 7.42 (1H, s), 8.53 (1H, 15 s,), 9.57 (1H, s), 9.66 (1H, d, J - 9.8Hz).

EXAMPLE 13

As usual, a Vilsmeier reagent is prepared from 1.0 ml of dry dimethylformamide, 4 ml of dry ethyl acetate and 2.1 g of phosphorus oxychloride. 45 ml of dry ethyl acetate and 2.85 g of 2-methoxy-imino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer) are added. This solution is added at -10 ° C to a stirred solution prepared by stirring for 1 hour at 40 ° C of a mixture of 4.5 g of 7-amino-3- (1-hexyl-1H-tetrazole-5 yl) thiomethyl-3-cephem-4-carboxylic acid, 10.4 g of trimethylsilylacetamide and 90 ml of dry ethyl acetate, and the resulting mixture is stirred for 1.5 hours at -5 - -10 ° C. To the reaction mixture is added 50 ml of water and the ethyl acetate phase is separated. 40 ml of water is added and the mixture is adjusted to pH 7.0 with a saturated aqueous sodium bicarbonate solution. The aqueous phase is separated, washed with ethyl acetate and adjusted to pH 2.5 with 10% hydrochloric acid. The precipitated material is isolated by filtration, washed with water and dried under reduced pressure to give 6.18 g of 7- [2-methoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-hexyl) 1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid (syn isomer) in the form of a powder.

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IR spectrum (nujol): 3250, 1777 and 1680 cm -1.

NMR Spectrum (dg-DMSO): δ (ppm) - 0.85 (3H, t, J - 5.5Hz), 1.65 (6H, m), 2.78 (2H, m), 3.72 (2H, m), 3.93 (3H, s), 4.07 »4.59 (4H, m),.

5.17 (1H, d, J - 5.0Hz), 5.83 (1H, dd, J - 5.0 and 8.2Hz), 7.46 (1H, 5 s), 9.56 (1H, s), 9.70 (1H, d, J - 8.2Hz).

EXAMPLE 14 0.92 g of phosphorus oxychloride is added dropwise over 3 minutes at -5 - -10 ° C to a solution of 0.44 g of dimethylformamide in 2 ml of ethyl acetate. Add 20 ml of ethyl acetate and after 10 minutes add at 1.2 DEG-10 DEG C. 1.29 g of 2-isopropoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetic acid (syn isomer). The mixture is stirred for 10 minutes to form a clear solution. Dissolve 1.37 g of 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid with stirring in a solution of 1.68 g of sodium bicarbonate in 30 ml of water, then add 20 ml of acetone. To the solution is added dropwise with stirring at 0-5 ° C and at pH 6.5-7.5 the ethyl acetate solution obtained above. After stirring for 20 minutes at the same temperature, the aqueous phase is separated and acetone is distilled off. The aqueous phase obtained as the residue is adjusted under ice-cooling and stirred to pH 3.0 with 10% hydrochloric acid. The precipitated material is isolated by filtration, washed with water and dried to give 1.5 g of 7- [2-isopropoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -3- carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3450, 3250, 1780, 1710, 1690 and 1650 cm cm ·.

NMR Spectrum (d6-DMSO): S (ppm) - 9.63 (1H, d, J - 8Hz), 8.53 (1H, s), 7.43 (1H, s), 6.60 ( 1H, s), 5.83 (1H, dd, J - 5.8Hz), 5.20 (1H, d, J - 5Hz), 4.77 (2H, ABq, J - 14Hz), 4.40 ( 1H, m), 3.57 (2H, broad s), 1.27 (6H, d, J - 6Hz).

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EXAMPLE 15 0.05 g of water is added to a suspension of 1.0 g of 2-allyloxyimino-2- (2-amino-1,3-thiazol-4-yl) acetic acid (syn isomer) in 10 ml of tetrahydrofuran . 0.84 g of phosphorus oxychloride is added at 0-5 ° C and the mixture is stirred for 20 minutes at the same temperature. 0.66 g of trimethylsilylacetamide is added and the mixture is stirred for 20 minutes at the same temperature, 0.84 g of phosphorus oxychloride is added and the resulting mixture is stirred for 20 minutes at 0-5 ° C and 0.45 g of dimethylformamide is added. and the resulting mixture is stirred for 1 .10 hour at the same temperature. The resulting solution is added dropwise at -5 - + 5 ° C and pH 7.0-8.0 to a solution prepared by adding 15 ml of acetone and 15 ml of tetrahydrofuran to a solution of 1.45 g. -amino-3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid in a mixture of 0.42 g of sodium bicarbonate and 10 ml of water. The resulting mixture is stirred for 2 hours under ice-cooling, maintaining the pH of the mixture between 7.0 and 8.0 and then adjusting to pH 7.5. An insoluble material is filtered off and the filtrate is washed with ethyl acetate. The aqueous phase is adjusted to pH 6.0, and organic solvent in the aqueous phase is distilled off under reduced pressure. The aqueous phase obtained as the residue is adjusted to pH 4.0 and an insoluble material is filtered off. The filtrate is adjusted to pH 3.0 and the precipitated material is isolated by filtration and dried to give 1.5 g of 7- [2-allyloxy-imino-2- (2-amino-1,3-thiazol-4-yl) ) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3350, 1780, 1680 and 1630 cm cm ".

NMR Spectrum (d 6 -DMSO): δ (ppm) = 9.63 (1H, d, J = 8Hz), 9.57 (1H, s), 7.23 (2H, m), 6.77 (1H) , s), 6.10 (1H, m), 5.83 (1H, dd, J = 5.8Hz), 5.43 (1H, m), 5.25 (1H, m), 5.17 ( 1H, d, J = 5Hz), 4.61 (2H, 30 m), 4.47 (2H, ABq, J = 14Hz), 3.72 (2H, m).

EXAMPLE 16

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57 0.1 ml of water are added to a suspension of 2.0 g of 2-hexyloxy imino-2- (2-imino-1,3-thiazol-4-yl) acetic acid (syn isomer) in 20 ml of tetrahydrofuran. Phosphorus oxychloride (1.4 g) is added at 0-5 ° C and the mixture is stirred for 20 minutes at the same temperature. 1.3 g of trimethylsilylacetamide is added and the mixture is stirred for 20 minutes at the same temperature, 1.4 g of phosphorus oxychloride is added and the resulting mixture is stirred for 20 minutes at 0-5 ° C and 0.75 g of dimethylformamide is added. and the resulting mixture is stirred for 10 hours at the same temperature. The resulting solution is added at once at -20 ° C to a solution of 3.3 g of 7-amino-3- (1H-1,2,3-triazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid in a mixture of 30 ml of tetrahydrofuran and 6.8 g of trimethylsilylacetamide. The resulting mixture is stirred for 1.5 hours at the same temperature. The reaction mixture is post-treated in an analogous manner to the previous examples to give 1.5 g of 7-12-hexoxyloxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1H -1,2,3-triazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3100, 1780 and 1630 cm

NMR Spectrum (d6-DMSO): S (ppm) = 10.17 (1H, d, J - 8Hz), 8.17 (2H, m), 7.97 (1H, s), 7.25 ( 1H, m), 6.70 (1H, s), 5.73 (1H, dd, J -5.8Hz), 5.13 (1H, d, J - 6Hz), 3.97 (2H, m) , 3.60 (2H, m), 1.25 (8H, m), 0.83 (3H, m).

EXAMPLE 17 0.51 g of phosphorus oxychloride is added dropwise over 5 minutes at 5 ° C to a solution of 0.24 g of dimethylformamide in 1 ml of dry ethyl acetate. After precipitation of crystals, the mixture is stirred for 30 minutes at 10 ° C, then 9 ml of dry ethyl acetate is added and at once at -10 ° C 0.89 g of 2-methoxyimino-2- [2- (2,2,2-trifluoroacetamido) -1 3-thiazol-4-yl) acetic acid (syn isomer). The resulting mixture is stirred for 30 minutes at -10 - -5 ° C. The resulting solution is added dropwise at -15 ° C over 5 minutes to a solution of 1.0 g of 7-

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58 amino-3-benzoyloxymethyl-3-cephem-4-carboxylic acid and 3.2 g of trimethylsilylacetamide in 10 ml of dry ethyl acetate, then the resulting mixture is stirred for 1 hour at -10-15 ° C. To the reaction mixture is added 10 ml of water and the ethyl acetate phase is separated. The aqueous phase 5 is further extracted with 10 ml of ethyl acetate. The ethyl acetate phases are combined and 20 ml of water is added. The resulting mixture is adjusted to pH 6 with sodium bicarbonate. The aqueous phase is separated and 25 ml of ethyl acetate is added. The mixture is adjusted to pH 2.5 under ice-cooling and stirred with 10% hydrochloric acid.

The ethyl acetate phase is separated and the aqueous phase is further extracted with 15 and 10 ml of ethyl acetate. reduced pressure to give 1.15 g of 7- (2-methoxyimino-2- [2- (2,2,2-trifluoroacetamido) -1,3-thiazol-4-yl] acetamido) -3-benzoyloxymethyl - 3 - cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3250, 1790, 1730 and 1650 cm -1.

NMR Spectrum (dg-DMSO): S (ppm) + = 9.95 (1H, d, J = 8Hz), 7.92-8.16 (2H, m), 7.4-7.84 (3H, m), 7.6 (1H, s), 5.92 (1H, dd, J - 5.8Hz), 5.26 (1H, d, J = 5Hz), 5.18 (2H, ABq , J - 13Hz), 3.96 (3H, s), 3.76 (2H, broad s).

EXAMPLE 18 0.56 g of phosphorus oxychloride is added at once below 5 ° C to a mixture of 0.6 g of 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetic acid (syn isomer) ) and 6 ml of dry ethyl acetate and the mixture is stirred for 20 minutes at 4-6 ° C. 0.3 g of bis (trimethylsilyl) acetamide is added at once at the same temperature and the mixture is stirred for 10 minutes at the same temperature. To the resulting mixture is added at once 0.56 g of phosphorus oxychloride and the mixture is stirred for 30 minutes at the same

temperature, then 0.24 g of dimethylformamide is added dropwise and the resulting mixture is stirred for 30 minutes at 4-6 ° C. The solution thus obtained is added at one time with stirring at -15 ° C

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59 to a solution of 7 g of 7-amino-3- (4-nitrobenzoyl) oxymethyl-3-cephem-4-carboxylic acid and 3.5 g of trimethylsilylacetamide in 20 ml of dry ethyl acetate and the resulting mixture is stirred for 2 hours. -5 - -10 ° C. The reaction mixture is adjusted to pH 7-7.5 with a 5 saturated aqueous sodium bicarbonate solution below 0 ° C, stirred for 1 hour at pH 7 below 5 ° C, adjusted to pH 2.5 and filtered.

The organic phase of the filtrate is isolated and 20 ml of water is added. The mixture is adjusted to pH 6.5 with sodium bicarbonate. The aqueous phase is separated and washed with diethyl ether. The remaining 10 solvent in the aqueous phase is removed by passing through nitrogen gas and the aqueous phase is adjusted to pH 2.5 with 10% hydrochloric acid under ice-cooling. The precipitated material is isolated by filtration, washed with water and dried to give 0.7 g of 7- [2-methoxyimino-2- (2-amino-1,3-thlazol-4-yl) acetamido] -3- (4 -nitrobenzoyl) oxymethyl-3-cephem-4-carboxylic acid (syn isomer) in the form of a pale yellow powder, mp 151-163 ° C (dec.).

IR Spectrum (nujol): 3250-3350, 2500-2600, 1780, 1725, 1680, 1650, 1600, 1535 and 1350 cm

NMR Spectrum (d6-DMSO): δ (ppm) - 9.68 (1H, d, J - 8Hz), 8.5 (4H, m),

7.28 (2H, s), 6.80 (1H, s), 5.88 (1H, dd, J - 5.8Hz), 5.24 (1H, d, J

- 5Hz), 5.20 (2H, ABq, J - 13Hz), 3.82 (3H, s), 3.72 (2H, ABq, J -18Hz).

EXAMPLE 19 In analogous manner to Examples 12-18, the following compounds are prepared: 1) 7- [2-Isopropoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1,3,4- thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) IR Spectrum (nujol): 3300, 3050, 1777, 1727 and 1672 cm cm ".

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60 NMR Spectrum (dg-DMSO): δ (ppm) = 1.28 (6H, d, J- 6Hz), 3.75 (2H, broad s), 4.43 (3H, m), 4.8 * 5.6 (1H), 5.90 (1H, dd, J - 5 and 8Hz), 7.45 (1H, s), 8.58 (1H, wide s), 9.60 (1H, s) , 9.77 (1H, d, J = 8Hz), 12.80 (1H, broad s).

2) 7- [2-Pentyloxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer).

IR Spectrum (nujol): 3300, 3250, 1785 and 1680 cm

NMR Spectrum (dg-DMSO): δ (ppm) = 0.6 * 1.9 (9H, m), 3.72 (2H, broad 10s), 4.11 (2H, t, J - 6Hz) , 4.47 (2H, ABq, J - 13Hz), 5.18 (1H, d, J = 5Hz), 5.82 (1H, dd, J = 5 and 8Hz), 7.41 (1H, s) , 8.53 (1H, s), 9.57 (1H, s), 9.64 (1H, d, J - 8Hz), 12.65 (1H, s).

3) 7- [Methoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-propyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) .

IR Spectrum (nujol): 3180, 1775 and 1665 cm -1.

NMR Spectrum (dg-DMSO): δ (ppm) = 0.85 (3H, t, J - 8.0Hz), 1.82 (2H, m), 3.69 (2H, m), 3.88 (3H, s), 4.06 * 4.66 (4H, m), 5.13 (1H, d, J = 5.0Hz), 5.81 (1H, dd, J - 5.0 and 8, 0Hz), 7.42 (1H, s), 8.52 (1H, s), 9.65 (1H, d, J = 8.0Hz).

4) 7- [2-Allyloxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-propyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer).

IR Spectrum (nujol): 3180, 1775 and 1670 cm

NMR Spectrum (dg-DMSO): δ (ppm) = 0.87 (3H, t, J = 8.0Hz), 1.65 (2H, 25 m), 3.73 (2H, ABq, J = 16 , 0.Hz), 4.00 ° 4.53 (4H, m), 4.69 (2H, d, J = 5.0Hz), 5.00 ~ 5.68 (3H, m), 5.68 ~ 6 , 36 (2H, m), 7.45 (1H, s), 8.56 (1H, s), 9.72 (1H, d, J - 8.0Hz).

5) 7- [2- Isopropoxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3175, 1780 and 1670 cm cm ’.

NMR Spectrum (dg-DMSO): δ (ppm) - 0.66 (3H, t, J - 5.0Hz), 1.05 »1.57 (6H, m), 1.92 (2H, m ), 3.77 (2H, m), 4.10 * 4.72 (5H, m), 5.24 (1H, d, J - 5.0Hz), 5.90 (1H, d, d, J) - 5.0 and 8.4Hz), 7.43 (1H, s), 8.56 (1H, s), 9.64 (1H, d, J - 8.4Hz).

6) 7- [2-Hexyloxyimino-2- (2-formamidothiazol-4-yl) acetamido] -3- (1-10 hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer).

IR Spectrum (nujol): 3175, 1785 and 1642 cm -1.

NMR Spectrum (d 6 -DMSO): δ (ppm) - 0.86 (6H, m), 1.00? 1.57 (12H, m), 1.57 = 2.07 (4H, m), 3.75 (2H, m), 3.97 * 4.60 (8H, m), 5.18 (1H, d, 15 J - 5.2Hz), 5.85 (1H, dd, J - 5.2 and 8 , 4Hz), 7.41 (1H, s), 8.56 (1H, s), 9.65 (1H, d, J - 8.4Hz).

7) 7- [2-Allyloxyimino-2- (2-formamidobthiazol-4-yl) acetamido] -3- (1-hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid isomer).

IR Spectrum (nujol): 3180, 1780 and 1680 cm

NMR Spectrum (dg-DMSO): δ (ppm) - 0.64 »1.97 (11H, m), 3.68 (2H, ABq, J - 18Hz), 4.30 (4H, m), 4 , 64 (2H, m), 5.00 * 5.46 (3H, m), 5.56 * 6.24 (2H, m), 7.37 (1H, s), 8.48 (1H, s) ), 9.67 (1H, d, J - 8Hz), 5.92 (1H, dd, J - 5 and 8Hz), 6.78 (1H, s), 6.88 (4H, s), 6, 95 (1H, 25 s), 7.04 * 7.64 (10H, m), 9.64 (1H, d, J - 8Hz).

8) Benzhydryl 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-pivaloyloxymethyl-3-cephem-4-carboxylate (syn isomer).

IR Spectrum (nujol): 3300, 1780, 1725, 1680, 1620 and 1530 cm -1.

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62 NMR Spectrum (d 6 -DMSO): δ (ppm) - 1.13 (9H, s), 3.62 (2H, broad s), 3.88 (3H, s), 4.86 (2H, ABq , J - 14Hz), 5.26 (1H, d, J - 5Hz), 5.96 (1H, dd, J = 5 and 8Hz), 6.80 (1H, s), 6.98 (1H, s) ), 7.12 * 7.68 (10H, m), 9.73 (1H, d, J - 8Hz).

9) Benzhydryl-7- [2-methoxyamino-2- (2-aminothiazol-4-yl) acetamido] -3- (N-phenylcarbamoyloxymethyl) -3-cephem-4-carboxylate (syn isomer).

IR Spectrum (nujol): 3300, 1780, 1720, 1675, 1600, 1530 and 1500 cm -1.

NMR Spectrum (d6-DMSO): δ (ppm) = 3.63 (2H, broad s), 3.80 (3H, s), 4.80 (2H, ABq, J = 13Hz), 5.20 ( 1H, d, J = 5Hz), 5.86 (1H, dd, J - 10 and 8Hz), 6.73 (1H, s), 6.93 (1H, s), 6.83 * 7.67 (15H, m), 9.57 (1H, d, J - 8Hz), 9.73 (1H, s).

10) 7- [2-Ethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (sync) isomer).

IR Spectrum (nujol): 3300, 1775 and 1660 cm

11) 7- [2-Isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn - isomer).

IR Spectrum (nujol): 3325, 1774 and 1656 cm

12) 7- [2-Pentyloxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn. isomer).

IR Spectrum (nujol): 3350, 3200, 1775 and 1675 cm -1.

13) 7- [2-Methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-propyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn. isomer).

IR Spectrum (nujol): 3350, 1780, 1670 and 1630 cm cm ".

14) 7- [2-Allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-propyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer).

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63 IR Spectrum (nujol): 3340, 3230, 1780, 1680 and 1630 cm cm 1.

15) 7- [2-Methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn. isomer).

IR Spectrum (nujol): 3350, 3230, 1777, 1675 and 1627 cm -1.

16) 7- [2-Isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer).

IR Spectrum (nujol): 3320, 1780, 1675 and 1630 cm -1

17) 7- [2-Hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-hexyl-10H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer).

IR Spectrum (nujol): 3350, 3230, 1765, 1670 and 1615 cm

18) 7- [2-Allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn. isomer).

IR Spectrum (nujol): 3240, 1780, 1720 and 1675 cm -1.

19) 7- [2-Methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-pivaloyl-oxymethyl-3-cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3300, 1780, 1720, 1670 and 1540 cm -1.

20) Benzhydryl 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-20 (4-nitrobenzoyloxymethyl) -3-cephem-4-carboxylate (syn isomer).

IR Spectrum (nujol): 3300, 1780, 1720, 1670, 1600 and 1520 cm cm ".

NMR Spectrum (dg-DMSO): δ (ppm) - 3.43 (2H, broad s), 3.92 (3H, s), 5.08 (2H, ABq, J - 13Hz), 5.2 ( 1H, d, J - 5Hz), 6.00 (1H, dd, J - 5

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64 and 8Hz), 6.83 (1H, s), 7.00 (1H, s), 7.10 ~ 7.80 (10H, m), 8.15 (2H, d, J - = 9Hz), 8.38 (2H, d, J = 9Hz), 9.73 (1H, d, J = 8Hz).

21) 7- [2-Methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (N-phenyl-carbamoyloxymethyl) -3-cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3300, 1780, 1710, 1670 and 1600 22) 7- [2-Ethoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl 3-cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3500, 3300, 1780, 1710 and 1660 cm

NMR Spectrum (dg-DMSO): δ (ppm) = 9.67 (1H, d, J = 8Hz), 8.53 (1H, 10 s), 7.43 (1H, s), 6.58 ( 1H, s), 5.87 (1H, dd, J - 5.8Hz), 5.23 (1H, d, J = 5Hz), 4.80 (2H, ABq, J = 13Hz), 4.23 ( 2H, q, J - 7Hz), 3.57 (2H, broad s), 1.3 (3H, t, J = 7Hz).

23) 7- [2-Ethoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3300, 3200, 1780, 1720 and 1660 cm

NMR Spectrum (dg-DMSO): δ (ppm) = 9.58 (1H, d, J = 8Hz), 7.33 (1H, broad s), 6.77 (1H, s), 6.58 ( 1H, s), 5.83 (1H, dd, J - 4, 8Hz), 5.20 (1H, d, J - 4Hz), 4.77 (2H, ABq, J = 12Hz), 4.16 ( 2H, q, J - 7Hz), 3.53 (2H, broad s), 1.23 (3H, t, J = 7Hz).

24) 7- [2-Propoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3250, 3200, 1780, 1700, 1660 and 1525 cm

NMR Spectrum (dg-DMSO): δ (ppm) = 9.62 (1H, d, J - 8Hz), 8.50 (1H, s), 7.43 (1H, s), 6.57 (2H , broad s), 5.84 (1H, dd, J - 5, 8Hz), 5.18 (1H, d, J - 5Hz), 4.58 (2H, ABq, J = 13Hz), 4.08 (2H, t, J - 7Hz), 3.54 (2H, ABq, J = 18Hz), 1.68 (2H, m), 0.92 (3H, t, J = 7Hz).

65) 7- [2-Isobutoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3450, 3300, 1780, 1710, 1680 and 1610 cm -1.

NMR Spectrum (dg-DMSO): δ (ppm) - 9.6 (1H, d, J - 8Hz), 8.5 (1H, s), 7.18 (1H, s), 6.6 ( 2H, broad s), 5.8 (1H, dd, J - 5.8Hz), 5.15 (1H, d, J - 5Hz), 4.76 (2H, ABq, J - 13Hz), 3.84 (2H, d, J - 6Hz), 3.5 (2H, ABq, J - 18Hz), 2.04 (1H, m), 0.88 (6H, d, J - 6Hz).

26) 7- [2-Isobutoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

IR spectrum (nujol): 3300, 1770, 1730 and 1660 cm -1.

NMR Spectrum (d6-DMSO): δ (ppm) - 9.55 (1H, d, J - 9Hz), 7.27 (2H, broad s), 6.73 (1H, s), 6.60 ( 1H, broad s), 5.83 (1H, dd, J - 5, 9Hz), 5.20 (1H, d, J - 5Hz), 4.80 (2H, ABq, J - 12Hz), 3.87 (2H, d, J - 7Hz), 3.53 (2H, ABq, J = 18Hz), 0.90 (6H, d, J - 7Hz).

27) 7- [2-Allyloxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3300, 1770, 1720, 1660 and 1630 cm cm-.

NMR Spectrum (d 6 -DMSO): δ (ppm) - 9.82 (1H, d, J - 8Hz), 7.20 (2H, m), 6.92 (1H, s), 6.7 (2H) , m), 6.0 (1H, m), 5.80 (1H, dd, J - 5, 8Hz), 5.40 (1H, m), 5.22 (1H, m), 5.13 (1H) , d, J - 5Hz), 4.70 (2H, ABq, J - 14Hz), 4.65 (2H, m), 3.50 (2H, ABq, J «16Hz).

28) 7- [2-Propoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem 4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3400-3200, 1780, 1670, 1625 and 1540 cm cm *.

NMR Spectrum (d6-DMSO): δ (ppm) - 9.50 (1H, s), 9.50 (1H, d, J -8Hz), 6.68 (1H, s), 5.74 (1H) , dd, J - 5Hz), 5.12 (1H, d, J - 5Hz),

66 DK 162391 B

4.40 (2H, ABq, J - 14Hz), 3.98 (2H, t, J - 7Hz), 3.66 (2H, ABq, J = 17Hz), 1.62 (2H, m), 87 (3H, t, J - 7Hz).

29) 7- [2-Ethoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -3- (1H-1,2,3-triazol-5-yl) thiomethyl-3- cephem-4-carboxylic acid (syn-iso-mer).

IR Spectrum (nujol): 3500, 3200, 1780, 1670 and 1620 cm -1.

NMR Spectrum (dg-DMSO): δ (ppm) = 9.64 (1H, d, J = 8Hz), 8.5 (1H, s), .7.9 (1H, s), 7.4 ( 1H, s), 5.76 (1H, dd, J - 4,8Hz), 5.14 (1H, d, J - 4Hz), 4.1 (2H, q, J J = 7Hz), 3.92 (2H, ABq, J - 13Hz), 3.58 (2H, 'ABq, J - 18Hz), 1.26 (6H, t, J - 7Hz).

30) 7- [2-Ethoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1H-1,2,3-triazol-5-yl) thiomethyl-3-cephem 4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3350, 3150, 1770 and 1670 cm cm ".

NMR Spectrum (dg-DMSO): δ (ppm) 9.56 (1H, d, J - 9Hz), 7.92 (1H, s),

7.28 (1H, m), 6.75 (1H, s), 5.75 (1H, dd, J - 5.9Hz), 5.06 (1H, d, J

- 5Hz), 4.05 (2H, q, J - 7Hz), 3.9 (2H, m), 3.64 (2H, ABq, J - 17Hz), 1.24 (3H, t, J - 7Hz) ).

31) 7- [2-Propoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -3- (1H-1,2,3-triazol-5-yl) thiomethyl-3- cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3300-3100, 1780, 1680, 1650 and 1550 cm cm ·.

NMR Spectrum (dg-DMSO): δ (ppm) = 9.62 (1H, d, J - 8Hz), 8.50 (1H, s), 7.92 (1H, s), 7.38 (1H) , s), 5.78 (1H, dd, J - 5.8Hz), 5.15 (1H, d, J - 5Hz), 4.20-3.70 (4H, m), 3.65 (2H , ABq, J - 17Hz), 1.66 (1H, 25 m), 0.90 (3H, t, J - 7Hz).

32) 7- [2-Propoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1H-1,2,3-triazol-5-yl) thiomethyl-3-cephem 4-carboxylic acid (syn-isomer).

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67 IR Spectrum (nujol): 3 / - (00-3100, 1770, 1670, 1630 and 1530 cm -1).

NMR Spectrum (dg-DMSO): δ (ppm) - 9.58 (1H, d, J - 8Hz), 7.97 (1H, s), 6.77 (1H, s), 5.78 (1H) , dd, J - 5.8Hz), 5.18 (1H, d, J - 5Hz), 4.23-3.76 (4H, m), 3.67 (2H, broad s), 1.67 ( 2H, m), 0.93 (3H, t, J -5 7Hz).

33) 7- [2-Isopropoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1H-1,2,3-triazol-5-yl) thiomethyl-3- cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3300, 3150, 1780, 1670 and 1640 cm cm ".

NMR Spectrum (d6-DMSO): δ (ppm) - 9.50 (1H, d, J - 9Hz), 7.97 (1H, s), 6.73 (1H, s), 5.77 ( 1H, dd, J - 5.9Hz), 5.17 (1H d, J - 5Hz), 4.33 (1H, m), 4.0 (2H, ABq, J - 13Hz), 3.67 (2H , ABq, J - 18Hz), 1.23 (6H, d, J - 6Hz).

34) 7- [2-Isobutoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (1H-1,2,3-triazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3470, 3320, 3200, 3160, 1770 and 1660 cm cm ".

NMR Spectrum (d6-DMSO): δ (ppm) - 9.57 (1H, d, J - 9Hz), 7.97 (1H, s), 7.22 (2H, broad s), 6.75 ( 1H, s), 5.77 (1H, dd, J - 5, 9Hz), 5.18 (1H, d, J - 5Hz), 4.03 (2H, ABq, J - 12Hz), 3.88 ( 2H, d, J - 6Hz), 3.70 (2H, ABq, J - 18Hz), 2.0 (1H, m), 0.92 (6H, d, J - 6Hz).

35) 7- [2-Isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3300, 3200, 1780, 1720 and 1640 cm cm ".

36) 7- [2-Propoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-carbamoyl-oxymethyl-3-cephem-4-carboxylic acid hydrochloride (syn-isomer).

IR Spectrum (nujol): 3350, 3200, 1770, 1720, 1665, 1630 and 1550 cm -1.

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68 37) 7- (2-Methoxyimino-2- [2- (2,2,2-trifluoroacetamido) -1,3-thiazol-4-yl] acetamido) -3- (4-nitrobenzoyl) oxymethyl-3 -cephem-4-carboxylic acid (syn-isomer) in the form of a pale yellow powder.

IR Spectrum (nujol): 3200, 2500-2600, 1785, 1720, 1680, 1650, 1600, 1525 and 1355 cm -1.

NMR Spectrum (d6-DMSO): δ (ppm) - 9.80 (1H, d, J - 8Hz), 8.4 (4H, m), 7.60 (1H, s), 5.78 (1H) , dd, J = 5.8Hz), 5.25 (1H, d, J - 5Hz), 5.15 (2H, ABq, J - 13Hz), 3.94 (3H, s), 3.75 (2H , ABq, J - 18Hz).

38) 7- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-benzoylloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3300, 1780, 1720 and 1680 cm

NMR Spectrum (d6-DMSO): δ (ppm) - 9.63 (1H, d, J - 8Hz), 7.87-8.1 (2H, m), 7.48-7.75 (3H, m), 6.75 (1H, s), 5.83 (1H, dd, J - 5.8Hz), 5.19 (1H, d, J - 5Hz), 5.15 (2H, ABq, J - 13Hz), 3.83 (3H, s), 3.72 (2H, broad s).

39) 7- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-phenylacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3350, 3300, 1780, 1710, 1660, 1542, 1535, 1460, 1400, 1380, 1320, 1280, 1260, 1240, 1130, 1115, 1065, 1042, 965, and 20720 cm -1 .

NMR Spectrum (d 6 -DMSO): δ (ppm) = 7.33 (5H, s), 7.23 (2H, broad s), 6.78 (1H, s), 5.81 (1H, dd, J = 4, 8Hz), 5.16 (1H, d, J - 4Hz), 4.78 and 5.06 (2H, ABq, J * = 8Hz), 3.9 (3H, s), 3.73 (2H, s), 3.5 (2H, broad s).

40) 7- [2-Methoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -3- (2-benzothiazolyl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) ).

IR Spectrum (nujol): 3200, 1780, 1680, 1620, 1545, 1460, 1435, 1385, 1040 and 1000 cm

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69 NMR Spectrum (d 6 -DMSO): δ (ppm) * 9.7 (1H, d, J - 8Hz), 8.53 (1H, s), 7.66-8.16 (2H, m), 7.16-7.66 (3H, m), 5.83 (1H, dd, J - 5, 8Hz), 5.18 (1H, d, J - 5Hz), 4.23 and 4.81 (2H , ABq, J - 15Hz), 3.93 (3H, s), 3.73 (2H, broad s).

EXAMPLE 20 0.85 g of concentrated hydrochloric acid is added under ice-cooling to a stirred solution of 2.3 g of 7- [2-ethoxyimino-2- (formamidothiazol-4-yl) acetamido] -3- (1,3,4 -thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) in a mixture of 23 ml of methanol and 23 ml of tetrahydrofuran and the mixture is stirred for 2.5 hours at room temperature. The solvent is evaporated under reduced pressure and the residue is dissolved in a saturated aqueous sodium bicarbonate solution (pH 7.0). The aqueous solution is washed with ethyl acetate and adjusted to pH 3.5 with concentrated hydrochloric acid. The precipitated material is isolated by filtration, washed with water and dried to give 1.865 g of 7- [2-ethoxyimino-2- (2-amino-thiazol-4-yl) acetamido] -3- (1,3,4- thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) in the form of a powder.

IR Spectrum (nujol): 3300, 1775 and 1660 cm cm ".

NMR Spectrum (dg-DMSO): δ (ppm) - 1.67 (3H, t, J - 7.6Hz), 3.75 (2H, 20 m), 4.16 (2H, q, J - 7 , 6Hz), 4.48 (2H, ABq, J - 13.6Hz), 5.18 (1H, d, J - 5.2Hz), 5.83 (1H, dd, J - 5.2 and 8, 0Hz), 6.79 (1H, s), 7.38 (2H, broad s), 9.63 (1H, s), 9.63 (1H, d, J - 8.0Hz).

EXAMPLE 21 2.1 g of concentrated hydrochloric acid are added under ice-cooling and stirred to a solution of 6.0 g of 7- [2-methoxyimino-2- (2-formamidothiazol-4-yl) -acetamido] -3- (1-hexyl (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) in 60 ml of methanol and the mixture is stirred for 4 hours at room temperature. The solvent is removed from the reaction mixture and 50 g of ethyl acetate are added. The mixture is adjusted

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70 to pH 7.0 with stirring with a saturated aqueous sodium bicarbonate solution. The aqueous phase is separated, washed with ethyl acetate and adjusted to pH 3.5 with concentrated hydrochloric acid. The precipitated material is isolated by filtration, washed with water and dried under reduced pressure to give 4.62 g of 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1 -hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) in the form of a powder.

IR Spectrum (nujol): 3350, 3230, 1777, 1675 and 1627 cm -1.

NMR Spectrum (dg-DMSO): δ (ppm) - 0.82 (3H, t, J - 5.0Hz), 1.23 (6H, 10 m), 1.80 (2H, m), 3, 69 (2H, m), 3.85 (3H, s), 4.05 * 4.63 (4H, m), 5.12 (1H, d, J - 5.0Hz), 5.75 (1H, d, d, J - 5.0, 8.6Hz), 6.76 (1H, s), 7.23 (2H, broad s), 9.59 (1H, d,; J - 8.6Hz).

EXAMPLE 22 1 ml of concentrated hydrochloric acid is added to a solution of 1.3 g of 7- [2-15 isopropoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3 cephem-4-carboxylic acid (syn isomer) in a mixture of 10 ml of tetrahydrofuran and 10 ml of methanol. The mixture is stirred for 3.5 hours at room temperature and then evaporated to dryness. Water is added to the residue and sodium bicarbonate is added to the mixture to form a solution. The solution is adjusted under ice-cooling to pH 3.0 with concentrated hydrochloric acid. The precipitated material is isolated by filtration, washed with water and dried to give 0.25 g of 7- [2-isopropoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl 3-cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3300, 3200, 1780, 1720 and 1640 cm -1.

NMR Spectrum (dg-DMSO): δ (ppm) - 9.48 (1H, d, J - 8Hz), 7.24 (2H, broad s), 6.7 (1H, s), 6.54 ( IH, s), 5.75 (1H, dd, J - 5.8Hz), 5.16 (1H, d, J - 5Hz), 4.72 (2H, ABq, J - 13Hz), 4.3 ( 1H, m), 3.5 (2H, broad s), 1.22 (6H, d, J - 6Hz).

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Example 23 0.5 g of 7- [2-propoxyimino-2- (2-formamide-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) is suspended in 15 ml of methanol. To the suspension is added 0.2 ml of concentrated hydrochloric acid, and the mixture is stirred for 2 hours at room temperature. The reaction mixture is evaporated and the residue is washed with tetrahydrofuran, isolated by filtration and dried to give 0.4 g of 7- [2-propoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- carbamoyloxymethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer).

IR spectrum (nujol): 3350, 3200, 1770, 1720, 1665, 1630 and 1550 cm · 1.

NMR Spectrum (d6-DMSO): δ (ppm) - 9.82 (1H, d, J - 8Hz), 6.98 (1H, s), 5.80 (1H, dd, J - 5, 8Hz) , 5.22 (1H, d, J - 5Hz), 4.80 (2H, ABq, J - 14Hz), 4.15 (2H, t, J - 7Hz), 3.58 (2H, broad s), 1.72 (2H, m), 0.92 (3H, t, J - 7Hz).

EXAMPLE 24

A solution of 7- g of 7- (2-methoxyimino-2- [2- (2,2,2-trifluoroacetamido) -1,3-thiazol-4-yl] acetamido) -3-benzoyloxymethyl-3- cephem-4-carboxylic acid (syn-isomer) in 4 ml of acetone is added at room temperature to a solution of 2.5 g of sodium acetate trihydrate in 10 ml of water and the mixture is allowed to stand for 3 days at room temperature. Acetone of steam is evaporated under reduced pressure and 10 ml of water is added. The resulting mixture is adjusted under ice-cooling to pH 2.5 with 10% hydrochloric acid. The precipitated material is isolated by filtration, washed with water and dried under reduced pressure to give 0.62 g of 7- [2-25 methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] - 3-benzoyloxymethyl-3-cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3300, 1780, 1720 and 1680 cm

NMR Spectrum (d 6 -DMSO): δ (ppm) δ 9.63 (1H, d, J - 8Hz), 7.87-8.1 (2H, m), 7.48-7.75 (3H, m), 6.75 (1H, s), 5.83 (1H, dd, J - 5.8Hz),

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72 5.19 (1H, d, J - = 5Hz), 5.15 (2H, ABq, J - 13Hz), 3.83 (3H, s), 3.72 (2H, broad s).

EXAMPLE 25

The following compounds are prepared in an analogous manner as in Examples 5 to 20-24.

1) 7- [2-Isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4 --------- thiadiazol-2 * yl) thiomethyl-3 -cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3325, 1774, 1656 cm

NMR Spectrum (d6-DMSO): δ (ppm) - 1.22 (6H, d, J = 6Hz), 3.70 (2H, 10 broad s), 4.37 (3H, m), 5.15 (1H, d, J = 5Hz), 5.77 (1H, dd, J - 5 and 8Hz), 6.70 (1H, s), 7.20 (2H, m), 9.50 (1H, d) , J = 8Hz), 9.55 (1H, s).

2) 7- [2-Pentyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn. isomer).

IR Spectrum (nujol): 3350, 3200, 1775 and 1675 cm -1.

NMR Spectrum (d6-DMSO): δ (ppm) = 0.62 = 2.0 (9H, m), 3.72 (2H, broad s), 4.06 (2H, t, J = 6Hz), 4.45 (2H, ABq, J = 13Hz), 5.17 (1H, d, J = 5Hz), 5.78 (1H, d, d, J = 5 and 8Hz), 6.73 (1H, s ), 7.2 (2H, s), 9.5 (1H, d, J = 8Hz), 9.55 (1H, s).

3) 7- [2-Methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-propyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer).

IR Spectrum (nujol): 3350, 1780, 1670 and 1630 cm

NMR Spectrum (d6-DMSO): δ (ppm) - 0.87 (3H, t, J - 7.0Hz), 1.84 (2H, m), 3.73 (2H, broad s), 3, 89 (3H, s), 4.06 * 4.72 (4H, m), 5.14 (1H, 25 d, J = 5.0Hz), 5.80 (1H, dd, J - 5.0 and 8.0Hz), 6.78 (1H, s), 7.23 (2H, broad s), 9.59 (1H, d, J = 8.0Hz).

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73 4) 7- [2-Allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-propyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer).

IR Spectrum (nujol): 3340, 3230, 1780, 1680 and 1630 cm cm ".

NMR Spectrum (dg-DMSO): δ (ppm) - 0.86 (3H, t, J - 7.0Hz), 1.83 (2H, 5 m), 3.71 (2H, broad s), δ Δ 4.80 (6H, m), 5.01 ″ 5.53 (3H, m), 5.63 * 6.42 (2H, m), 6.75 (1H, s), 7.20 (2H, broad s), 9.59 (1H, d, J - 8.2Hz).

5) 7- [2-Isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn. isomer).

IR Spectrum (nujol): 3320, 1780, 1675 and 1630 cm cm 1.

NMR Spectrum (dg-DMSO): δ (ppm) - 0.84 (3H, t, J - 6.0Hz), 1.00 * 1.50 (12H, m), 1.80 (2H, m) , 3.72 (2H, ABq, J - 17.0Hz), 4.10 ° 4.60 (5H, m), 5.15 (1H, d, J = 5.0Hz), 5.81 (1H, dd, J - 5.0, 8.0Hz), 6.77 (1H, s), 9.59 (1H, d, J - 8.0Hz).

6) 7- [2-Hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer).

IR Spectrum (nujol): 3350, 3230, 1765, 1670 and 1615 cm -1.

NMR Spectrum (d 6 -DMSSO): δ (ppm) = 0.84 (6H, m), 1.26 (12H, m), 1.70 (4H, m), 3.20 [4.60 (8H) , m), 5.40 (1H, d, J = 5.0Hz), 5.68 (1H, dd, 20 J »5.0, 8.0Hz), 6.72 (1H, s), 7, 23 (2H, broad s), 9.49 (1H, d, J = 8.0Hz).

7) 7- [2-Allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- (1-hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn. isomer).

IR Spectrum (nujol): 3240, 1780, 1720 and 1675 cm -1.

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74 NMR Spectrum (d 6 -DMSO): δ (ppm) - 0.63 w 2.13 (11H, m), 3.73 (2H, ABq, J - 18Hz), 4.08 * 4.90 (6H , m), 5.10 * 6.30 (5H, m), 6.94 (1H, s), 7.93 (2H, broad s), 9.80 (1H, d, J - 8Hz).

8) 7- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3- (4- nitrobenzoyl) oxymethyl-3-cephem-4-carboxylic acid (sync) isomer in the form of a pale yellow powder, mp 151-163 ° C (dec.).

IR Spectrum (nujol): 3250-3350, 2500-2600, 1780, 1725, 1680, 1650, 1600, 1535 and 1350 cm cm *.

NMR Spectrum (dg-DMSO): δ (ppm) = 9.68 (1H, d, J = 8Hz), 8.5 (4H, m),

7.28 (2H, s), 6.80 (1H, s), 5.88 (1H, dd, J - 5.8Hz), 5.24 (1H, d, J

- 5Hz), 5.20 (2H, ABq, J - 13Hz), 3.82 (3H, s), 3.72 (2H, ABq, J * = 18Hz).

9) 7- [2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-phenylacetoxymethyl-3-cephem-4-carboxylic acid (syn isomer).

IR spectrum (nujol): 3350, 3300, 1780, 1710, 1660, 1542, 1535, 1460, 1400, 1380, 1320, 1280, 1260, 1240, 1130, 1115, 1065, 1042, 965 and 720 cm * 1 .

NMR Spectrum (d 6 -DMSO): δ (ppm) = 7.33 (5H, s), 7.23 (2H, broad s), 6.78 (1H, s), 5.81 (1H, d). J - 4Hz), 4.78 and 5.06 (2H, ABq, J - 8Hz), 3.9 (3H, s), 3.73 (2H, s), 3.5 (2H, wide s) .

Example 26 0.80 g of 2-allyloxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer) and 10 ml of dry ethyl acetate are added at 0-5 ° C with stirring to a suspension of Vilsmeier reagent prepared from 0.25 g of dry 25 dimethylformamide and 0.528 g of phosphorus oxychloride in 0.75 ml of dry ethyl acetate in conventional manner, and the resulting mixture is stirred for 30 minutes at the same temperature to give a yellow solution. The solution is added at -10 ° C with stirring to a solution of 1.11 g of 7- amino-3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid.

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75 acid and 2.96 g of trimethylsilylacetamide in 15 ml of dry ethyl acetate and the mixture is stirred for 1.5 hours at the same temperature. After adding 15 ml of water to the reaction mixture, the ethyl acetate phase is separated and extracted with an aqueous solution of 30 ml of sodium bicarbonate. The aqueous extract is acidified to pH 2.0 with 10% hydrochloric acid and extracted with 150 ml of ethyl acetate. The extract is washed with water, dried and evaporated. The residue is pulverized with diisopropyl ether to give 1.48 g of a colorless powder of 7- (2-allyloxyimino-2- (2-form-amidothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazole) 5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3180, 1775 and 1665 cm

NMR Spectrum (dg-DMSO): δ (ppm) - 9.68 (1H, d, J - 8Hz), 8.51 (1H, s), 7.40 (1H, s), 5.60-6 , 33 (3H, m), 4.85-5.57 (7H, m), 4.27-4.77 (4H, m), 3.70 (2H, ABq, J - 18Hz).

EXAMPLE 27

The Vilsmeier reagent is prepared from 0.4 g of dry dimethylformamide, 0.9 g of phosphorus oxychloride and 1.6 ml of dry ethyl acetate in a conventional manner. 18 ml of dry ethyl acetate and then 1.3 g of 2-ethoxy-amino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer) are added at 0 ° C.

The mixture is stirred for 30 minutes at the same temperature. The resulting mixture is added below -10 ° C to a stirred solution of 1.8 g of 7-amino-3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid and 4 6 g of trimethylsilylacetamide in 36 ml of dry ethyl acetate and the mixture is stirred for 1 hour at the same temperature. To the reaction mixture is added 30 ml of water. The ethyl acetate phase is separated and extracted with a saturated aqueous solution of sodium bicarbonate (pH 7.5).

The aqueous phase is washed three times with ethyl acetate and adjusted to pH 2.0 with concentrated hydrochloric acid after addition of 100 ml of ethyl acetate. The ethyl acetate phase is separated, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated charcoal and evaporated to dryness to give 2.56 g of 7- (2-ethoxy-imino-2- (2-formamidothiazol-4-yl) ) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

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76 IR Spectrum (nujol): 3200, 1765 and 1665 cm -1.

NMR Spectrum (dg-DMSO): δ (ppm) - = 1.26 (3H, t, J - 7.0Hz), 3.68 (2H, m), 4.18 (2H, q, J - 7 , 0.Hz), 4.36 (2H, ABq, J - 14.0Hz), 4.75-5.57 (5H, m), 5.68-6.40 (2H, m), 7.37 (1H) , s), 8.48 (1H, s), 9.60 (1H, d, 5 J * = 8.0Hz).

EXAMPLE 28

The Vilsmeier reagent is prepared from 0.209 g of dry dimethylformamide, 0.434 g of phosphorus oxychloride and 0.75 ml of dry ethyl acetate in a conventional manner. Dry tetrahydrofuran (6.5 ml) and then 0.65 g of 2-methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer) are added at 0 ° C. The mixture is stirred for 30 minutes at the same temperature. The resulting mixture is added dropwise at -5 - 0 ° C to a stirred solution of 1.25 g of 7-amino-3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid in a mixture of 10 ml of water and 15 ml of acetone, keeping the pH at 7.5 with triethylamine and stirring for 30 minutes at the same temperature at pH 7.5. To the reaction mixture is added 60 ml of ethyl acetate and the mixture is adjusted to pH 2.5 with 10% hydrochloric acid. Insoluble material is filtered off and the filtrate is extracted twice with ethyl acetate. The combined extracts are washed twice with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off and the residue is pulverized with diethyl ether to give 1.03 g of yellow powder of 7- (2-methylthiomethoxy-imino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1-allyl) 1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3250, 3200, 1780, 1670 and 1540 cm -1.

NMR Spectrum (dg-DMSO): δ (ppm) - 2.23 (3H, s), 3.72 (2H, s), 4.38 (2H, ABq, J = 14Hz), 4.8-5 , 6 (7H, m), 5.7-6.4 (2H, m), 7.48 (1H, s), 8.55 (1H, s), 9.75 (1H, d, J - 8Hz) ), 12.69 (1H, broad s).

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EXAMPLE 29

The Vilsmeier reagent is prepared from 0.74 g of dry dimethylformamide, 1.56 g of phosphorus oxychloride and 2.0 ml of dry ethyl acetate in conventional manner. Add 15 ml of dry tetrahydrofuran and then 1.50 g of 2- (3-isoxazolyl) methoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer) at 0 ° C. The mixture is stirred for 30 minutes at the same temperature. The resulting mixture is added dropwise at -5-0 ° C to a stirred solution of 2.34 g of 7-amino-3- (1-allyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid in a mixture of 11.5 ml of water and 11.5 ml of acetone, keeping the pH at 7.5 by means of triethylamine and stirring for 30 minutes at the same temperature at pH 7.5. To the reaction mixture is added 60 ml of ethyl acetate and the mixture is adjusted to pH 2.5 with 10% hydrochloric acid. Insoluble material is filtered off and the filtrate is extracted twice with ethyl acetate. The combined extracts are washed twice with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off and the residue is pulverized with diethyl ether to give 2.15 g of yellow powder of 7- (2- (3-isoxazolyl) methoxyimino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3250, 1780, 1670 and 1550 cm cm ".

NMR Spectrum (dg-DMSO): δ (ppm) - 3.72 (2H, s), 4.40 (2H, ABq, J -14Hz), 4.8-5.6 (7H, m), δ , 6-6.5 (2H, m), 6.67 (1H, d, J - 2Hz), 7.50 (1H, s), 8.56 (1H, s), 8.92 (1H, d) , J - 2Hz), 9.80 (1H, d, J - 8Hz), 12.72 (1H, broad s).

Example 30 1.0 g of phosphorus oxychloride is added at once to a suspension of 1.4 g of 2-benzyloxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer in 14 ml of dry tetrahydrofuran at 2 ° C and the mixture is stirred for 15 minutes at 2-4 DEG C. 1.0 g of trimethylsilylacetamide is added dropwise and the resulting mixture is stirred for 20 minutes at 2-6 ° C. 1.0 g of phosphorus oxychloride is added and the mixture is stirred for 20 minutes.

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78 ter. 0.5 g of dry dimethylformamide is added at one time at 4-6 ° C and the mixture is stirred for 1 hour to form a clear solution.

5.3 g of trimethylsilylacetamide are added to a stirred suspension of 1.8 g of 7-amino-3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid in 27 ml of dry ethyl acetate and the solution is stirred for 30 minutes at 40 ° C. To this solution is added the above-prepared tetrahydrofuran solution at once at -30 ° C and the resulting mixture is stirred for 1 hour at -5 - -20 ° C. To the reaction mixture is added 30 ml of water and 20 ml of ethyl acetate. An organic phase is separated and extracted with an aqueous solution of sodium bicarbonate. The extract is adjusted to pH 3.0 with 10% hydrochloric acid. The precipitates are collected by filtration and washed with water to give 0.85 g of 7- (2-benzyloxy-imino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5 -yl) -thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3350, 3230, 1780, 1675 and 1635 cm

NMR Spectrum (dg-DMSO): δ (ppm) - 3.67 (2H, m), 4.40 (2H, ABq, J = 15.0Hz), 4.85-5.56 (6H, m) , 5.62-6.45 (2H, m), 6.77 (1H, s), 7.01- 7.65 (7H, m), 9.71 (1H, d, J - 8Hz).

EXAMPLE 31 20 Vilsmeier Reagent One is prepared from 0.44 g of dry dimethylformamide, 0.9 g of phosphorus oxychloride and 1.0 ml of dry ethyl acetate in conventional manner. 20 ml of dry ethyl acetate and then 1.1 g of 2-methoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer) are added at -5 - -10 ° C. The mixture is stirred for 10 minutes at the same temperature.

The resulting mixture is added dropwise at 0-5 ° C and pH 6.5-7.5 with stirring to a solution of 2.12 g of 7-amino-3- (4-allyl-4H-1,2, 4-Triazol-3-yl) thiomethyl-3-cephem-4-carboxylic acid and 2 g of sodium bicarbonate in a mixture of 20 ml of water and 20 ml of acetone and the mixture is stirred for 20 minutes at the same temperature. The aqueous phase is separated and the acetone is evaporated. The aqueous phase is adjusted under ice-cooling and stirred to pH 3.0 with 10% hydrochloric acid.

The precipitates are collected by filtration, washed with water and dried to give 0.94 g of 7- (2-methoxyimino-2- (2-formamidothiazol-4-yl) acetate).

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79 amido) -3- (4-allyl-4H-1,2,4-triazol-3-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3200, 1780, 1680 and 1550 crn.

NMR Spectrum (d 6 -DMSO): δ (ppm) - 3.72 (2H, broad s), 3.93 (3H, s), δ 4.20 (2H, broad s), 4.65 (2H, m), 4.72-5.43 (3H, m), 5.55-6.45 (2H, m), 7.43 (1H, s), 8.55 (1H, s), 8.65 (1H, s), 9.68 (1H, d, J - 8Hz), 12.82 (1H, m).

EXAMPLE 32 The following compounds are prepared in the same way as described in Examples 26-31: 1) 7- (2-Isopropoxyimino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazole) -5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3220, 1780 and 1670 cm

NMR Spectrum (d6-DMSO): δ (ppm) - 1.20 (3H, s), 1.32 (3H, s), 3.70 (2H, broad s), 4.07-4.87 (3H, m), 4.93-5.50 (4H, m), 5.67-6.23 (2H, m), 7.40 (1H, s), 8.50 (1H, s), 9.58 (1H, d, J - 8Hz).

2) 7- (2-Butoxyimino) 2- (2-formamidothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid isomer).

IR Spectrum (nujol): 3200, 1780, 1695, 1675 and 1655 cm -1.

NMR Spectrum (d 6 -DMSO): δ (ppm) - 0.88 (3H, m), 1.10-2.01 (4H, m), 3.71 (2H, m), 4.14 (2H , t, J = 7.0Hz), 4.38 (2H, ABq, J - 14.0Hz), 4.83-5.51 (5H, m), 5.63-6.40 (2H, m) , 7.42 (1H, s), 8.56 (1H, s), 9.65 (1H, d, J = 9.0Hz).

3) 7- (2-Hexyloxyimino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer).

IR Spectrum (nujol): 3175, 1780, 1757, 1684 and 1640 crn

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80 NMR Spectrum (d6-DMSO): δ (ppm) - 0.84 (3H, m), 1.06-2.03 (8H, m), 3.73 (2H, m), 4.14 ( 2H, t, J - 6.0Hz), 4.40 (2H, ABq, J - 14.0Hz), 4.85-5.52 (5H, m), 5.75-6.45 (2H, m ), 6.97 (1H, broad), 7.41 (1H, s), 8.54 (1H, s), 9.63 (1H, d, J - 8.0 Hz).

4) 7- (2- (2-Formyloxyethoxy) imino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3- cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3265, 1780, 1720 and 1680 cm cm ·.

NMR Spectrum (d 6 -DMSO): δ (ppm) = 3.74 (2H, m), 4.13-4.70 (6H, m), 4.85-5.53 (5H, m), 5.70-6.42 (2H, m), 7.48 (1H, s), 8.26 (1H, s), 8.56 (1H, s), 9.69 (1H, d, J) 9.0Hz).

5) 7- (2-Ethoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid ( syn isomer).

IR Spectrum (nujol): 3500, 3280, 1780, 1735 and 1690 crn

NMR Spectrum (dg-DMSO): δ (ppm) - 1.24 (3H, t, J - 7Hz), 3.74 (2H, s), 4.20 (2H, q, J = 7Hz), δ , 42 (2H, s), 4.77 (2H, s), 4.5 -5.6 (5H, m), 5.7-6.4 (3H, m), 7.50 (1H, s) ), 8.57 (1H, s), 9.68 (1H, d, J -8Hz), 12.69 (1H, wide s).

6) 7- (2-tert-Butoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3250, 1780, 1720, 1680 and 1540 cm

NMR Spectrum (dg-DMSO): δ (ppm) δ 1.44 (9H, s), 3.71 (2H, ABq, J -25 18Hz), 4.37 (2H, ABq, J - 14Hz), 4.62 (2H, s), 4.8-5.4 (5H, m), 5.5-6.4 (2H, m), 7.46 (1H, s), 8.52 (1H, s), 9.58 (1H, d, J - 8Hz), 12.60 (1H, wide s).

7) 7- (2-Ethoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer).

IR Spectrum (nujol): 3350, 1780, 1675 and 1635 cm cm-.

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8) 7- (2- (Isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid ( syn iso mer).

IR Spectrum (nujol): 3350, 3250, 1780, 1675 and 1630 cm

9) 7- (2-Butoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer).

IR Spectrum (nujol): 3360, 1780 and 1672 cm

10) 7- (2-Hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid isomer).

IR spectrum (nujol); 3350, 3240, 1780, 1675 and 1630 cm 2

11) 7- (2-Allyloxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn. isomer).

IR Spectrum (nujol): 3350, 3210, 1778 and 1675 cm -1.

12) 7- (2-Ethoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3360, 3230, 1780, 1680 and 1630 cm

13) 7- (2-tert-Butoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) -acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carb Oxylic acid (syn-isomer).

IR Spectrum (nujol): 3330, 1780, 1730, 1680 and 1630 cm

14) 7- (2-Methylthiomethoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn. isomer).

IR Spectrum (nujol): 3270, 1760, 1650 and 1520 cm cm *.

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82 15) 7- (2- (3-Isoxazolyl) methoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-trazol-5-yl) thiomethyl-3 - cephem-4-carboxylic acid (syn-isomer).

IR spectrum (nujol): 3300, 1770, 1660 and 1530 cm -1.

16) 7- (2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid isomer).

IR Spectrum (nujol): 3360, 1780, 1680 and 1630 cm cm ".

17) 7- (2-Methoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (4-allyl-4H-1,2,4-triazol-3-yl) thiomethyl-3-cephem -4-carboxylic acid (syn isomer) IR Spectrum (nujol): 3350, 1775, 1670 and 1530 cm -1.

18) 7- (2- (4-Fluorobenzyloxyimino) -2- (2- (2,2,2-trifluoroacetamido) thiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazole) 5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3250, 3170, 1780, 1720 and 1650 cm -1.

NMR Spectrum (DMSO-d 6): δ (ppm) = 3.64 (2H, m), 4.34 (2H, ABq, J -14Hz), 4.79-5.44 (7H, m), δ , 65-6.27 (2H, m), 6.95-7.61 (4H, m), 7.51 (1H, s), 9.83 (1H, d, J - 8Hz).

19) 7- (2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4 carboxylic acid (syn isomer), mp 157-161 ° C (dec.).

IR Spectrum (nujol): 3500, 1770, 1660, 1630 and 1600 cm cm ·.

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S3 20) 7- (2- (3,4-Dichlorobenzyloxyimino) -2- (2- (2,2,2-trifluoroacetamido) -thiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazole) -5-yl) thiomethyl-3-ce-phem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 1770 and 1650 cm -1.

NMR Spectrum (DMSO-d6): δ (ppm) - 3.72 (2H, m), 4.40 (2H, m), 5.00-5.43 (7H, m), 5.73. 6.60 (2H, m), 7.30-7.77 (4H, m), 9.90 (1H, d, J 8Hz).

21) 7- (2- (3,4-Dichlorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3- cephem-4-carboxylic acid 10 (syn isomer), mp 155-175 ° C (dec.).

IR Spectrum (nujol): 1770, 1660-1620 and 1450 cm

EXAMPLE 33 0.33 g of concentrated hydrochloric acid is added to a solution of 1.30 g of 7- (2-allyloxyimino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1-allyl-1 5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) in 13 ml of methanol and the mixture is stirred for 4.5 hours at room temperature. The solvent is distilled off under reduced pressure and the residue is dissolved in a saturated aqueous solution of 25 ml of sodium bicarbonate. The aqueous solution is washed with 25 ml of ethyl acetate and adjusted to pH-20 2.0 with 10% hydrochloric acid. The precipitates are collected by filtration, washed with water and dried to give 0.95 g of a colorless powder of 7- (2-allyloxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3350, 3210, 1778 and 1675 cm cm '.

NMR Spectrum (dg-DMSO): δ (ppm) - 3.68 (2H, ABq, J - 18Hz), 4.40-4.71 (4H, m), 4.80-5.45 (7H, m), 5.64-6.24 (3H, m), 6.74 (1H, s), 7.35 (2H, broad s), 9.62 (1H, d, J - 8Hz).

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EXAMPLE 34 0.9 g of concentrated hydrochloric acid is added at room temperature to a solution of 2.4 g of 7- (2-ethoxyimino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1-allyl-1 tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) in a mixture of 16.8 ml of methanol and 4.8 ml of tetrahydrofuran, and the mixture is stirred for 3 hours at 30 ° C. The solvent is distilled off under reduced pressure and the residue dissolved in a saturated aqueous solution of sodium bicarbonate. The aqueous solution is washed with ethyl acetate and adjusted to pH 2.8 with concentrated hydrochloric acid.

The precipitates are collected by filtration, washed with water and dried to give 1.72 g of 7- (2-ethoxyimino-2- (2-amino-thiazol-4-yl) acetamido) -3- (1-allyl) (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3350, 1780, 1675 and 1635 cm cm ".

NMR Spectrum (dg-DMSO): δ (ppm) - 1.24 (3H, t, J - 7.3Hz), 3.71 (2H, m), 4.13 (2H, q, J - 7 , 3Hz), 4.37 (2H, ABq, J - 13.5Hz), 4.80-5.53 (5H, m), 5.64-6.45 (2H, m), 6.77 (1H) , s), 7.25 (2H, broad), 9.62 (1H, d, J - 8.0Hz).

EXAMPLE 35 A mixture of 0.95 g of 7- (2-methylthiomethoxyimino-2- (2-formamido-thiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl 3-cephem-4-carboxylic acid (syn isomer), 0.324 g of concentrated hydrochloric acid, 9.5 ml of methanol and 2 ml of tetrahydrofuran are stirred for 2 hours at room temperature. The solvent is distilled off under reduced pressure and the residue is dissolved in a saturated aqueous solution of sodium bicarbonate.

The aqueous solution is washed with 25 ml of ethyl acetate and adjusted to pH 1.5 with 10% hydrochloric acid. The precipitates are collected by filtration, washed with water and dried to give 0.78 g of 7- (2-methylthiomethoxy-imino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-4H-tetrazole) (5-yl) -30-thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3270, 1760, 1650 and 1520 cm cm ".

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85 NMR Spectrum (d6-DMSO): δ (ppm) - 2.21 (3H, s>, 3.72 (2H, s), 4.38 (2H, ABq, J - 14Hz), 4.8 5.6 (7H, m), 5.7-6.4 (2H, m), 6.80 (1H, s), 7.26 (2H, wide s), 9.66 (1H, d, J - 8Hz).

EXAMPLE 36

A mixture of 1.5 g of 7- (2- (3-isoxazolyl) methoxyimino-2- (2-formamido-thiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl 3-ce-phem-4-carboxylic acid (syn isomer), 0.497 g of concentrated hydrochloric acid, 15 ml of methanol and 3 ml of tetrahydrofuran are stirred for 2 hours at room temperature. The solvent is distilled off under reduced pressure and the residue is dissolved in a saturated aqueous solution of sodium bicarbonate.

The aqueous solution is washed with 25 ml of ethyl acetate and adjusted to pH 1.5 with 10% hydrochloric acid. The precipitates are collected by filtration, washed with water and dried to give 0.65 g of 7- (2- (3-isoxazolyl) -15-methoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1- allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3300, 1770, 1660 and 1530 cm cm ".

NMR Spectrum (d6-DMSO): δ (ppm) - 3.71 (2H, s), 4.40 (2H, d, J -14Hz), 4.8-5.6 (7H, m), δ , 6-6.5 (2H, m), 6.62 (1H, d, J - 2Hz), 6.83 (1H, s), 7.29 (2H, wide s), 8.92 (1H) , d, J - 2Hz), 9.73 (1H, d, J »8Hz).

EXAMPLE 37

A mixture of 0.9 g of 7- (2-methoxyimino-2- (2-formamidothiazol-4-yl) -acetamido) -3- (4-allyl-4H-1,2,4-triazol-3-yl) thiomethyl-3-cephem-4-25 carboxylic acid (syn isomer), 0.3 ml of concentrated hydrochloric acid, 7 ml of methanol and 7 ml of tetrahydrofuran are stirred for 4.5 hours at room temperature. The solvent is distilled off under reduced pressure and the residue is dissolved in a saturated aqueous solution of sodium bicarbonate. The aqueous solution is washed with 25 ml of ethyl acetate and adjusted to pH

DK 162391 B

86 value 2.0 with 10% hydrochloric acid. The precipitates are collected by filtration, washed with water and dried to give 0.5 g of 7- (2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (4-allyl-4H-1,2) (4-triazol-3-yl) thio-methyl-3-cephem-4-carboxylic acid (syn isomer).

IR spectrum (nujol): 3350, 1775, 1670 and 1530 cm -1.

NMR Spectrum (dg-DMSO): δ (ppm) - 3.65 (2H, broad s), 3.83 (3H, s), 4.15 (2H, broad s), 4.58 (2H, m ), 4.77-5.5 (3H, m), 5.58-6.33 (2H, m), 6.73 (1H, s), 8.60 (1H, s), 9.58 ( 1H, d, J - 8Hz).

EXAMPLE 38 The following compounds are prepared in the same manner as described in Examples 33-37: 1) 7- (2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazole) -5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3350, 3230, 1780, 1675 and 1635 cm -1.

2) 7- (2-Isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer).

IR Spectrum (nujol): 3350, 3250, 1780, 1675 and 1630 cm -1.

NMR Spectrum (d 6 -DMSO): δ (ppm) = 1.20 (3H, s), 1.30 (3H, s), 3.70 (2H, broad), 4.30 (3H, m), 4.97-5.40 (4H, m), 5.63-6.27 (2H, m), 6.70 (1H, s), 9.55 (1H, d, J = 8Hz).

3) 7- (2-Butoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid isomer).

IR Spectrum (nujol): 3360, 1780 and 1672 cm -1.

NMR Spectrum (dg-DMSO): δ (ppm) - 0.91 (3H, t, J - 6.0Hz), 1.18-1.96 (4H, m), 3.73 (2H, m ), 3.87-4.73 (4H, m), 4.83-5.57 (5H, m), 5.63-

87 DK 162391 B

6.40 (2H, m), 6.74 (1H, s), 7.20 (2H, broad s), 9.55 (1H, d, J -8.0Hz).

4) 7- (2-Hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid isomer).

IR spectrum (nujol): 3350, 3240, 1780, 1675 and 1630 cm -1.

NMR Spectrum (d 6 -DMSO): δ (ppm) - 0.85 (3H, m), 1.00-2.00 (8H, m), 3.68 (2H, m), 4.05 (2H , m), 4.37 (2H, m), 4.80-5.47 (5H, m), 5.60- 6.47 (2H, m), 6.69 (1H, s), 7, 20 (2H, broad s), 9.50 (1H, d, J -8.0Hz).

5) 7- (2-Ethoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer).

IR Spectrum (nujol): 3360, 3230, 1780, 1680 and 1630 cm cm '.

NMR Spectrum (dg-DMSO): δ (ppm) -1.21 (3H, t, J - 7Hz), 3.68 (2H, 15 s), 4.14 (2H, q, J 7Hz), 4.38 (2H, s), 4.66 (2H, s), 4.8-5.5 (5H, m), 5.6-6.4 (3H, m), 6.80 (1H, s), 7.20 (2H, broad s), 9.48 (1H, d, J - 8Hz).

6) 7- (2-tert-Butoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carbamide 20 oxylic acid (syn isomer).

IR Spectrum (nujol): 3330, 1780, 1730, 1680 and 1630 cm cm ·.

NMR Spectrum (d 6 -DMSO): δ (ppm) - 1.43 (9H, s), 3.67 (2H, s), 4.37 (2H, ABq, J - 14Hz), 4.56 (2H , s), 4.8-5.5 (5H, m), 5.6-6.4 (2H, m), 6.78 (1H, s), 7.20 (2H, wide s), 9 , 43 (1H, d, J - 8Hz).

7) 7- (2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido-3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid) isomer).

IR Spectrum (nujol): 3360, 1780, 1680 and 1630 cm cm ·.

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8) 7- (2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4 -carboxylic acid (syn isomer), mp 157-161 ° C (dec.).

IR Spectrum (nujol): 3500, 1770, 1660, 1630 and 1600 cm

NMR Spectrum (DMSO-d6): δ (ppm) - 3.69 (2H, m), 4.39 (2H, ABq, J -14Hz), 4.75-5.48 (7H, m), 5.63-6.57 (2H, m), 6.76 (1H, s), 6.86-7.76 (4H, m), 9.67 (1H, d, J - 8Hz).

9) 7- (2- (3,4-Dichlorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3- cephem-4-carboxylic acid 10 (syn isomer), mp 155-175 ° C (dec.).

IR Spectrum (nujol): 1770, 1660-1620 and 1450 cm

NMR Spectrum (DMSO-d6): δ (ppm) - 3.63 (2H, m), 4.33 (2H, m), 4.93-5.37 (7H, m), 5.67-6 , 40 (2H, m), 6.73 (1H, s), 7.10-7.70 (3H, m), 9.73 (1H, d, J - 8Hz).

EXAMPLE 39 20 ml of trifluoroacetic acid is added under ice-cooling to a stirred suspension of 2.05 g of 7- (2-tert-butoxycarbonylmethoxyimino-2- (2-amino-thiazol-4-yl) acetamido) -3- (1-allyl) (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer) in 2 ml of anisole and the resulting mixture is stirred for 2 hours at room temperature. The reaction mixture is evaporated under reduced pressure and diethyl ether is added. The precipitates are collected by filtration, washed with diethyl ether, dried and dissolved in an aqueous solution of sodium bicarbonate. Insoluble material is filtered off and the filtrate is adjusted to pH 3.2 with 25 concentrated hydrochloric acid. The precipitates are collected by filtration, washed with water and dried to give 0.8 g of 7- (2-earboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazole-5 - yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3360, 1780, 1680 and 1630 cm cm ".

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NMR Spectrum (d6-DMSO): S (ppm) - 3.68 (2H, ABq, J - 19Hz), 4.36 (2H, ABq, J - 14Hz), 4.60 (2H, s), 4 , 60-6.2 (7H, m), 6.80 (1H, s), 7.24 (2H, broad s), 9.51 (1H, d, J - 9Hz).

EXAMPLE 40

To a solution of 4.8 g of 7- (2-allyloxyimino-2- (2-aminothiazol-4-yl) -acetamido) cephalosporanoic acid (syn isomer) in a solution of 100 ml of phosphate buffer of pH 6.4 is added 2.1 g of 1-allyl-1H-tetrazole-5-thiol, and the mixture is stirred for 2 hours at 55-60 ° C. The reaction mixture is cooled and adjusted to a pH of 3.0 with 10% hydrochloric acid. The precipitates are collected by filtration, washed with water and dried to give 2.0 g of 7- (2-allyloxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazole) -5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3350, 3210, 1778 and 1675 cm -1, NMR Spectrum (DMSO-d6): S (ppm) = 3.68 (2H, ABq, J - 18Hz), 4.40 -4.71 (4H, m), 4.80-5.45 (7H, m), 5.64-6.24 (3H, m), 6.74 (1H, s), 7.35 (2H) , broad s), 9.62 (1H, d, J - 8Hz).

EXAMPLE 41 The following compounds are prepared in the same manner as described in Example 40.

1) 7- (2-Allyloxyimino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid isomer).

IR Spectrum (nujol): 3180, 1775 and 1665 cm -1.

90 DK 162391 B

2) 7- (2-Ethoxyimino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn. isomer).

IR Spectrum (nujol): 3200, 1765 and 1665 cm cm,, 3) 7- (2-Methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazole) -5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3250, 3200, 1780, 1670 and 1540 cm cm ·.

4) 7- (2- (3-Isoxazolyl) methoxyimino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem -4 - carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3250, 1780, 1670, and 1550 cm -1, 5) 7- (2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H- tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3350, 3230, 1780, 1675 and 1635 cm

6) 7- (2-Methoxyimino-2- (2-formamidothiazol-4-yl) acetamido) -3- (4-allyl-4H-1,2,4-triazol-3-yl) thiomethyl-3 -cephem-4-carboxylic acid (synis omer).

IR Spectrum (nujol): 3200, 1780, 1680 and 1550 cnT-k7) 7- (2-Isopropoxyimino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1-20 allyl-1H tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3220, 1780 and 1670 cm

8) 7- (2-Butoxyimino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn. isomer).

IR Spectrum (nujol): 3200, 1780, 1695, 1675 and 1655 cm -1. · 91

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9) 7- (2-Hexyloxyimino-2- (2-formamidothiazo-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephetin-4-carboxylic acid (syn. is o-mer).

IR spectrum (nujol): 3175, 1780, 1757, 1684 and 1640 cm -1.

10) 7- (2-Ethoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3500, 3280, 1780, 1735 and 1690 cm · 1.

11) 7- (2-tert-Butoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3250, 1780, 1720, 1680 and 1540 cm -1.

12) 7- (2-Ethoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer).

IR Spectrum (nujol): 3350, 1780, 1675 and 1635 cm -1.

13) 7- (2-Isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid ( syn isomer).

IR Spectrum (nujol): 3350, 3250, 1780, 1675 and 1630 cm -1.

14) 7- (2-Butoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer).

IR Spectrum (nujol): 3360, 1780 and 1672 cm cm 1.

15) 7- (2-Hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn. isomer).

DK 162391 B

IR Spectrum (nujol): 3350, 3240, 1780, 1675 and 1630 cm -1.

92 16) 7- (2-Ethoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

IR spectrum (nujol): 3360, 3230, 1780, 1680 and 1630 cm cm *.

17) 7- (2-tert-Butoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) -acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carb -oxylic acid (syn-isomer).

IR Spectrum (nujol): 3330, 1780, 1730, 1680 and 1630 cm cm ".

18) 7- (2-Methylthiomethoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (synis) omer).

IR Spectrum (nujol): 3270, 1760, 1650 and 1520 cm

19) 7- (2- (3-Isoxazolyl) methoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3- cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3300, 1770, 1660 and 1530 cm

20) 7- (2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid isomer).

IR Spectrum (nujol): 3360, 1780, 1680 and 1630 cm

21) 7- (2-Methoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (4-allyl-4H-1,2,4-triazol-3-yl) thiomethyl-3-cephem 4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3350, 1775, 1670 and 1530 cm

93

DK 162391 B

22) 7- (2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4 carboxylic acid (syn-isomer). Melting point 157-161 ° C (dec.).

IR Spectrum (nujol): 3500, 1770, 1660, 1630 and 1600 cm

23) 7- (2- (3,4-Dichlorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido) -3- (1-allyl-1H-tetrazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn isomer), mp 155-175 ° C (dec.).

IR Spectrum (nujol): 1770, 1660-1620 and 1450 crn

Example 42 The Vilsmeier reagent is prepared from 0.139 g of dry dimethylformamide,

0.290 g of phosphorus oxychloride and 1.0 ml of dry tetrahydrofuran in conventional manner. Dry tetrahydrofuran (3.0 ml) and then 0.4 g of 2-methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer) are added at -5 DEG C. The mixture is stirred for 30 minutes at the same temperature. The resulting mixture is added dropwise at -5 - 0 ° C

to a stirred solution of 725 g of 7-amino-3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid in a mixture of 7 ml of water and 7 ml of acetone, pH the value is maintained at 7.5-8.5 by means of triethylamine and the mixture is stirred for 30 minutes at the same temperature 20 at pH 7.5-8.5. Acetone is removed from the reaction mixture. To the residue is added ethyl acetate and water and the mixture is adjusted to pH 2.0 with 10% hydrochloric acid. Insoluble material is filtered off and the filtrate is extracted twice with ethyl acetate. The combined extracts are washed twice with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off and the residue is pulverized with diethyl ether to give 0.64 g of 7- (2-methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) aeteamido) -3- (1,3,4-thiadiazol-2-yl) ) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3230, 1780, 1680 and 1550 cm -1.

94 DK 162391 B

NMR Spectrum (d 5 ~ DMSO): δ (ppm) - 2.22 (3H, s), 3.72 (2H, ABq, J «18Hz), 4.44 (2H, ABq, J - 14Hz), δ , 18 (1H, d, J 5Hz), 5.23 (2H, s), 5.84 (1H, d, d, J - 5 and 9Hz), 7.46 (1H, s), 8.52 (1H, s), 9.54 (1H, s), 9.74 (1H, d, J - 9Hz), 12.64 (1H, broad s).

EXAMPLE 43 2.3 g of phosphorus oxychloride was added at once to a suspension of 3.4 g of 2-benzyloxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer) in 30 ml of dry tetrahydrofuran at -3 ° C and the mixture is stirred for 20 minutes at the same temperature. 2.4 g of trimethylsilylacetamide and 5 ml of tetrahydrofuran are added dropwise and the resulting mixture is stirred for 20 minutes at the same temperature. 2.3 g of phosphorus oxychloride is added and the mixture is stirred for 30 minutes at 0-3 ° C.

1.1 g of dry dimethylformamide is added at 0-3 ° C at once, and the mixture is stirred for 1 hour at the same temperature to give a clear solution.

12.7 g of trimethylsilylacetamide are added to a stirred suspension of 4.0 g of 7-amino-3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid in 60 ml of dry ethyl acetate. and the solution is stirred for 1 hour at room temperature. To this stirred solution is added the above 20 tetrahydro uranium solution prepared at one time at -20 ° C and the resulting mixture is stirred for 2 hours at -5 - -15 ° C. To the reaction mixture is added 50 ml of a saturated aqueous solution of sodium chloride. An organic phase is separated and extracted with a saturated aqueous solution of sodium bicarbonate (pH 7.0). The extract 25 is washed with ethyl acetate, treated with activated charcoal and adjusted to pH 4.5 with 10% fs hydrochloric acid. The precipitates are collected by filtration, washed with water and dried to give 1.03 g of a powder of 7- (2-benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1,3,4 (thiadlazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3320, 3200, 1770, 1670 and 1610 cm cm ".

NMR Spectrum (dg-DMSO): δ (ppm) - 3.59 (2H, ABq, J - 18.0Hz), 4.47 (2H, ABq, J - 12.0Hz), 5.09 (1H , d, J - 4.0Hz), 5.15 (2H, s), 5.73 95

DK 16239 1 B

(1H, d, d, J - 4.0 and 8.0Hz), 6.74 (1H, s), 7.36 (5H, m), 9.56 (1H, s), 9.69 (1H) , d, J - 8.0Hz).

EXAMPLE 44

The Vilsmeier reagent is prepared from 0.667 g of dry dimethylformamide, 5.40 g of phosphorus oxychloride and 4 ml of dry ethyl acetate in conventional manner. 16 ml of dry ethyl acetate and then 2 g of 2-tert-butoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer) are added at 0 ° C. The mixture is stirred for 30 minutes at the same temperature. The resulting mixture is added dropwise at -15 ° C to a stirred solution of 3.01 g of 7-amino-3- (1,3,4-thiadiazol-2-yl) thio-methyl-3-cephem-4-carboxylic acid and 9.6 g of trimethylsilylacetamide in 30 ml of dry ethyl acetate and the mixture is stirred for 50 minutes at -15 - -5 ° C. To the reaction mixture is added 50 ml of water. Insoluble material is filtered off and the filtrate is extracted twice with ethyl acetate. The extracts are washed twice with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue is pulverized with diethyl ether and the powder is collected by filtration and dried to give 2.67 g of 7- (2-tert-butoxycarbonyl-methoxyimino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1.3 (4-Thia-diazol-2-yl) thiomethyl-3-eephem-4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3225, 1780, 1725, 1685 and 1550 cnT1.

NMR Spectrum (dg-DMSO): δ (ppm) = 1.38 (9H, s), 3.64 (2H, ABq, J = 17Hz), 4.38 (2H, ABq, J = 14Hz), δ , 56 (2H, s), 5.12 (1H, d, J = 5Hz), 5.77 (1H, d, d, J - 5 and 9Hz), 7.38 (1H, s), 8.47 (1H, s), 9.49 (1H, 25 s), 9.54 (1H, d, J = 9Hz), 12.57 (1H, broad s).

EXAMPLE 45 The following compounds are prepared in the same manner as described in Examples 42-44:

DK 162391 B

96 1) 7- (2- (2-Ethoxyethoxy) imino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem 4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3500, 3200, 1780, 1720 and 1680 cm cm ‘.

NMR Spectrum (dg-DMSO): δ (ppm) - 1.13 (3H, t, J - 7Hz), 3.2 »4.0 (6H, m), 4.30 (2H, t, J - 4Hz), 4.50 (2H, ABq, J - 13Hz), 5.23 (1H, d, J - 5Hz), 5.87 (1H, d, d, J - 5 and 8Hz), 7.48 (1H, s), 8.58 (1H, s), 9.60 (1H, s), 9.70 (1H, d, J - 8Hz).

2) 7- (2- (2-Formyloxyethoxy) imino-2- (2-formamidothiazol-4-yl) acetyl-10-amido) -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer).

IR spectrum (nujol): 1770, 1710 and 1670 cm

NMR Spectrum (d 6 -DMSO): δ (ppm) - 3.50 (2H, m), 4.10 * 4.60 (4H, m), 4.79 (2H, m), 5.16 (1H) , d, J - 5.0 Hz), 5.81 (1H, d, d, J - 5.0 and 8.0Hz), 6.58 (2H, wide s), 7.47 (1H, s) , 8.28 (1H, s), 8.55 (1H, s).

3) 7- (2- (2-Formyloxyethoxy) imino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3- cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3180, 1775 and 1673 cm

In NMR Spectrum (d 6 -DMSO): δ (ppm) - 3.75 (2H, m), 4.25 * 4.65 (6H, m), 5.22 (1H, d, J - 5). 0Hz), 5.88 (1H, d, d, J - 5.0 and 9.0Hz), 7.49 (1H, s), 8.26 (1H, s), 8.57 (1H, s) , 9.59 (1H, s), 9.71 (1H, d, J -9.0Hz).

4) 7- (2-Ethoxycarbonylmethoxyphenyl-2- (2-formamidothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

! IR Spectrum (nujol): 3250, 1775, 1720, 1680 and 1540 cm -1.

97

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MR spectrum (d6-DMSO): S (ppm) - 1.22 (3H, t, J - 7Hz), 3.74 (2H, s), 4.20 (2H, q, J - 7Hz), 4 , 77 (2H, s), 5.22 (1H, d, J - 5Hz), 5.88 (1H, d, d, J - 5 and 8Hz), 7.51 (1H, s), 8.58 (1H, s), 9.63 (1H, s), 9.70 (1H, d, J - 8Hz), 12.68 (1H, wide s).

5) 7- (2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn - isomer).

IR Spectrum (nujol): 3350, 3250, 1780, 1680 and 1633 cm cm ".

NMR Spectrum (d6-DMSO): δ (ppm) - 0.86 (3H, m), 0.97 1,5 1.53 (6H, m), 1.53 * 2.10 (2H, m), δ , 70 (2H, m), 4.10 * 4.77 (4H, m), 5.00 * 5.50 (3H, m), 5.85 (1H, d, d, J - 5.0 and 8.0Hz), 6.80 (1H, s), 6.98 * 7.63 (7H, m), 9.71 (1H, d, J - 8.0Hz).

6) 7- (2- (3-Isoxazolyl) methoxyimino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem -4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3200, 1775, 1675 and 1540 cm cm *.

NMR Spectrum (dg-DMSO); S (ppm) - 3.72 (2H, s), 4.45 (2H, ABq, J-13Hz), 5.18 (1H, d, J - 5Hz), 5.30 (2H, s), 5 , 96 (1H, d, d, J - 5 and 8Hz), 6.67 (1H, d, J - 2Hz), 7.50 (1H, s), 8.55 (1H, s), 8.90 (1H, d, J - 2Hz), 9.58 (1H, s), 9.79 (1H, d, J - 8Hz), 12.69 (1H, s).

7) 7- (2-Methylthiomethoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer).

IR Spectrum (nujol): 3340, 3200, 1775 and 1670 cm cm ".

8) 7- (2- (2-Ethoxyethoxy) imino-2- (2-aminothiazol-4-yl) acetamido) -3-25 (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem 4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3160, 3100, 1780, 1670 and 1630 cm -1.

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9) 7- (2-Ethoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer).

IR Spectrum (nujol): 3350, 3230, 3100, 1780, 1680 and 1630 cm

10) 7- (2-tert-Butoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4 carboxylic acid (synsomes).

IR Spectrum (nujol): 3300, 1775, 1730, 1675 and 1630 cnT

11) 7- (2- (3-Isoxazolyl) methoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3- cephem-4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3350, 3230, 3110, 1775 and 1675 cm

12) 7- (2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (sync) Isomer).

IR Spectrum (nujol): 3360, 3240, 3100, 1780, 1680 and 1635 cm

13) 7- (2- (tert-Butoxycarbonylmethoxyimino) -2- (2-formamidothiazol-4-yl) acetamido) -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn. isomer).

IR Spectrum (nujol): 3170, 1770, 1720 and 1670 cm

NMR Spectrum (DMSO-d6): δ (ppm) - 1.44 (9H, s), 3.68 (2H, m), 4.33 (2H, ABq, J - 12.0Hz), 4.63 (2H, s), 5.16 (1H, d, J - 5.0Hz), 5.82 (1H, dd, J - 5.0 and 8.0Hz), 7.43 (1H, s), 8 , 51 (1H, s), 9.56 (1H, d, J - 8.0Hz).

14) 7- (2-Ethoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) ), mp 112-125 ° C (dec.).

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99 IR Spectrum (nujol): 3250, 1770, 1730 and 1680 cm cm ".

NMR Spectrum (DMSO-d6): δ (ppm) - 1.20 (3H, t, J - 8Hz), 3.71 (2H, m), 4.07 (2H, q, J - 8Hz), δ , 36 (2H, m), 4.77 (2H, m), 5.20 (1H, d, J

- 5Hz), 5.88 (1H, dd, J - 5 and 8Hz), 7.50 (1H, s), 8.57 (1H, s), 9.67 (1H, d, J - 8Hz) , 12.38 (1H, broad s).

15) 7- (2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), m.p. 172-174 ° C (dec.).

IR Spectrum (nujol): 3250, 3150, 1770 and 1620 cm cm ·.

NMR Spectrum (DMSO-d6): δ (ppm) - 3.67 (2H, m), 4.33 (2H, m), 5.08-5.36 (3H, m), 5.83 ( 1H, dd, J - 4 and 8Hz), 6.88 (1H, s), 7.39 (5H, s), 9.73 (1H, d, J - 8Hz).

16) 7- (2- (4-Fluorobenzyloxyimino) -2- (2- (2,2,2-trifluoroacetamido) thiazol-4-yl) acetamido) -3- (1,3,4-thiadiazole-2) -yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3200, 1770, 1720 and 1650 cm

NMR Spectrum (DMSO-d 6): δ (ppm) δ 3.73 (2H, ABq, J «18Hz), 4.49 (2H, ABq, J - 14Hz), 5.03-5.46 (3H, m), 5.88 (1H, dd, J · 4 and 8Hz), 7.03-7.84 (4H, m), 7.59 (1H, s), 9.60 (1H, s), 9 , 88 (1H, d, J - 8Hz).

17) 7- (2-Cinnamyloxyimino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn iso mer).

IR Spectrum (nujol): 3400-3100, 1780, 1680 and 1540 cm cm ".

NMR Spectrum (DMSO-d 6): δ (ppm) - 3.67 (2H, m), 4.45 (2H, ABq, J -25 14Hz), 4.83 (2H, d, J = 5Hz), 5.18 (1H, d, J «5Hz), 5.87 (1H, dd, J

- 5 and 8Hz), 6.65 (1H, s), 6.12-7.0 (2H, m), 7.1-7.7 (5H, m), 8.53 (1H, s), 9.57 (1H, s), 9.73 (1H, d, J - 3Hz), 12.6 (1H, broad s).

100 DK 162391 B

18) 7- (2- (4- Fluorobenzyloxyimino) -2- (2- (2,2,2-trifluoroacetamido) thiazol-4-yl) acetamido) -3- (1H-tetrazol-5-yl) ) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), IR Spectrum (nujol): 3200, 1780, 1730 and 1660 cm

19) 7- (2- (3-Hydroxy-4-bromobenzyloxyimino) -2- (2-formamidothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3400-3100, 1780, 1680 and 1540 cm cm '.

NMR Spectrum (DMSO-d 6): δ (ppm) = -3.7 (2H, broad s), 4.45 (2H, ABq, J 10-13Hz), 5.13 (1H, d, J = 5Hz ), 5.18 (2H, s), 5.82 (1H, dd, J "5 and 8Hz), 6.97 (1H, d, J = 2Hz), 7.4 (1H, s), 7, 45 (1H, d, J - 8Hz), 8.5 (1H, s), 9.68 (1H, d, J = 8Hz), 12.6 (1H, wide s).

20) 7- (2- (tert-Butoxycarbonylmethoxyimino) -2- (2-aminothiazol-4-yl) acetamido) -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer).

IR Spectrum (nujol): 3280, 3200, 1770, 1670 and 1630 cm

21) 7- (2-Ethoxycarbonylmethoxyimino-2-6-aminothiazol-yl-acetamido) -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), m.p. 168-185 ° C (dec.).

IR Spectrum (nujol): 3250, 1765, 1670 and 1625 cm cm-.

22) 7- (2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4- carboxylic acid (syn-isomer), mp 145-149 ° C (dec.).

IR Spectrum (nujol): 3250, 1765 and 1650 cm -1.

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(23) 7- (2-Cinnamyloxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer).

IR Spectrum (nujol): 3350-3100, 1760, 1650, 1620 and 1520 cm cm ·.

24) 7- (2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido) -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (synthetic acid) -isomer).

IR Spectrum (nujol): 3300, 3200, 1770, 1660, 1630 and 1600 cm

25) 7- (2- (3- Hydroxy-4-bromobenzyloxyimino) -2- (2-aminothiazol-4-yl) -acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl -3-cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3400-3100, 1760, 1660, 1620 and 1520 cm

26) 7- (2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), m.p. 178-180 ° C (dec.).

IR Spectrum (nujol): 3300, 3280, 1770, 1670 and 1630 cm

EXAMPLE 46

A mixture of 0.58 g of 7- (2-methylthiomethoxyimino-2- (2-formamido-thiazol-4-yl) acetamido) -3- (1,3,4-tadiazol-2-yl) thiomethyl-3-cephem 4-carboxylic acid (syn isomer), 0.405 g of concentrated hydrochloric acid, 8.7 ml of methanol and 5 ml of tetrahydrofuran are stirred for 2 hours and 10 minutes at room temperature. The solvent is distilled off under reduced pressure and the residue is dissolved in a 10¾ aqueous sodium hydroxide solution (pH 7 »8.5). Insoluble material is filtered off and the filtrate is adjusted to pH 3.4 with 10% hydrochloric acid under ice-cooling and stirred for 30 minutes. The precipitates are collected by filtration, washed with water and dried to give 0.4 g of 7- (2-methylthiomethoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazole-2) -yl) thiomethyl-3-cephem-4-carboxylic acid (syn-isomer).

DK 162391 B

102 IR Spectrum (nujol): 3340, 3200, 1775 and 1670 cm cm '.

NMR Spectrum (d6-DMSO): δ (ppm) - = 2.23 (3H, s), 3.74 (2H, s), 4.48 (2H, ABq, J - 13Hz), 5.20 ( 1H, d, J - 5Hz), 5.24 (2H, s), 5.83 (1H, d, d, J - 5 and 9Hz), 6.83 (1H, s), 7.28 (2H, broad s), 9.62 (1H, s), δ 9.68 (1H, d, J - 9Hz).

EXAMPLE 47

A mixture of 2.3 g of 7- (2-tert-butoxyearbonylmethoxyimino-2- (2-form-amidothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3 cephem-4-carboxylic acid (syn isomer), 3.74 g of concentrated hydrochloric acid and 10 ml of methanol are stirred for 2 hours and 40 minutes at room temperature.

The solvent is distilled off under reduced pressure and the residue is dissolved in a 10% aqueous solution of sodium hydroxide (pH 7 ~ 8). The aqueous solution is adjusted to pH 3.0 with 10% hydrochloric acid under ice-cooling and stirring and stirred for 30 minutes.

The precipitates are collected by filtration, washed with water and dried to give 1.1 g of 7- (2-tert-butoxycarbonylmethoxyimino-2- (2-amino-thiazol-4-yl) acetamido) -3- (1.3, 4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3300, 1775, 1730, 1675 and 1630 cm cm-.

NMR Spectrum (d6-DMSO): δ (ppm) - 1.46 (9H, s), 3.67 (2H, s), 4.42 (2H, ABq, J - 14Hz), 4.55 ( 2H, s), 5.16 (1H, d, J - 5Hz), 5.78 (1H, dd, J - 5 and 9Hz), 6.77 (1H, s), 7.21 (2H, s) , 9.43 (1H, d, J J 9Hz), 9.52 (1H, s).

Example 48 To a stirred solution of 2.7 g of sodium acetate in 46 ml of water is added 2.3 g of 7- (2- (4-fluorobenzyloxyimino) -2- (2- (2,2,2-trifluoroacetamido) -thiazole). 4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), and the mixture is stirred for 20.5 hours at room temperature. The reaction mixture is adjusted to pH 5.0 with 30% hydrochloric acid after addition of ethyl acetate, and the resulting

m DK 162391 B

mixture is shaken. The aqueous phase is separated, washed twice with ethyl acetate and adjusted to pH 3.0 with 10% hydrochloric acid. The precipitates are collected by filtration, washed with water and dried to give 1.82 g of 7- (2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acet-5-amido) -3- (1, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 145-149 ° C (dec.).

IR Spectrum (nujol): 3250, 1765 and 1650 cm cm ".

NMR Spectrum (DMSO-d 6): δ (ppm) - 3.73 (2H, ABq, J - 18Hz), 4.48 (2H, ABq, J - 14Hz), 5.01-5.39 (3H, m), 5.85 (1H, dd, J - 4 and 8Hz), 6.83 (1H, s), 7.02-7.75 (4H, m), 9.63 (1H, s), 9.75 (1H, d, J - 8Hz).

EXAMPLE 49 The following compounds are prepared in a similar manner as described in Examples 46-48.

1) 7- (2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer).

IR Spectrum (nujol): 3320, 3200, 1770, 1670 and 1610 cm cm ".

2) 7- (2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid isomer).

IR Spectrum (nujol): 3350, 3250, 1780, 1680 and 1633 cm cm ".

3) 7- (2- (2-Ethoxyethoxy) imino-2- (2-aminothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem 4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3160, 3100, 1780, 1670 and 1630 cm cm ".

NMR Spectrum (d6-DMSO): δ (ppm) - 1.08 (3H, t, J - 7Hz), 3.45 (2H, q, 25 J - 7Hz), 3.5 ° 3.90 (4H , m), 4.20 (2H, t, J - 4Hz), 4.47 (2H, ABq, J - 13Hz), 5.17 (1H, d, J - 5Hz), 5.80 (1H, dd) , J - 5 and 8Hz), 6.77 (1H, s), 9.55 (1H, s), 9.55 (1H, d, J - 8Hz).

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4) 7- (2-Ethoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer).

IR Spectrum (nujol): 3350, 3230, 3100, 1780, 1680 and 1630 cm cm 1.

Δ NMR Spectrum (dg-DMSO): δ (ppm) - 1.21 (3H, t, J - 7Hz), 3.72 (2H, ABq, J - 18Hz), 4.18 (2H, q, J - 7Hz), 4.70 (2H, s), 5.20 (1H, d, J = 5Hz), 5.84 (1H, d, d, J - 5 and 8Hz), 6.84 (1H, s) ), 7.26 (2H, broad s), 9.56 (1H, d, J - 8Hz), 9.60 (1H, s).

5) 7- (2- (3-Isoxazolyl) methoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem 4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3350, 3230, 3110, 1775, 1675 cm -1.

NMR Spectrum (dg-DMSO): δ (ppm) - 3.71 (2H, ABq, J - 18Hz), 4.46 (2H,

ABq, J - 14Hz), 5.17 (1H, d, J · = 5Hz), 5.27 (2H, s), 5.82 (1H, d, d, J

15 = 5 and 8Hz), 6.66 (1H, s), 6.83 (1H, s), 7.30 (2H, wide s), 8.87 (1H, s), 9.57 (1H, s), 9.75 (1H, d, J - 8Hz).

6) 7- (2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (sync) isomer).

IR Spectrum (nujol): 3360, 3240, 3100, 1780, 1680 and 1635 cm -1.

7) 7- (2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) , mp 172-174eC (dec.).

IR Spectrum (nujol): 3250, 3150, 1770 and 1620 cm -1.

8) 7- (2- (tert-Butoxycarbonylmethoxyimino) -2- (2-aminothiazol-4-yl) acetamido) -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid ( syn-is omer).

IR Spectrum (nujol): 3280, 3200, 1770, 1670 and 1630 cm cm 1.

105 DK 162391 B

9) 7- (2-Ethoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), m.p. 168-185 ° C (dec.).

IR Spectrum (nujol): 3250, 1765, 1670 and 1625 cm

NMR Spectrum (DMSO-d 6): δ (ppm) - 1.21 (3H, t, J - 7Hz), 3.70 (2H, broad s), 4.18 (2H, q, J - 7Hz) , 4.31 (2H, m), 4.72 (2H, broad s), 5.17 (1H, d, J - 4Hz), 5.82 (1H, dd, J = 4 and 7Hz), 6, 83 (1H, s), 7.17 (2H, broad s), 9.57 (1H, d, J = 7Hz).

10) (2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 145-149 ° C (dec.).

IR Spectrum (nujol): 3250, 1765 and 1650 cm

11) 7- (2-Cinnamyloxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cepbem-4-carboxylic acid (sync) isomer).

IR Spectrum (nujol): 3350-3100, 1760, 1650, 1620 and 1520 cm cm '.

NMR Spectrum (DMSO-d 6): δ (ppm) - 3.47-3.97 (2H, m), 4.47 (2H, ABq, J

- 14Hz), 4.8 (2H, d, J - 5Hz), 5.18 (1H, d, J - 5Hz), 5.83 (1H, dd, J

- 5 and 8Hz), 6.83 (1H, s), 6.1-7.0 (2H, m), 7.08-7.72 (5H, m), 9.6 (1H, s) , 9.72 (1H, d, J - 8Hz).

12) 7- (2- (4-Fluorobenzyloxyimino) -2- (2-aminotbiazol-4-yl) acetamido) -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (sync) isomer).

IR Spectrum (nujol): 3300, 3200, 1770, 1660, 1630 and 1600 cm -1.

NMR Spectrum (DMSO-d6): S (ppm) - 3.69 (2H, ABq, J - 18Hz), 4.35 (2H, ABq, J = 15Hz), 4.93-5.43 (3H , m), 5.81 (1H, dd, J - 5 and 8Hz), 6.80 (1H, s), 6.96-7.70 (4H, m), 9.73 (1H, d, J - 8Hz).

13) 7- (2- (3-Hydroxy-4-bromobenzyloxyimino) -2- (2-aminothiazol-4-yl) -acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn-isomer).

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106 IR Spectrum (nujol): 3400-3100, 1760, 1660, 1620 and 1520 cm cm ".

MR spectrum (DMSO-d6): S (ppm) - 3.72 (2H, broad s), 4.47 (2H, ABq, J - 14Hz), 5.1 (1H, d, J - 5Hz), 5.22 (2H, s), 5.83 (1H, dd, J - 5 and 8Hz), 6.85 (1H, s), 6.87 (1H, dd, J = 2 and 8Hz), 7, 08 (1H, d, J -5 2Hz), 7.52 (1H, d, J - 8Hz), 9.67 (1H, s), 9.77 (1H, d, J - 8Hz).

14) 7- (2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) , mp 178-180 ° C (dec.).

IR Spectrum (nujol): 3300, 3280, 1770, 1670 and 1630 cm

EXAMPLE 50 4 ml of trifluoroacetic acid is added under ice-cooling to a stirred suspension of 1.0 g of 7- (2-tert-butoxycarbonylmethoxyimino-2- (2-amino-thiazol-4-yl) acetamido) -3- (1,3, 4-Thiadiazol-2-yl) thiomethyl-3-ce-phem-4-carboxylic acid (syn isomer) in 1 ml of anisole, and the resulting mixture is stirred for 70 minutes at room temperature. The reaction mixture is concentrated under reduced pressure and diethyl ether is added. The precipitates are collected by filtration, washed with diethyl ether, dried, suspended in 10 ml of water and then dissolved in a 10% solution. aqueous solution of sodium hydroxide (pH 7-7.5). The solution 20 is adjusted to pH 3.0 with 10% hydrochloric acid under ice-cooling and stirring and stirred for 30 minutes under ice-cooling. The precipitates are collected by filtration, washed with water and dried to give 0.75 g of 7- (2-carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazole-2) -yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer).

! In IR Spectrum (nujol): 3360, 3240, 3100, 1780, 1680 and 1635 οπΤ ^ ·.

MR Spectrum (dg-DMSO): S (ppm) - 3.68 (2H, s), 4.46 (2H, ABq, J + = 15Hz), 4.61 (2H, s), 5.17 (1H, d, J = 5Hz), 5.82 (1H, dd, J - 5 and 9Hz), 6.83 (1H, s), 7.23 (2H, wide s), 9.50 (1H, d, J - 9Hz), 9.53 (1H, s).

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Example 51 The following compound is prepared in a similar manner as described in Example 50: 7- (2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1H-5 tetrazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn-isomer), m.p. 178-180 ° C (decomposition).

IR Spectrum (nujol): 3300, 3280, 1770, 1670 and 1630 cm -1.

NMR Spectrum (DMSO-d 6): δ (ppm) δ 3.69 (2H, m), 4.32 (2H, ABq, J -14Hz), 4.60 (2H, m), 5.14 (1H) , d, J - 5Hz), 5.79 (1H, dd, J - 5 and 10Hz), 6.79 (1H, s), 9.47 (1H, d, J - 8Hz).

Example 52 1.1 g of 7- (2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido) cephalosporanoic acid (syn isomer) and 0.23 gl, 3,4-thiadiazole 2-Thiol is added to a stirred solution of 0.34 g sodium bicarbonate in 30 ml of pH 6.8 phosphate buffer and the mixture is stirred for 3 hours at 60-65 ° C. The reaction mixture is cooled and adjusted to pH 3 with 10% hydrochloric acid. The precipitates are collected by filtration, washed with water and dried to give 0.45 g of 7- (2- (4-fluorobenzyloxyimino) -2- (2-amino-thiazol-4-yl) acetamido) -3- (1,3) (4-Thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 145-149 ° C (dec.).

IR Spectrum (nujol): 3250, 1765 and 1650 cm

NMR Spectrum (DMSO-d 6): δ (ppm) - 3.73 (2H, ABq, J «= 18Hz), 4.48 (2H, ABq, J - 14Hz), 5.01-5.39 (3H , m), 5.85 (1H, dd, J - 4 and 8Hz), 6.83 (1H, s), 7.02-7.75 (4H, m), 9.63 (1H, s), 9.75 (1H, d, J - 8Hz).

EXAMPLE 53 The following compounds are prepared in a similar manner as described in Example 52.

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108 1) 7- (2-Methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer).

IR Spectrum (nujol): 3230, 1780, 1680 and 1550 cm cm '.

2) 7- (2-Benzyloxyimino-2- (2-aminothlazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer).

IR Spectrum (nujol): 3320, 3200, 1770, 1670 and 1610 cm

3) 7- (2-tert-Butoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) -acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxyl - 10 acid (syn-isomer).

IR Spectrum (nujol): 3225, 1780, 1725, 1685 and 1550 cm cm ".

4) 7- (2- (2-Ethoxyethoxy) imino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4 -carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3500, 3200, 1780, 1720 and 1680 cm

5) 7- (2-Ethoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid ( syn isomer).

IR Spectrum (nujol): 3250, 1775, 1720, 1680 and 1540 cm cm ".

6) 7- (2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1-hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid ( syn isomer).

in IR Spectrum (nujol): 3350, 3250, 1780, 1680 and 1633 cm

7) 7- (2- (3-Isoxazolyl) methoxyimino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem -4-carboxylic acid (syn-isomer).

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109 IR Spectrum (nujol): 3200, 1775, 1675 and 1540 cm

8) 7- (2-Methylthiomethoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn. isomer).

IR spectrum (nujol): 3340, 3200, 1775 and 1670 cm -1.

9) 7- (2- (2-Ethoxyethoxy) imino-2- (2-aminothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4 -carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3160, 3100, 1780, 1670 and 1630 cm cm ".

10) 7- (2-Ethoxycarbonylmethoxyimino-2-6-aminothiazol-2-ylacetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) ).

IR Spectrum (nujol): 3350, 3230, 3100, 1780, 1680 and 1630 cm cm ".

11) 7- (2-tert-Butoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) -acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4 carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3300, 1775, 1730, 1675 and 1630 cm cm-.

12) 7- (2- (3-Isoxazolyl) methoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem -4-carboxylic acid (syn isomer).

IR Spectrum (nujol): 3350, 3230, 3110, 1775 and 1675 cm cm ”.

13) 7- (2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (sync) isomer).

IR Spectrum (nujol): 3360, 3240, 3100, 1780, 1680 and 1635 cm cm '.

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14) 7- (2- (tert -Butoxycarbonylmethoxyimino) -2- (2-formamidothiazol-4-yl) acetamido) -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid ( syn isomer).

IR Spectrum (nujol): 3170, 1770, 1720 and 1670 cm cm ".

15) 7- (2-Ethoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer) ), mp 112-125 ° C (dec.).

IR Spectrum (nujol): 3250, 1770, 1730 and 1680 crn.

16) 7- (2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), mp 172-174 ° C (dec.).

IR Spectrum (nujol): 3250, 3150, 1770 and 1620 cm cm -.

17) 7- (2-Cinnamyloxyimino-2- (2-formamidothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (sync) isomer), IR Spectrum (nujol): 3400-3100, 1780, 1680 and 1540 cm

18) 7- (2- (3-Hydroxy-4-bromobenzyloxyimino) -2- (2-formamidothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3- cephem-4-carboxylic acid (syn-isomer).

in IR spectrum (nujol): 3400-3100, 1780, 1680 and 1540 cm cm “.

19) 7- (2- (tert-Butoxycarbonylmethoxyimino) -2- (2-aminothiazol-4-yl) acetamido) -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn. isomer).

IR Spectrum (nujol): 3280, 3200, 1770, 1670 and 1630 cm cm ".

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20) 7- (2-Ethoxycarbonylmethoxyimino) 2- (2-aminothiazol-4-yl) acetamido) -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (sync) isomer), mp 168-185 ° C (dec.).

IR Spectrum (nujol): 3250, 1765, 1670 and 1625 cm

21) 7- (2-Cinnamyloxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer).

IR Spectrum (nujol): 3350-3100, 1760, 1650, 1620 and 1520 cm cm ·.

22) 7- (2- (4-Fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetamido) -3-10 (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn -isomer).

IR Spectrum (nujol): 3300, 3200, 1770, 1660, 1630 and 1600 cm -1.

23) 7- (2- (3-Hydroxy-4-bromobenzyloxyimino) -2- (2-aminothiazol-4-yl) -acetamido) -3- (1,3,4-thiadiazol-2-yl) thiomethyl-3 -cephem-4-carboxylic acid (syn-isomer).

IR Spectrum (nujol): 3400-3100, 1760, 1660, 1620 and 1520 cm -1.

24) 7- (2-Carboxymethoxyimino-2- (2-aminothiazol-4-yl) acetamido) -3- (1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (syn isomer), m.p. 178-180 ° C (dec.).

IR Spectrum (nujol): 3300, 3280, 1770, 1670 and 1630 cm -1.

Reference 1

A suspension of 1.7 g of phosphorus pentachloride in 20 ml of methylene chloride is converted to a solution by stirring for 2 hours at room temperature.

0.8 g of 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetic acid (syn-isomer) is added at once at room temperature and the mixture is stirred. The methylene chloride is distilled off under reduced pressure and

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The solvent is dissolved in 20 ml of acetone. On the other hand, 1.0 g of 7- amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid is suspended in a solution of 0.59 g of sodium bicarbonate in 20 ml of water and dissolved by the addition of 10 ml of acetone. To this solution is added dropwise the solution obtained in the manner described above containing the acid chloride with stirring and ice cooling, while keeping the solution at pH 7.5-8.5 with a 20% aqueous solution of sodium carbonate. After stirring for 1 hour at pH 8 under ice cooling, insoluble material is filtered off. The acetone is distilled off under reduced pressure from the filtrate and insoluble material is filtered off. The filtrate is adjusted to pH 2.5 with 10% hydrochloric acid. The precipitate is isolated by filtration and dried to give 0.4 g of 7- [2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetamido] -3-carbamoyloxymethyl-3-cephem 4-carboxylic acid (one mixture of syn and anti-isomers). The filtrate is saturated with sodium chloride and stirred under ice-cooling to give precipitated material. The precipitated substance is isolated by filtration and dried to give 0.3 g of the same compound. Total yield 0.7 g.

IR Spectrum (nujol): 3400, 1775 and 1705 cm

NMR Spectrum (d6-DMSO): 5 - 9.71 (1H, d, J - 8Hz), 9.42 (1H, d, J - 8Hz), 7.70 (1H, s), 7.40 (4H, broad s), 7.00 (1H, s), 6.61 (4H, s), 5.76 (2H, m), 5.16 (2H, d, J - 4.5Hz), 4 , 76 (4H, ABq, J - 12Hz), 3.98 (3H, s), 3.89 (3H, s) and 3.53 (4H, ABq, J - 18Hz) ppm.

Reference 2 A mixture of 0.22 g of dimethylformamide and 0.46 g of phosphorus oxychloride is heated to 40 ° C for 1 hour. The mixture is dissolved in 20 ml of dry methylene chloride and 0.73 g of 2-methoxyimino-2- (2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl) acetic acid ( anti-isomer) with stirring and ice-cooling, after which the resulting mixture is stirred for 11/2 hours under ice-cooling. On the other hand, 0.82 g of 7- amino-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid is dissolved in a solution of 1.5 g of bis (trimethylsilyl) acetamide. in 20 ml of dry methylene chloride. Add to this solution at -30 ° C it

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The mixture is stirred for 2 hours at a temperature between -5 and -20 ° C.

After distilling off the methylene chloride at low temperature, water is added to the residue and the mixture is extracted with ethyl acetate.

The extract is washed with an aqueous sodium chloride solution and 50 ml of water is added. The resulting mixture is adjusted to pH 7 with an aqueous solution of sodium bicarbonate and the aqueous phase is separated. The aqueous phase is adjusted to pH 1.5, saturated with sodium chloride and extracted with ethyl acetate. The extract is washed with an aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off and the residue is pulverized with a mixture of diisopropyl ether and ether. The powder is isolated by filtration and dried to give 1.0 g of 7- [2-methoxyimino-2- (2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (anti-isomer). This powder (1.0 g) is suspended in 30 ml of water and dissolved by adjusting the pH to 6 with an aqueous solution of sodium bicarbonate. After removal of the solvent by bubbling nitrogen gas, the aqueous solution is lyophilized to give 0.98 g of sodium 7- [2-methoxyimino-2- (2-mesylimino-3-methyl-2,3-dihydro-1) (3-thiazol-4-yl) acetamido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate (anti-isomer).

IR Spectrum (KBr): 1760 and 1675 cm

NMR Spectrum (D20): 6 - 8.05 (1H, s), 5.76 (1H, d, J - 5Hz), 5.16 (1H, d, J - 5Hz), 4.14 (2H , ABq, J - 13Hz), 4.10 (3H, s), 4.02 (3H, 25 s), 3.52 (2H, ABq, J - 17Hz), 3.45 (3H, s) and 3 , 24 (3H, s) ppm.

Reference 3

The compound listed below is prepared in a similar manner as described for reference 2, 7- [2-Methoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetamido] -3-30 (1,3,4) (thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (anti-isomer), mp 152 ° C (dec.).

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114 IR Spectrum (nujol): 3300-3100, 1775, 1720, 1670 and 1630 cm cm ".

NMR Spectrum (dg-DMSO): 8 - 12.63 (1H, broad s), 9.66 (1H, s), 9.57 (1H, d, J - 8Hz), 8.50 (1H, s) ), 8.07 (1H, s), 5.75 (1H, dd, J - 5.8Hz), 5.15 (1H, d, J - 5Hz), 4.27 (2H, ABq, J - 13Hz) ), 4.00 (3H, s) 5 and 3.70 (2H, broad s) ppm.

Preparation of the starting materials to be used in the above examples and references.

Preparation 1 1) A mixture of 12.4 g of sodium nitrite in 150 ml of water is added dropwise 10 with stirring at 5-7 ° C to a solution of 30 g of ethyl 4-bromoacetoacetate in 200 ml of acetic acid and the mixture is stirred for 2 hours. hours at 10 ° C.

200 ml of water are added to the reaction mixture and the resulting mixture is extracted with 500 ml of ether. The extract is washed twice with 200 ml of water and 200 ml of an aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was equilibrated under reduced pressure to give 32.6 g of yellowish-brown crystals of ethyl 2-hydroxyimino-4-bromoacetoacetate (a mixture of vision and anti-isorers).

In IR Spectrum (film): 3350, 1740, 1710 and 1620 cm -1.

in 20 NMR Spectrum (CDCl 3): 8 - 8.75 (2H, broad s), 4.35 (8H, m) and 1.35 L (6H, m) ppm.

2) 160 g of powdered potassium carbonate are added to a solution of 152 g of ethyl 2-hydroxyiminoacetoacetate (a mixture of syn and anti-isomers) in 500 ml of acetone. 130 g of dimethyl sulfate are added dropwise to it with stirring over 1 hour at 45-50 ° C and the mixture is stirred for 2 hours. Insoluble material is filtered off and the filtrate is evaporated under reduced pressure. The filtered insoluble material is dissolved in 500 ml of water and this solution is added to the residue. The mixture I is extracted twice with 300 ml of ethyl acetate. The extract is washed twice with 200 ml of water and 200 ml of a saturated aqueous sodium chloride.

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riding solution and dried over magnesium sulfate. The solvent is equilibrated under reduced pressure and the residue is distilled under reduced pressure to give 145.3 g of a colorless oil of ethyl 2-methoxyiminoacetoacetate (a mixture of syn and anti-isomers), boiling point 55-64 ° C / 0.5 mm Hg.

IR Spectrum (film): 1745, 1695 and 1600 cm cm ".

NMR Spectrum (CDCl3): δ - 4.33 (4H, q, J - 8Hz), 4.08 (3H, s), 3.95 (3H, s), 2.40 (3H, s), 1 , 63 (3H, s) and 1.33 (6H, t, J - 8Hz) ppm.

3) 100 g of bromine is added dropwise over 40 minutes under boiling 10 to reflux to a solution of 100 g of ethyl 2-methoxyiminoacetoacetate (a mixture of syn and anti-isomers) in a mixture of 300 ml of carbon tetrachloride and 300 ml of acetic acid. The mixture is stirred at 70-80 ° C until the evolution of hydrogen bromide has ceased. The reaction mixture is washed twice with 300 ml of water, with an aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solution is treated with 2 g of activated charcoal and evaporated under reduced pressure to give 120.8 g of ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of syn and anti-isomers).

IR Spectrum (film): 1740, 1705 and 1600 cm cm ·.

NMR Spectrum (CDCl 3): δ -4.17-4.54 (8H, m), 4.15 (3H, s), 4.13 (3H, s) and 1.33 (6H, t, J 8Hz) ppm.

4) A mixture of 11.1 g of selenium dioxide, 250 ml of dioxane and 5 ml of water is stirred for 15 minutes at 110-115 ° C to give a yellow solution. 26.4 g of ethyl 2- (2-mesylamino-1,3-thiazol-4-yl) acetate are added thereto with stirring at the same temperature. After stirring for 1 hour, the reaction mixture is decanted under heating and cooled to precipitate yellow crystals. The crystals are isolated by filtration, washed with dioxane and ether and dried to give 23.5 g of ethyl 2- (2-mesylamino-1,3-thiazol-4-yl) glyoxylate.

IR Spectrum (nujol): 3300, 1718 and 1682 cm -1.

116

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5) Add 13.9 g of ethyl 2- (2-mesylamino-1,3-thiazol-4-yl) glyoxylate with stirring at room temperature to a solution of 5.0 g of sodium hydroxide in 150 ml of water. The mixture is stirred for 1 hour at room temperature, adjusted to pH 7 with concentrated hydrochloric acid and washed with 5 ethyl acetate. The aqueous phase is adjusted to pH 0.5 with concentrated hydrochloric acid to precipitate yellow crystals. The crystals are isolated by filtration, washed with water and dried to give 10.16 g of 2- (2-mesylamino-1,3-thiazol-4-yl) glyoxylic acid.

IR Spectrum (nujol): 3350, 1725 and 1650 cm

6) To a solution of 14 g of ethyl 2- (2-amino-1,3-thiazol-4-yl) acetate in a mixture of 40 g of pyridine and 300 ml of methylene chloride is gradually added 70 ml of a diethyl ether solution of chloroformic acid. tert.pentyl ester containing 0.35 mole of chloromyric acid tert.pentyl ester over 10 minutes at -20 ° C with stirring, and the mixture is stirred for 2 hours at the same temperature and stirred for an additional 1/2 hour at 0 ° C . After the reaction, the reaction mixture is poured into 200 ml of water and the organic phase is separated. The organic phase is washed with 2N hydrochloric acid, water, 5% aqueous sodium bicarbonate solution and water in sequence and then dried over magnesium sulfate. The solvent 20 is distilled off from the organic phase to give 12 g of a dark brown oil of ethyl 2- (2-tert.pentyloxycarbonylamino-1,3-thiazol-4-yl) acetate.

IR Spectrum (liquid): 1667 and 1660 (CO) cm -1.

NMR Spectrum (CDCl 3): δ - 3.75 (2H, s) and 6.75 (1H, s) ppm.

7) 0.3 g of ethyl 2- (2-tert.-pentyloxycarbonylamino-1,3-thiazol-4-yl) acetate and 0.11 g of selenium dioxide are treated in a similar manner as described in Preparation 1-4), to give 0.22 g of a brown oil of ethyl 2- (2-tert. pentyloxycarbonylamino-1,3-thiazol-4-yl) glyoxylate.

IR Spectrum (liquid): 1720 and 1690 (CO) cm - + -.

NMR Spectrum (CDCl 3): 6 - 8.3 (1H, s) ppm.

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8) 2.8 g of ethyl 2- (2-tert.-pentyloxycarbonylamino-1,3-thiazol-4-yl) glyoxylate and a solution of 0.54 g of sodium hydroxide in 20 ml of water are treated in a similar manner as described for preparation. 1-5) to give 1.75 g of a brown powder of 2- (2-tert.pentyloxycarbonylamino-1,3-thiazol-4-yl) glyoxylic acid.

IR Spectrum (nujol): 1730 and 1680 (CO) cm

NMR Spectrum (dg-dimethylsulfoxide): 6-8.4 (1H, s) ppm.

9) A mixture of 0.37 g of ethyl 2-hydroxyimino-2- (2-amino-1,3-thiazol-4-yl) acetate (a mixture of syn and anti-isomers), 5 ml of ethanol, 10 5 ml of water and 0.72 g of sodium bisulfite are stirred for 12 hours at 65-70 ° C.

The reaction mixture is evaporated and 10 ml of water are added to the residue.

The resulting mixture is desalted and extracted with ethyl acetate.

The extract is dried over magnesium sulfate and evaporated to give 0.18 g of ethyl 2- (2-amino-1,3-thiazol-4-yl) glyoxylate, yellow crystals, mp 115-120 ° C.

IR Spectrum (nujol): 3420, 3250, 3120, 1730, 1665 and 1612 cm · 1.

10) 235 ml of sulfuryl chloride are added dropwise over 20 minutes with stirring and ice-cooling to a solution of 500 g of ethyl 2-methoxyiminoacetoacetate (syn-isomer) in 500 ml of acetic acid, and the mixture is stirred overnight under cooling with water. Nitrogen gas is fed into the reaction mixture for 2 hours and the resulting mixture is poured into 2.5 liters of water. After extraction with 500 ml of methylene chloride and twice extraction with 200 ml of methylene chloride, the extracts are combined. The combined extracts are washed with a saturated aqueous solution of sodium chloride and adjusted to pH 6.5 by the addition of 800 ml of water and sodium bicarbonate. The methylene chloride phase is separated, washed with an aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was equilibrated to give 559 g of ethyl 2-methoxyimino-4-chloroacetoacetate (syn isomer).

IR Spectrum (film): 1735 and 1705 cm -1.

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118

Preparation 2 1) A mixture of 22.0 g of ethyl 2-hydroxyimino-4-bromoacetoacetate (a mixture of syn- and anti-isomers), 7.5 g of thioacetamide and 100 ml of benzene is refluxed for 3 hours. After cooling, 5 g of triethylamine was added and the mixture stirred for 1 hour. Insoluble material is filtered off and the filtrate is evaporated under reduced pressure to give 8.6 g of ethyl 2-hydroxyimino-2- (2-methyl-1,3-thiazol-4-yl) acetate (a mixture of syn- anti-isomers). This substance is subjected to column chromatography on 80 g of silica gel using benzene as a developing agent. First, the eluate containing the anti-isomer is isolated and evaporated to give 2.5 g of ethyl 2-hydroxyimino-2- (2-methyl-1,3-thiazol-4-yl) acetate (anti-isomer), mp 90-92 ° C.

IR Spectrum (nujol): 1720 cm '..

NMR Spectrum (d6-DMSO): δ - 12.55 (1H, s), 8.25 (1H, s), 4.27 (2H, q, J - 7Hz), 2.63 (3H, s) ) and 1.25 (3H, t, J - 7Hz) ppm.

After eluting the eluate containing the anti-isomer, the eluate containing the syn isomer is eluted and evaporated to give 0.5 g of ethyl 2-hydroxyimino-2- (2-methyl-1,3-thiazol-4-yl) acetate (syn-isomer), mp 134-136 ° C.

IR Spectrum (nujol): 1720 cm -1 NMR Spectrum (dg-DMSO): S - 11.81 (1H, s), 7.81 (1H, s), 4.35 (2H, q, J - 7Hz) ), 2.70 (3H, s) and 1.30 (3H, t, J - 7Hz) ppm.

2) 3 drops of phenolphthalein indicator are added to a solution of 4.2 g of hydroxylamine hydrochloride in 60 ml of dry methanol. To dissolve

The mixture is added dropwise with stirring at room temperature 60 ml IN

in methanolic solution of sodium methoxide until the color of the solution changes to bluish-red. The hydroxylamine hydrochloride is added in small portions until the solution becomes colorless. The mixture is stirred for 30 minutes at room temperature. After precipitation, the sodium chloride, 12.5 g of 2- (2-mesylamino-1,3-thiazol-4-yl) glyoxylic acid, is filtered off / MH / KW / HRA / KPJ / A26 / 1991 06 27 119

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is added to the filtrate and the mixture is refluxed with stirring for 1 1/2 hours. The reaction mixture is cooled to precipitate crystals. The crystals are isolated by filtration and dried to give 5.5 g of crude 2-hydroxyimino-2- (2-mesylamino-1,3-thiazol-4-yl) acetic acid (a mixture of syn and anti-isomers ). The filtrate is evaporated to 1/4 volume and ether is added. Precipitated crystals are isolated by filtration, washed with ether and dried to give 8.78 g of the same compound. Total yield 14.3 g.

3) A mixture of 2.4 g of ethyl 2-hydroxyimino-4-bromoacetoacetate (a mixture of syn and anti-isomers) and 0.76 g of thiourea in 15 ml of ethanol is stirred for 1 hour at 60 ° C. The ethanol is distilled off under reduced pressure and water is added to the residue. The resulting mixture is adjusted to pH 1.0 and washed with ethyl acetate. The aqueous phase is adjusted to pH 4.5 with triethylamine and extracted with ethyl acetate. The extract is washed with water and a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is subjected to column chromatography on silica gel using a mixture of ethyl acetate and benzene in the ratio of 1: 3 as the developing agent. The eluates containing syn isomers are isolated and evaporated to give 0.3 g of ethyl 2-hydroxyimino-2- (2-amino-1,3-thiazol-4-yl) acetate (syn isomer).

IR Spectrum (nujol): 3450, 3300, 3200, 1725 and 1620 cm cm ".

NMR Spectrum (CDCl3): S - 7.65 (1H, s), 5.33 (2H, broad s), 4.40 (2H, 25 q, J - 7.5Hz) and 1.38 (3H, t, J - 7.5Hz) ppm.

After collecting the eluates containing syn isomers, the eluates containing a mixture of syn and anti isomers are isolated and evaporated to give 0.3 g of ethyl 2-hydroxyimino-2- (2-amino-1,3- thiazol-4-yl) acetate (a mixture of syn and anti-isomers).

IR Spectrum (nujol): 3400, 3300, 3200, 1715 and 1620 cm

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120 NMR Spectrum (d6-DMSO): S - 12.42 (1H, broad s), 11.55 (1H, s), 7.52 (1H, s), 7.12 (4H, broad s), 6.83 (1H, s), 4.23 (4H, m) and 1.26 (6H, m) ppm.

4) A solution of 1.1 g of ethyl 2-hydroxyimino-2- (2-amino-1,3-thiazol-5-yl) acetate (a mixture of syn and anti-isomers) in 15 ml of 1 N aqueous sodium hydroxide solution is allowed to stand for 2 hours at room temperature. The reaction mixture is adjusted to pH 3.5 with 10% hydrochloric acid and precipitated crystals are isolated by filtration, washed with acetone and dried to give 0.52 g of 2-hydroxyimino-2- (2-amino-1,3). -thiazol-10-yl) acetic acid (a mixture of syn and anti-isomers), mp 184-186 ° C (dec.).

IR Spectrum (nujol): 3200, 1670 and 1530 cnT

Preparation 3 1) 3.8 g of thioacetamide is added to a solution of 12.6 g of ethyl 2- methoxyimino-4-bromoacetoacetate (a mixture of syn and anti-isomers) in 50 ml of ethanol and the mixture is stirred for 5 hours. at 50 ° C. The ethanol is distilled off under reduced pressure and water is added to the residue.

The resulting mixture is extracted with ethyl acetate. The extract is washed with water, an aqueous sodium hydroxide solution and a saturated aqueous sodium chloride solution in this order and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to give 9.0 g of ethyl 2-methoxyimino-2- (2-methyl-1,3-thiazol-4-yl) acetate (a mixture of syn and anti-isomers).

2) A mixture of 7.6 g of ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of syn and anti-isomers), 3.0 g of O-ethylthiocarbamate and 5 ml of dimethylacetamide is stirred for 3 hours at 50 ° C. . 50 ml of ethyl acetate is added to the reaction mixture and the resulting mixture is washed with water and with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The ethyl acetate is distilled off to give a crystalline residue. The residue is washed with diisopropyl ether to give 2.35 g of ethyl 2-methoxyimino-2- (2-oxo-2,3-dihydro-1,3-thiazol-4-yl) acetate (syn isomer).

IR Spectrum (nujol): 3200, 1735, 1680 and 1650 cm cm ".

121

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NMR Spectrum (CDCl 3): S - 9.13 (1H, broad s), 6.37 (1H, s), 4.40 (2H, q, J - 6Hz), 4.01 (3H, s) and 1.38 (3H, t, J * 6Hz) ppm.

The mother liquor of diisopropyl ether is evaporated and the residue is subjected to 5 column chromatography on 70 g of silica gel using a mixture of benzene and ethyl acetate in the ratio of 9: 1 as the developing agent.

The eluate containing the syn isomer is isolated and evaporated to give an additional 0.65 g of the syn isomer obtained in the manner described above. Total yield 3.0 g. A mixture of 10 benzene and ethyl acetate in the ratio of 5: 1 is then used as the developing agent. The eluate containing the anti-isomer is isolated and evaporated to give 0.26 g of ethyl 2-methoxyimino-2- (2-oxo-2,3-dihydro-1,3-thiazol-4-yl) acetate (anti-isomer) ).

IR Spectrum (nujol): 3250, 3200, 1720 and 1690 cm cm *.

NMR Spectrum (CDCl 3): i - 9.90 (1H, broad s), 7.30 (1H, s), 4.40 (2H, q, J - 6Hz), 4.03 (3H, s) and 1.38 (3H, t, J - 6Hz) ppm.

3) A solution of 17.4 g of ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of syn- and anti-isomer) and 5.4 g of thiourea in 100 ml of ethanol is refluxed for 4 hours. The reaction mixture 20 is left to stand and cooled in a refrigerator to precipitate crystals.

The crystals are isolated by filtration, washed with ethanol and dried to give 9.5 g of ethyl 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetate hydrobromide (anti-isomer). The filtrates and washings are poured and evaporated under reduced pressure. 100 ml of water are added to the residue and the mixture is washed with ether. The aqueous phase is adjusted to basic reaction with a 28% aqueous solution of ammonia and extracted with ethyl acetate. The extract is washed with water and a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to give 5.2 g of a crystalline substance of ethyl 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetate (syn isomer).

IR Spectrum (nujol): 3400, 3300, 3150, 1725, 1630 and 1559 cm -1.

122

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NMR Spectrum (CDCl 3): δ 6.72 (1H, s), 5.91 (2H, broad s), 4.38 (2H, q, J - 7Hz), 4.03 (3H, s) and 1.38 (3H, t, J - 7Hz) ppm.

9.5 g of the ethyl-2-methoxyimino-5-2- (2-amino-1,3-thiazol-4-yl) acetate hydrobromide (anti-isomer) obtained in the above-described manner are suspended in 200 ml. ml of ethyl acetate and 4.0 g of triethylamine are added.

After stirring for 1 hour at room temperature, insoluble material is filtered off and the filtrate is evaporated under reduced pressure to give 6.15 g of a crystalline substance of ethyl 2-methoxyimino-2- (2-10 amino-1,3-thiazole 4-yl) acetate (anti-isomer).

IR Spectrum (nujol): 3450, 3250, 3150, 1730 and 1620 cm

NMR Spectrum (CDCl 3): δ ~ 7.50 (1H, s), 5.60 (2H, broad s), 4.35 (2H, q, J - 7Hz), 4.08 (3H, s) and 1.33 (3H, t, J = 7Hz) ppm.

4) 3 drops of phenolphthalein indicator are added to a solution of 1.25 g of O-methylhydroxylamine hydrochloride in 15 ml of dry methanol. To the solution is added dropwise with stirring at room temperature 13 ml of 1N methanolic solution of sodium methoxide until the color of the solution changes to bluish-red. The o-methylhydroxylamine hydrochloride is added in small portions until the solution becomes colorless. The mixture is stirred for 30 minutes at room temperature. After filtration of precipitated sodium chloride, 3.8 g of ethyl 2- (2-mesylamino-1,3-thiazol-4-yl) glyoxylate is added to the filtrate and the mixture is refluxed under stirring for 2 hours. After distilling off the methanol, the residue is dissolved in ethyl acetate. Insoluble material is filtered off and the filtrate is evaporated. The residue is subjected to column chromatography on silica gel using a benzene-ethyl acetate 9: 1 mixture as a developing agent. The eluate containing the syn isomer is isolated and evaporated to give 2.8 g of ethyl 2-methoxyimino-2- (2-mesylamino-1,3-thiazol-4-yl) acetate (syn isomer).

IR Spectrum (nujol): 1725 cm -1.

m DK 162391 B

NMR Spectrum (CDCl3): S - 6.76 (1H, s), 4.44 (2H, q, J - 7Hz), 4.04 (3H, s), 3.04 (3H, s) and 1 , 37 (3H, t, J - 7Hz) ppm.

5) 0.33 g of powdered potassium carbonate is suspended in a solution of 0.5 g of ethyl 2-hydroxyimino-2- (2-methyl-1,3-thiazol-4-yl) acetate (syn isomer) in 20 ml acetone. A solution of 0.3 g of dimethyl sulfate in 5 ml of acetone is added dropwise with stirring at 40-45 ° C. After stirring for 2 hours at the same temperature, insoluble material is filtered off. The filtrate is evaporated and water is added to the residue. The resulting mixture is extracted with ethyl acetate. The extract is washed with water, aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution in the order given and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to give 0.5 g of a light yellow oil of ethyl 2-methoxyimino-2- (2-methyl-1,3-thiazol-4-yl) acetate (syn isomer).

IR Spectrum (film): 1740, 1710 and 1595 cm -1.

NMR Spectrum (CDCl 3): S - 7.40 (1H, s), 4.25 (2H, q, J - 7Hz), 4.03 (3H, s), 2.73 (3H, s) and 1 , 38 (3H, t, J - 7Hz) ppm.

6) 14.3 g of 2-hydroxyimino-2- (2-mesylamino-1,3-thiazol-4-yl) acetic acid (a mixture of synthetic and anti-isomers) prepared in Preparation 2-2) , is suspended in 300 ml of dry acetone. To the suspension are added 22.8 g of potassium carbonate and 20.8 g of dimethyl sulfate. The mixture is refluxed with stirring for 9 hours. The acetone is distilled off from the reaction mixture and water is added to the residue. The resulting mixture is extracted with ethyl acetate. The extract is washed with an aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off to give 13 g of an oil. The oil is subjected to column chromatography on silica gel using a benzene-ethyl acetate 9: 1 mixture as a developing agent. The eluate containing the anti-isomer is first eluted, isolated and evaporated. 2.4 g of the oil recovered as the residue is triturated with cooling to crystallize. The crystals are isolated by filtration by the addition of petroleum ether to give 2.1 g of methyl 2-methoxyimino-2- (2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl) ) acetate (anti-isomer).

IR spectrum (nujol); 1740 cm "

124 DK 162391 B

MRI Spectrum (CDCl3): δ - 7.90 (1H, s), 4.10 (3H, s), 3.90 (3H, s), 3.47 (3H, s) and 3.07 (3H) , s) ppm.

After eluting the eluate containing the anti-isomer, eluate 5 containing the syn isomer is isolated and evaporated to give 5.5 g of crystals of methyl 2-methoxyimino-2- (2-mesylimino-3-methyl-2,3). -dihydro-1,3-thiazol-4-yl) acetate (syn-isomer).

IR Spectrum (nujol): 1740 cm -1 MR Spectrum (CDCl3): δ - 6.72 (1H, s), 4.05 (3H, s), 3.92 (3H, s), 3.72 (3H, s) and 3.01 (3H, s) ppm.

7) The compound listed below is prepared in a similar manner as described in Preparation 3-4):

Ethyl 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetate (syn isomer).

IR Spectrum (nujol): 3400, 3300, 3150, 1725, 1630 and 1559 cm -1 MR Spectrum (CDCl3): δ - 6.72 (1H, s), 5.91 (2H, broad s), 4 , 38 (2H, q, J - 7Hz), 4.03 (3H, s) and 1.38 (3H, t, J - 7Hz) ppm.

8) A mixture of 6.1 g of acetic anhydride and 2.8 g of formic acid is stirred for 2 hours at 50 ° C. The resulting mixture is cooled and at 15 ° C 4.6 g of ethyl 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetate (syn isomer) are added. After stirring the mixture for 3 1/2 hours at room temperature, 100 ml of cooled water is added. The resulting mixture is extracted with 200 ml of ethyl acetate. The extract is washed with water and then with a saturated aqueous solution of sodium bicarbonate until the washing liquids change to slightly alkaline solution. The extract 25 is further washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent is distilled off and the residue washed with diisopropyl ether, isolated by filtration and dried to give 4.22 g of ethyl 2-methoxyimino-2- (2-formamido-1,3

125 DK 162391 B

thiazol-4-yl) acetate (syn isomer), mp 122-124 ° C (dec.).

IR Spectrum (nujol): 3150, 1728 and 1700 cm cm 1.

NMR Spectrum (CDCl 3): S - 12.58 (1H, broad s), 8.95 (1H, s), 7.17 (1H, 5 s), 4.42 (2H, q, J - 8Hz) , 4.00 (3H, s), 1.37 (3H, t, J - 8Hz) ppm.

9) 3 g of pyridine are added to a solution of 6.5 g of ethyl 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetate (syn isomer) in a mixture of 60 ml of ethyl acetate and 20 ml of dimethylformamide. To the solution, 8 g of chloromyric acid ethyl ester are added dropwise with stirring at 4 ° C. After adding 10 ml of water to the reaction mixture, the organic phase is separated, washed with water and then with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent is distilled off under reduced pressure. The residue is subjected to column chromatography on 120 g of silica gel using a 5: 2 ether / petroleum ether mixture as eluent to give 5.4 g of ethyl 2-methoxyimino-2- (2-ethoxycarbonylamino-1,3-thiazole) -4-yl) acetate (syn-isomer).

NMR Spectrum (CDCl 3): δ - 9.36 (1H, broad s), 7.10 (1H, s), 4.00-4.66 (4H, m), 4.00 (3H, s) and 1.20-1.60 (6H, m) ppm.

10) 50 g of ethyl 2-methoxyimino-4-chloroacetoacetate (syn isomer) is added over 3 minutes with stirring at room temperature to a solution of 18.4 g of thiourea and 19.8 g of sodium acetate in a mixture of 250 ml. methanol and 250 ml of water. After stirring for 35 minutes at 40-45 ° C, the reaction mixture is cooled with ice and adjusted to pH 25 6.3 with a saturated aqueous solution of sodium bicarbonate. After stirring for 30 minutes at the same temperature, precipitated material is isolated by filtration, washed with 200 ml of water and then with 100 ml of diisopropyl ether and dried to give 37.8 g of colorless crystals of ethyl 2-methoxyimino-2- (2-amino) -1,3-thiazol-4-yl) acetate (syn-isomer), mp 161-162 ° C.

IR Spectrum (nujol): 3400, 3300, 3150, 1725, 1630 and 1559 cm -1.

DK 162391 B

126 NMR Spectrum (CDCl 3): δ - 6.72 (1H, s), 5.91 (2H, broad s), 4.38 (2H, q, J - 7Hz), 4.03 (3H, s) and 1.38 (3H, t, J - 7Hz) ppm.

11) 0.3 g of ethyl 2-hydroxyimino-2- (2-methyl-1,3-thiazol-4-yl) acetate (anti-isomer) and 0.18 g of dimethyl sulfate are reacted in a similar manner to that described in preparation 3-5) to give 0.27 g of a light yellow oil of ethyl 2-methoxyimino-2- (2-methyl-1,3-thiazol-4-yl) acetate (anti-isomer).

IR Spectrum (film): 1750 and 1605 cm -1, NMR Spectrum (CDCl 3): δ - 8.07 (1H, s), 4.41 (2H, q, J - 7Hz), 4.13 (3H, s), 2.75 (3H, s) and 1.40 (3H, t, J - 7Hz) ppm.

12) The compound listed below is prepared in a similar manner as described in Preparation 3-8):

Ethyl 2-methoxyimino -2- (2-formamido -1,3-thiazol-4-yl) acetate (anti-isomer), m.p. 96-99 "G (dec.).

IR Spectrum (nujol): 3150, 1740, 1650 and 1600 cm cm *.

NMR Spectrum (CDCl 3): δ - 11.20 (1H, broad s), 8.60 (1H, s), 7.90 (1H, s), 4.32 (2H, q, J - 8Hz), 4.13 (3H, s) and 1.32 (3H, t, J - 8Hz) ppm.

Preparation 4

1) 10 ml of ethanol is added to a suspension of 2.2 g of ethyl 2-methoxy-imino-2- (2-amino-1,3-thiazol-4-yl) acetate (syn isomer) in 12 ml of 1N

aqueous sodium hydroxide solution and the mixture is stirred for 15 hours at room temperature. The reaction mixture is adjusted to pH 7.0 with 10% hydrochloric acid and the ethanol is distilled off under reduced pressure.

The aqueous solution obtained as the residue is washed with ethyl acetate, adjusted to pH 2.8 with 10% hydrochloric acid and stirred under ice-cooling to precipitate crystals. The crystals are isolated by filtration, washed with acetone and recrystallized from ethanol, thereby

DK 162391B

127 g of colorless needles of 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetic acid (syn isomer) are obtained.

IR Spectrum (nujol): 3150, 1670, 1610 and 1585 cm -1.

NMR Spectrum (d6-DMSO): δ - 7.20 (2H, broad s), 6.85 (1H, s) and 3.83 δ (3H, s) ppm.

2) 1.5 ml of 1N aqueous solution of sodium hydroxide are added to a solution of 0.3 g of ethyl 2-methoxyimino-2- (2-methyl-1,3-thiazol-4-yl) acetate (syn isomer) ) in 5 ml of ethanol and the resulting mixture is stirred for 2 hours at 40 ° C. The reaction mixture is adjusted to pH 7.0 with 10% hydrochloric acid, evaporated under reduced pressure, adjusted to pH 1.5 with 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed with water and a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off to give 0.14 g of a crystalline substance of 2-methoxyimino-2- (2-methyl-1,3-thiazol-4-yl) acetic acid (syn isomer).

IR spectrum (nujol): 1730 cm cm ".

NMR Spectrum (d6-DMSO): S - 7.80 (1H, s), 3.85 (3H, s) and 2.62 (3H, s) ppm.

3) The compounds listed below are prepared in a similar manner as described for Preparations 4-1) to 4-2): 1) 2-Methoxyimino-2- (2-oxo-2,3-dihydro-1,3-thiazole-1 4-yl) acetic acid (syn-isomer).

IR Spectrum (nujol): 3250, 1710 and 1650 cm

NMR Spectrum (d6-DMSO): S - 10.61 (1H, broad s), 6.73 (1H, s) and 3.95 (3H, s) ppm.

2) 2-Methoxyimino-2- (2-mesylamino-1,3-thiazol-4-yl) acetic acid (syn isomer).

IR Spectrum (nujol): 3150 and 1720 cm "·.

128

DK 162391 B

NMR Spectrum (d 6 -DMSO): S - 7.17 (1H, s), 3.93 (3H, s) and 3.02 (3H, s) ppm.

3) 2-Methoxyimino-2- (2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-5 yl) acetic acid (syn-isomer).

IR spectrum (nujol): 1730 cm cm ".

4) 2-Methoxyimino-2- (2-formamido-1,3-thiazol-4-yl) acetic acid (syn isomer), mp 152 ° C (dec.).

IR Spectrum (nujol): 3200, 2800-2100, 1950 and 1600 cm cm *.

NMR Spectrum (d 6 -DMSO): S = 8.60 (1H, s), 7.62 (1H, s), and 3.98 (1H, s) ppm.

5) 2-Methoxyimino-2- (2-ethoxycarbonylamino-1,3-thiazol-4-yl) acetic acid (syn isomer).

IR Spectrum (nujol): 3200, 1730, 1710, 1690 and 1570 cm cm ·.

NMR Spectrum (d 6 -DMSO): δ = 12.16 (1H, broad s), 7.50 (1H, s), 7.20 (1H, broad s), 4.25 (2H, q, J - 7Hz), 3.93 (3H, s) and 1.25 (3H, t, J + = 7Hz) ppm.

4) 5 ml of pyridine are added to a suspension of 2.0 g of 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetic acid (syn isomer) in 20 ml of ethyl acetate. A solution of 2.5 g of bis (2,2,2-trifluoroacetic acid) aryhydride in 3 ml of ethyl acetate is added dropwise with stirring at 5-7 ° C and the mixture is stirred for 30 minutes at 3-5 ° C. 30 ml of water are added to the reaction mixture and the ethyl acetate phase is separated. The aqueous phase 1 is further extracted with ethyl acetate and the two ethyl acetate phases are combined, washed with water and a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to give 0.72 g of 2-methoxyimino-2-

129 DK 162391 B

[2- (2,2,2-Trifluoroacetamido) -1,3-thiazol-4-ylacetic acid (syn isomer), IR Spectrum (nujol): 1725 and 1590 cm cm ".

NMR Spectrum (d 6 -DMSO): S - 7.68 (1H, s) and 3.91 (3H, s) ppm.

5) The compound listed below is prepared in a similar manner as described for Preparation 4-4): 2-Methoxyamino-2- (2-acetamido-1,3-thiazol-4-yl) acetic acid (syn isomer), m.p. 184 -185 ° C (decomposition).

IR Spectrum (nujol): 3200, 3050, 1695 and 1600 crn.

6) 3 drops of phenolphthalein indicator are added to a solution of 0.84 g of O-allyl hydroxylamine hydrochloride in 10 ml of dry methanol. To the solution is added dropwise with stirring at room temperature 6 ml of 1N methanolic solution of sodium methoxide until the color of the solution changes to pink. O-Allyl hydroxylamine hydrochloride is added in small portions until the solution becomes colorless. The mixture is stirred for 30 minutes at room temperature. After precipitation, sodium chloride, 2.0 g of 2- (2-tert.-pentyloxycarbonylamino-1,3-thiazol-4-yl) -glyoxylic acid, is filtered off and the mixture is stirred for 1 hour at room temperature. After distilling off the methanol at low temperature, the residue is dissolved in 1N aqueous solution of sodium hydroxide. The solution is washed with ether and ethyl acetate is added. The mixture is adjusted to pH 1.5 with phosphoric acid and extracted with ethyl acetate. The extract is washed with an aqueous sodium chloride solution and dried over magnesium sulfate. The ethyl acetate is distilled off and the residue is washed with diisopropyl ether, isolated by filtration and dried to give 1.62 g of 2-allyloxyimino-2- (2-tert.pentyloxycarbonylamino-1,3-thiazol-4-yl) acetic acid (syn isomer), IR Spectrum (nujol): 3200 and 1712 cnT

130

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NMR Spectrum (d 6 -DMSO): δ - 7.40 (1H, s), 6.24-5.76 (1H, m), 5.26 (2H, dd, J - 9, 10Hz), 4, 65 (2H, d, J - 5Hz), 1.78 (2H, q, J - 8Hz), 1.44 (6H, s) and 0.88 (3H, t, J - 8Hz) ppm.

7) The compounds listed below are prepared in a similar manner as described for Preparation 4-6): 1) 2-Methoxyimino-2- (2-tert.pentyloxycarbonylamino-1,3-thiazol-4-yl) acetic acid (syn isomer) ).

IR Spectrum (nujol): 3200 and 1712 cm "·.

NMR Spectrum (d 6 -DMSO): δ - 7.40 (1H, s), 3.88 (3H, s), 1.77 (2H, q, 10 J - 8Hz), 1.44 (6H, s) ) and 0.88 (3H, t, J - 8Hz) ppm.

2) 2-Allyloxyimino-2- (2-mesylamino-1,3-thiazol-4-yl) acetic acid (syn isomer).

IR Spectrum (nujol): 3150, 1710 and 1605 cm

3) 2-Methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetic acid (syn-isomer).

IR Spectrum (nujol): 3150, 1670, 1610 and 1585 cm

NMR Spectrum (d 6 -DMSO): δ - 7.20 (2H, broad s), 6.85 (1H, s) and 3.83 (3H, s) ppm.

8) 15.5 g of ethyl 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetate-20 hydrobromide (anti-isomer) are dissolved in a solution of 4.4 g of sodium hydroxide in 150 ml of water and the resulting solution is stirred for 1 hour at room temperature. Insoluble material is filtered off and the filtrate is adjusted to pH 5.0 to precipitate crystals. The crystals are isolated by filtration and dried to give 8.0 g of 2-methoxyimino-2- (2-amino-1,3-thiazol-4-yl) acetic acid (anti-isomer).

IR Spectrum (nujol): 3150, 1655, 1595 and 1550 cm cm ".

DK 162391 B

131 NMR Spectrum (d 6 -DMSO): S - 7.53 (1H, s), 7.23 (2H, broad s), and 3.99 (3H, s) ppm.

9) The compounds listed below are prepared in a similar manner as described for Preparation 4-8): 5 1) 2-Methoxyimino-2- (2-methyl-1,3-thiazol-4-yl) acetic acid (anti-isomer).

IR Spectrum (nujol): 1730 and 1590 crn

NMR Spectrum (d6-DMSO): S - 8.10 (1H, s), 4.00 (3H, s) and 2.65 (3H, s) ppm.

2) 2-Methoxyimino-2- (2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl) acetic acid (anti-isomer).

IR Spectrum (nujol): 1730 cm * 3) 2-Methoxyimino -2- (2-formamido-1,3-thiazol-4-yl) acetic acid (anti-isomer), mp 156-158 ° C (dec.) .

IR Spectrum (nujol): 3200, 2700-2100, 1690, 1590 and 1560 cm

NMR Spectrum (d 6 -DMSO): S - 8.05 (1H, s) and 4.02 (3H, s) ppm.

Preparation 5

To a solution of 30 g of 2- (2-formamidothiazol-4-yl) glyoxylic acid and 12.6 g of sodium bicarbonate in 1300 ml of water is added 19.8 g of allyloxyamine-hydrochloride and the mixture is stirred for 7 hours at room temperature and pH 6. Add 500 ml of ethyl acetate to the reaction mixture. After the mixture is adjusted to pH 1.9 with 10% hydrochloric acid, the ethyl acetate phase is separated. The ethyl acetate phase is washed with an aqueous sodium chloride solution and dried over magnesium sulfate and then the solvent is evaporated. The residue is pulverized in diisopropyl acid.

DK 162391 B

132 ether, isolated by filtration and then dried to give 25.3 g of 2-allyloxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer).

IR Spectrum (nujol): 3110, 1730, 1660 and 1540 cm -1.

NMR Spectrum (d 6 -DMSO): δ (ppm) - 4.70 (2H, m), 5.13-5.60 (2H, m), δ 5.73-6.27 (1H, m), 7.57 (1H, s), 8.35 (1H, s).

Preparation 6 1) 35.2 g of sulfuryl chloride are added at room temperature at once to a stirred solution of 48.9 g of ethyl 2-ethoxyimino-3-oxobutyrate (syn isomer) in 49 ml of acetic acid and stirred at 1 10 hours. After adding the resulting solution to 200 ml of water, the solution is extracted with methylene chloride. The extract is washed with a saturated aqueous sodium chloride solution, neutralized with an aqueous sodium bicarbonate solution, and washed with water. The solution is dried over magnesium sulfate and evaporated under reduced pressure to give 53.8 g of ethyl 2-ethoxyimino-3-oxo-4-chlorobutyrate (syn isomer) as a pale yellow oil.

2) A mixture of 38.7 g of ethyl 2-ethoxyimino-3-oxo-4-chlorobutyrate (syn isomer), 13.2 g of thiourea, 14.3 g of sodium acetate, 95 ml of methanol and 95 ml of water is stirred at 48 ° C for 40 minutes. After the resulting solution is adjusted to pH 6.5 with an aqueous sodium bicarbonate solution, precipitates are obtained which are isolated by filtration and washed with diisopropyl ether to give 14.7 g of ethyl 2-ethoxyimino-2- (2). -aminothiazol-4-yl) acetate (syn-isomer), m.p. 130-131 ° C.

in IR spectrum (nujol): 3450, 3275, 3125, 1715 and 1620 cm cm ·.

3) 5 g of ethyl 2-ethoxyimino-2- (2-aminothiazol-4-yl) acetate (syn isomer) are added to a mixture of 45.9 ml of 1N sodium hydroxide solution and 30 ml of ethanol and stirred at room temperature for 5 hours. After evaporation of the ethanol from the resulting solution under reduced pressure, the residue is dissolved in 60 ml of water and adjusted to pH 2.0 with 133

DK 162391 B

10% hydrochloric acid. The solution is salted and the precipitated material is isolated by filtration and dried to give 2.9 g of 2-ethoxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer).

IR Spectrum (nujol): 3625, 3225 (shoulder), 3100, 1650 and 1615 cm cm ".

NMR Spectrum (dg-DMSO): δ (ppm) - 1.20 (3H, t, J - 7Hz), 4.09 (2H, q, J - 7Hz), 6.82 (1H, s), 7.24 (2H, broad s).

4) 100 g of 2-ethoxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer), 85.5 g of formic acid and 190.1 g of acetic anhydride are treated in the same manner as in Preparation 4-4) to give 99.1 g of 2-ethoxy-10-imino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer).

IR Spectrum (nujol): 3200, 3140, 3050 and 1700 cm

NMR Spectrum (d6-DMSO): δ (ppm) - 1.18 (3H, t, J - 6Hz), 4.22 (2H, q, J - 6Hz), 7.56 (1H, s), δ , 56 (1H, s), 12.62 (1H, broad s).

Preparation 7 The following compounds are prepared in a similar manner to Preparations 5 and 6.

IR Spectrum (nujol): 3170, 3070, 1720, 1700 and 1660 cm

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134 NMR Spectrum (d 6 -DMSO): δ (ppm) - 0.6-2.1 (11H, m), 4.15 (2H, t, J = 6Hz), 7.53 (1H, s), 8.56 (1H, s), 12.69 (1H, s).

4) 2-Pentyloxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer), m.p. 176 ° C (dec.).

IR spectrum (nujol): 3160, 1655, 1620 and 1460 cm

NMR Spectrum (d 6 -DMSO): δ (ppm) = 7.20 (2H, s), 6.82 (1H, s), 4.07 (2H, t, J - 6Hz), 0.6-2 , 2 (9H, m).

5) 2-Propoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer), mp 164 ° C (dec.).

IR Spectrum (nujol): 3200, 3120, 3050, 1700 and 1550 cm cm ".

6) 2-Pentyloxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer), mp 125 ° C (dec.).

IR Spectrum (nujol): 3200, 3140, 1700 and 1565 cm

7) 2-Allyloxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer), m.p. 187 ° G (dec.).

IR Spectrum (nujol): 3350, 1630, 1580 and 1460 crn

8) 2-Hexyloxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer), mp 174 ° G (dec.).

IR Spectrum (nujol): 1660, 1625 and 1425 cm cm ·.

9) 2-Isopropoxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer), mp 151 ° C (dec.).

10) 2 -1 s of obutoxy imino -2- (2-amino thiazol-4-yl) acetic acid (syn isomer), mp 122-124 ° C.

DK 162391 B

11) 2-Propoxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer), mp 161 ° C (dec.).

12) 2-Isobutoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer), mp 163 ° C (dec.).

Preparation 8 1) Add 500 ml of water to 490.0 g of hexylamine and add, under ice-cooling and stirring, a solution of 193.6 g of sodium hydroxide in 700 ml of water. 367.8 g of carbon disulfide is added dropwise over 2 hours at 2-10 ° C and then dropwise added at 0-5 ° C 687.3 g of methyl iodide over 1 hour 10. The resulting mixture is stirred for 30 minutes at the same temperature and for 2 hours at room temperature. The reaction mixture is extracted with 1.5 liters of diethyl ether. The extract is washed with 300 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to give 825.5 g of thyme-N-hexyldi-15 thiocarbamate as an oil.

IR Spectrum (film): 3225, 2960, 2935 and 2860 cm cm ·.

NMR Spectrum (CDCl3): δ (ppm) - 0.86 (3H, t, J - 5.0Hz), 1.10 δ 1.90 (8H, m), 2.58 (3H, s), δ , 72 (2H, m).

2) 155.9 g of sodium azide and 0.8 liter of water are added with stirring to a solution of 430 g of methyl N-hexyldithiocarbamate in 1.7 liters of ethanol and the resulting mixture is refluxed for 3.5 hours at 90 ° C.

Ethanol is distilled off from the reaction mixture and the residue is washed with 1 liter of diethyl ether, adjusted to pH 2.0 with concentrated hydrochloric acid and extracted with 1 liter of diethyl ether. The extract is washed with water, dried over magnesium sulfate and evaporated to give 431.3 g of 1-hexyl-1H-tetrazole-5-thiol in the form of an oil.

IR Spectrum (film): 3110, 2960, 2930 and 2860 cm

NMR Spectrum (CDCl 3): δ (ppm) - 0.91 (3H, t, J - 5.0Hz), 1.10 δ 1.65 (6H, m), 1.97 (2H, m), δ , 33 (2H, t, J = 7.0Hz).

DK 162391 B

136 3) To 150.0 g of 7-aminocephalosporanoic acid is added 3 liters of 0.2 M phosphate buffer solution prepared by dissolving 62.1 g of sodium biphosphate dihydrate and 25.5 g of disodium hydrogen phosphate in 3 liters of water, and the resulting mixture adjusted to pH 6.5 with a 5 2N aqueous sodium carbonate solution. To the mixture is added 154.6 g of 1-hexyl-1H-tetrazole-5-thiol, and the resulting mixture is stirred for 2 hours at 60-65 ° C and at pH 6.0-6.5 with nitrogen bubbling. The reaction mixture is adjusted to pH 3.5 with concentrated hydrochloric acid under ice-cooling. The precipitate is isolated by filtration and washed with water, and 4 liters of methanol and 400 ml of concentrated hydrochloric acid are added. The mixture is stirred for 2 hours and an insoluble material is filtered off. The filtrate is treated with activated charcoal and adjusted to pH 3.5 with a 28% ammonia solution. The precipitate is isolated by filtration, washed with water, acetone and diethyl ether in the above order and dried to give 116.38 g of 7-amino-3- (1-hexyl-1H-tetrazol-5-yl) thiomethyl-3-cephem -4-carboxylic acid in the form of a powder.

IR Spectrum (nujol): 1803, 1620 and 1350 cm

NMR Spectrum (dg-DMSO): δ (ppm) - 0.95 (3H, t, J - 6.5Hz), 1.26 (6H, 20 m), 1.80 (2H, m), 3, 65 (2H, ABq, J - 18Hz), 4.00 = 4.50 (4H, m), 4.79 (1H, d, J - 6.0Hz), 4.95 (1H, d, J - 6 , 0Hz).

Preparation 9 283.0 g of 7-aminocephalosporanoic acid and 225.0 g of 1-propyl-1H-tetrazol-5-thiol are treated in 5.5 liters of 0.2M phosphate buffer solution in a similar manner to Preparation 8-3) to give 125 0 g of 7-amino-3- (1-propyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid.

IR Spectrum (nujol): 3300, 1795 and 1610 cm

NMR Spectrum (dg-DMSO): δ (ppm) - 0.91 (3H, t, J - 7.5Hz), 1.60 * 2.28 (2H, m), 3.63 (2H, ABq, J - 18.0Hz), 3.98 ° 4.58 (4H, m), 5.08 (1H, d, J - 5.0Hz), 5.49 (1H, d, J - 5.0Hz) .

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137

Preparation 10 1) Add 3.7 g of 3-chlorophenyl isocyanate at room temperature to a solution of 10.3 g of benzhydryl 7- (2-phenylacetamido) -3-hydroxymethyl-3-cephem-4-carboxylate in a mixture of 200 ml of tetrahydrofuran and 2.4 g of triethylamine, and the mixture is stirred for 1 hour. The reaction mixture is evaporated under reduced pressure. The residue is dissolved in 200 ml of ethyl acetate and the solution is washed with 10% hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution in the above order to give a solution containing a mixture of benzhydryl-7- (2). -phenylacetamido) -3- [N- (3-chlorophenyl) carbamoyloxymethyl] -3-cephem-4-carboxylate and benzhydryl-7- (2-phenylacetamido) -3- [N- (3-chlorophenyl) carbamoyloxymethyl] -2- cephem-4-carboxylate.

2) To the ethyl acetate solution obtained above is added dropwise at 7-10 ° C a solution of 5.2 g of 3-chloroperbenzoic acid in ethyl acetate and the mixture is stirred for 1 hour at the same temperature. The precipitated precipitate is isolated by filtration, washed with diethyl ether and dried to give 7.7 g of benzhydryl-7- (2-phenylacetamido) -3- [N- (3-chlorophenyl) carbamoyloxymethyl] -3-cephem-4 carboxylate 1-oxide.

IR Spectrum (nujol): 3280, 1790, 1700, 1650, 1600 and 1530 cm -1.

3) 3.2 g of phosphorus trichloride is added at -40 ° C to a stirred solution of 7.6 g of benzhydryl-7- (2-phenylacetamido) -3- [N- (3-chlorophenyl) carbamoyl oxymethyl] -3-cephem -4-carboxylate-1-oxide in 50 ml of dimethylformamide and the mixture is stirred for 1 hour at -20 - -40 ° C. The reaction mixture is poured into cooled water. The precipitated material is isolated by filtration, washed with water and dried to give 5.0 g of benzhydryl-7- (2-phenylacetamido) -3- [N- (3-chlorophenyl) carbamoyloxymethyl] -3-cephem-4-carboxylate.

IR Spectrum (nujol): 3280, 3190, 1780, 1730, 1710, 1660, 1620, 1600 and 1540 cm -1 NMR Spectrum (dg-DMSO): δ (ppm) - 3.56 (2H, s), 3.64 (2H, s), 4.86 (2H, ABq, J - 12Hz), 5.14 (1H, d, J - 5Hz), 5.76 (1H, dd, J - 5) and

138 DK 162391 B

8Hz), 6.95 (1H, s), 7.00 * 7.70 (19H, m), 9.10 (1H, d, J - 8Hz), 10.00 (1H, s).

4) 1.9 g of pyridine is added at 5 ° C to a solution of 4.93 g of phosphorus pentachloride in 50 ml of methylene chloride and the suspension is stirred for 30 minutes at room temperature. To the reaction mixture is added at 5 ° C

5.0 g of benzhydryl 7- (2-phenylacetamido) -3- [N- (3-chlorophenyl) carbamoyl-oxymethyl] -3-cephem-4-carboxylate and stir for 1.5 hours at 5-7 ° C to give a homogeneous solution. The above solution is cooled to -30 ° C and 8 ml of methanol is added. After the solution is stirred for 1 hour at -10 - -20 ° C, 5 ml of water is added and stirring is continued for 30 minutes at 0-5 ° C. After evaporation of the solvent under reduced pressure, 80 ml of water and 100 ml of diethyl ether are added to the residue and the aqueous phase containing oil is separated. The aqueous solution containing oil is adjusted to pH 8.0 with 20% aqueous sodium carbonate solution and extracted with ethyl acetate. The extracts are washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue is pulverized with diisopropyl ether to give 2.2 g of benzhydryl-7-amino-3- [N- (3-chlorophenyl) carbamoyl-oxymethyl] -3-cephem-4-carboxylate.

IR Spectrum (nujol): 3410, 3360, 1760, 1700, 1650, 1595 and 1520 cm -1.

NMR Spectrum (dg-DMSO): δ (ppm) - 3.60 (2H, broad s), 4.80 (1H, d, J - 5Hz), 4.83 (2H, ABq, J - 13Hz), 5.05 (1H, d, J - 5Hz), 6.93 (1H, s), 6.90 * 7.70 (14H, m), 9.97 (1H, s).

Preparation 11

The following compounds are prepared in a similar manner as in Preparation 10.

1) Benzhydryl-7-amino-3- (N-phenylcarbamoyloxymethyl) -3-cephem-4-carboxylate.

IR Spectrum (nujol): 3420, 3380, 1770, 1725, 1660, 1600 and 1530 cm cm 1.

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139 NMR Spectrum (dg-DMSO): δ (ppm) - 3.65 (2H, broad s), 4.83 (2H, ABq, J - 13Hz), 4.90 (1H, d, J - 5Hz) , 5.10 (1H, d, J - 5Hz), 7.00 (1H, s), 6.83 * 7.73 (15H, m), 9.78 (1H, s), 2) Benzhydryl-7 -amino-3- (4-nitrobenzoyloxymethyl) -3-cephem-4-carboxy-5late hydrochloride.

IR Spectrum (nujol): 3400, 3350, 1770, 1720, 1630, 1600 and 1540 cm -1.

NMR Spectrum (d6-DMSO): δ (ppm) - 3.74 (2H, broad s), 4.72 (5.32) (4H, m), 6.92 (1H, s), 7.0 7.64 (10H, m), 8.12 (2H, d, J - 9Hz), 8.32 (2H, d, J - 9Hz).

10 Preparation of starting compounds.

Preparation 12 1) Add 21.3 g of 1-allyl-1H-tetrazole-5-thiol at 76-78 ° C to a solution of 10.6 g of sodium bicarbonate in 220 ml of water. Over 15 minutes, 54.9 g of sodium 7- (5-amino-5-carboxyvaleramido) -15 cephalosporanate are added and the mixture is stirred for 80 minutes at 76-78 ° C.

The reaction mixture is adjusted to pH 3.0 with 6N hydrochloric acid under ice-cooling and filtered. The filtrate is subjected to column chromatography on non-ionic adsorption resin "Diaion" ® HP-204 (manufactured by Mitsubishi Chemical Industries Ltd.) and eluted with 30% aqueous isopropyl alcohol solution. The eluate is adjusted to pH 6.5 with 28% aqueous ammonia solution, evaporated and lyophilized to give 21.7 g of ammonium 7- (5-amino-5-carboxyvaleramido) -3- (1-allyl-1 tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate.

IR Spectrum (nujol): 3175, 1760, 1590 cm "^.

NMR Spectrum (d6-DMSO): S (ppm): 1.23-2.42 (6H, m), 3.12-3.97 (3H, m), 4.37 (2H, broad s) , 4.80-5.15 (3H, m), 5.15-5.51 (2H, m), 5.51-6.25 (2H, m), 8.77 (1H, d, J - 8Hz).

2). 18.2 ml of Ν, Ν-dimethylaniline are added to a mixture of 10.0 g of ammonium 7- (5-amino-5-carboxyvaleramido) -3- (1-allyl-1H-tetrazol-5-yl) -thiomethyl -3-cephem-4-carboxylate, 20.9 ml of trimethylsilyl chloride and

DK 162391 B

140 ml of methylene chloride and the mixture is stirred at reflux for 2.5 hours. At -30 - -35 ° C, 5.83 g of phosphorus pentachloride is added and the mixture is stirred for 2 hours at the same temperature. At the same temperature, 38 ml of 2-ethoxyethanol is added dropwise and the mixture is stirred for 5 l at the same temperature. 80 ml of water is added at -5 - -10 ° C over 10 minutes and the resulting mixture is stirred for 5 minutes at the same temperature. The aqueous phase is separated and adjusted to pH 4.2 with 28% aqueous ammonia solution. The precipitates are collected by filtration, washed with 40 ml of 70% aqueous acetone 10 and 40 ml of methanol and dried to give 4.1 g of 7-amino-3- (1-allyl-1H-tetrazol-5-yl) thiomethyl 3 - cephem-4 carboxylic acid.

IR Spectrum (nujol): 3150, 1800, 1610, 1530 cm -1.

NMR Spectrum (dg-DMSO): δ (ppm) - 3.65 (2H, ABq, J - 18Hz), 4.33 (2H, ABq, J - 13Hz), 6.38-4.70 (7H, m).

Preparation 13 1) 126.4 g of ethyl 2-hydroxyimino-2- (2-aminothiazol-4-yl) acetate (syn isomer), 81.3 g of formic acid and 180 g of acetic anhydride are treated in the same manner as in Preparation 4 -4 to give 109.6 g of ethyl 2-hydroxyimino-2- (2-formamidothiazol-4-yl) acetate (syn isomer).

IR Spectrum (nujol): 3320, 3140, 3050, 1710 and 1555 cm -1 NMR Spectrum (dg-DMSO): S (ppm) - 1.30 (3H, t, J - 7Hz), 4.33 ( 2H, q, J - 7Hz), 7.54 (1H, s), 8.54 (1H, s), 11.98 (1H, s), 12.58 (1H, s).

2) A mixture of 7.97 g of chloromethylthiomethane, 15.1 g of powdered potassium iodide and 79 ml of acetone is stirred at room temperature for 1 hour. The resulting mixture is filtered and washed with a small amount of acetone. The washings and filtrate are combined and added to a stirred suspension of 17.5 g of ethyl 2-hydroxyimino-2- (2-formamidothiazol-4-yl) acetate (syn isomer) in 300 ml of acetone. The mixture is stirred at room temperature for 3 hours, filtered and washed with acetone. The washings and filtrate are combined and evaporated in vacuo. The residue is dissolved in ethyl acetate, washed twice with a saturated aqueous solution of sodium chloride.

DK 162391 B

141 chloride, dried over magnesium sulfate and evaporated in vacuo. The oily residue is subjected to column chromatography on silica gel and eluted with chloroform to give 2.4 g of ethyl 2-methylthiomethoxy-imino-2- (2-formamidothiazol-4-yl) acetate (syn isomer), m.p. 130-131 ° C.

IR Spectrum (nujol): 3160, 3125, 3050, 1740 and 1695 cm

NMR Spectrum (d6-DMSO): δ (ppm) - 1.32 (3H, t, J - 7Hz), 2.22 (3H, s), 4.38 (2H, q, J - 7Hz), δ , 33 (2H, s), 7.67 (1H, s), 8.56 (1H, s).

3) A mixture of 2.4 g of ethyl 2-methylthiomethoxyimino-2- (2-form-10-amidothiazol-4-yl) acetate (syn isomer), 23.8 ml of 1N aqueous sodium hydroxide and 19.8 ml of methanol stirred at 30 ° C for 2.5 hours. The resulting solution is adjusted to pH 7 with 10% hydrochloric acid and methanol and evaporated in vacuo. The aqueous solution is adjusted to pH 1 with 10% hydrochloric acid under ice-cooling and extracted 3 times with ethyl acetate. The extracts are washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give 1.13 g of 2-methylthiomethoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer), m.p. 157 DEG C. ).

IR Spectrum (nujol): 3210, 3160, 3075, 1700 and 1555 cm -1.

NMR Spectrum (d6-DMSO): δ (ppm) - 2.24 (3H, s), 5.31 (2H, s), 7.61 (1H, s), 8.57 (1H, s) , 12.73 (1H, s).

Preparation 14 The following compounds are prepared in a similar manner as described in the preceding preparations: 1) 2-Isopropoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer), mp 168-169 ° C (dec.).

IR Spectrum (nujol): 3200, 3130, 1710, 1600 and 1560 cm -1.

2) 2-Butoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer).

142

DK 162391 B

IR Spectrum (nujol): 3350, 3160, 3050, 1700, 1680 and 1570 cm cm ".

3) 2-Hexyloxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer), mp 115-116 ° C (dec.).

IR Spectrum (nujol): 3170, 3070, 1720, 1700 and 1660 cm cm ".

NMR Spectrum (d6-DMSO): δ (ppm) - 0.6-2.1 (11H, m), 4.15 (2H, t, J -6Hz), 7.53 (1H, s), 8.56 (1H, s), 12.69 (1H, s).

4) 2- (2-Formyloxyethoxy) imino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer).

IR Spectrum (nujol): 3200, 1710 and 1690 cm

5) 2-Benzyloxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer).

IR Spectrum (nujol): 3330, 3200, 3100, 1660 and 1590 cm cm ".

6) 2-Ethoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer), mp 112 ° C (dec.).

IR Spectrum (nujol): 3150, 1740, 1670 and 1550 cm

7) 2-tert.Butoxycarbonylmethoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer), mp 117 ° C (dec.).

IR Spectrum (nujol): 3180, 3140, 1750, 1690 and 1630 cm

8) 2- (3-Isoxazolyl) methoxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer), m.p. 110 ° C (dec.).

IR Spectrum (nujol): 3270, 3130, 1680 and 1540 cm cm ".

9) 2-Ethoxycarbonylmethoxyimino-2- (2-aminothiazol-4-yl) acetic acid (syn isomer).

IR Spectrum (nujol): 3170, 1720, 1660 and 1620 cm

143

DK 162391 B

NMR Spectrum (d6-DMSO): δ (ppm) - 1.27 (3H, t, J - 7Hz), 4.25 (2H, q, J - 7Hz), 4.77 (2H, s), δ , 96 (1H, s).

10) 2- (2-Ethoxyethoxy) imino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer).

IR spectrum (nujol): 3350, 3140, 1740 and 1700 crn

Preparation 15

A solution of 17.4 g of 4-bromo-3-hydroxybenzyloxyamine phosphate in 200 ml of water and 200 ml of ethanol is stirred at room temperature and adjusted to pH 7.0 with sodium bicarbonate. 10.0 g of 2- (2-formamidothiazol-4-10 yl) glyoxylic acid are added to the solution and the resulting suspension adjusted to pH 4.0-4.5. After stirring the solution at room temperature for 2 hours, ethanol is removed from the resulting solution in vacuo. Ethyl acetate is added to the aqueous residue and adjusted to pH 2.5 with 10% hydrochloric acid. The ethyl acetate phase 15 is separated, washed with water and dried over magnesium sulfate. The solution is evaporated in vacuo to give 14.8 g of 2- (2-formamidothiazol-4-yl) -2- (4-bromo-3-hydroxybenzyloxyimino) acetic acid (syn isomer).

IR Spectrum (nujol) umax: 3350, 3150, 1720, 1680 and 1570 cm -1.

NMR Spectrum (DMSO-d 6): δ (ppm), - 5.13 (2H, m), 6.8 (1H, dd, J - 8Hz, 2Hz), 7.02 (1H, d, J - 2Hz), 7.5 (1H, d, J - 8Hz), 7.58 (1H, s), 8.58 (1H, s), 10.35 (1H, wide s), 12.7 (1H, wide s).

Preparation 16 1) 40.0 g of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer), 43.6 g of 4-fluorobenzyl chloride, 60.0 ml of N, N-dimethylformamide, 52.0 g of potassium carbonate and 60.0 ml of ethyl acetate is treated in a conventional manner to give 64.4 g of 2- (4-fluorobenzyloxyimino) -3-oxobutyrate (syn isomer).

IR Spectrum (film): 3000, 2940, 1730, 1690 and 1600 cm cm ·.

DK 162391 B

144 NMR Spectrum (DMSO-d6): S (ppm) - 1.21 (3H, t, J - 7, OHz), 2.34 (3H, s), 4.26 (2H, q, J - 7 , OHz), 5.32 (2H, s), 6.97-7.73 (4H, m).

2) 64.0 g of ethyl 2- (4-fluorobenzyloxyimino) -3-oxobutyrate (syn isomer), 35.6 g of sulfuryl chloride and 70.0 ml of acetic acid are treated in a similar manner as described in Preparation 6-1, whereby 29.55 g of ethyl 2- (4-fluorobenzyloxyimino) -3-oxo-4-chlorobutyrate (syn isomer) are obtained.

IR Spectrum (film): 1720 and 1600 cm "·.

NMR Spectrum (DMSO-d 6): δ (ppm) - 1.20 (3H, t, J - 7.0Hz), 4.28 (2H, q, J - 7.0Hz), 4.87 (2H, s), 5.36 (2H, s), 7.00-7.75 (4H, m).

3) 29.0 g of ethyl 2- (4-fluorobenzyloxyimino) -3-oxo-4-chlorobutyrate (syn isomer), 8.8 g of thiourea, 7.9 g of sodium acetate, 72.5 ml of water, 60 ml tetrahydrofuran and 72.5 ml of ethanol are treated in a similar manner as described in Preparation 6-2 to give 28.0 g of ethyl 2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetate (syn. isomer).

IR Spectrum (nujol): 3450, 3150, 3100, 1710 and 1620 cm cm ·.

NMR Spectrum (DMSO-d 6): δ (ppm) - 1.23 (3H, t, J - 7.0Hz), 4.30 (2H, q, J - 7Hz), 5.15 (2H, s) , 6.90 (1H, s), 6.95-7.60 (4H, m).

4) 25.5 g of ethyl 2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetate (syn isomer), 1.3 g of 1-methylimidazole, 118.3 ml of 1N sodium 20 hydroxide solution, 250 ml methanol and 200 ml tetrahydrofuran are treated in a similar manner as described in Preparation 6-3 to give 22.11 g of 2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) vinegar. acid (syn-isomer).

IR Spectrum (nujol): 3650, 3450, 3300, 3150 and 1630 cnT

NMR Spectrum (DMSO-d6): δ (ppm) - 5.16 (2H, s), 6.88 (1H, s), 7.04-7.66 (4H, m).

5) 23.4 g of 2- (4-fluorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetic acid (syn isomer), 32.2 g of bis (trimethylsilyl) acetamide, 49.9 g of 2.2 , 2-trifluoroacetic anhydride and 234 ml of dry ethyl acetate are treated in a similar manner as described in Preparation 4-4 to give

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145 18.9 g of 2- (4-fluorobenzyloxyimino) -2- (2- (2,2,2-trifluoroacetamido) thiazol-4-yl) acetic acid (syn isomer), m.p. 180-182 ° C.

IR Spectrum (nujol): 3200, 3150 and 1730 cm cm 1.

NMR Spectrum (DHSO-d6): δ (ppm) - 5.25 (2H, s), 7.02-7.60 (4H, m), δ 7.72 (1H, s).

Preparation 17 1) The following compound is obtained by reacting ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer) with 3 ', 4-dichlorobenzyl chloride in conventional manner: Ethyl 2- (3,4-dichlorobenzyloxyimino) -3- oxobutyrate (syn-isomer), oil.

IR Spectrum (film): 1730, 1690, 1600, 1470, 1400, 1370, 1310, 1240, 1130, 1080 and 1010 cm -1.

NMR Spectrum (CC14): S (ppm) - 1.30 (3H, t, J - 6Hz), 2.30 (3H, s), 4.30 (2H, q, J - 6Hz), 4.47 (2H, s), 7.00-7.53 (3H, m).

2) The following compound is prepared in a similar manner as described in Preparation 6-1:

Ethyl 2- (3,4-dichlorobenzyloxyimino) -3-oxo-4-chlorobutyrate (syn isomer), oil.

IR Spectrum (film): 1740, 1710, 1590, 1470, 1400, 1370, 1320, 1260, 20 1200, 1130 and 1010 cm -1.

NMR Spectrum (CCl4): δ (ppm) - 1.37 (3H, t, J - 6Hz), 4.23 (2H, q, J - 6Hz), 4.43 (2H, s), 5.27 (2H, s), 7.10-7.60 (3H, m).

3) The following compound is prepared in a similar manner as described in Preparation 6-2: Ethyl 2- (3,4-dichlorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetate (syn isomer).

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146 IR Spectrum (nujol): 3460, 1720, 1600, 1540, 1460, 1390, 1260, 1180, 1020, 1010, 880 and 810 cm -1.

NMR Spectrum (DMSO-d 6): δ (ppm) - 1.25 (3H, t, J - 7Hz), 4.30 (2H, q, J - 7Hz), 5.17 (2H, s), δ , 93 (1H, s), 7.27-7.73 (3H, m).

4) The following compound is prepared in a similar manner as described in Preparation 6-3: 2- (3,4-Chlorobenzyloxyimino) -2- (2-aminothiazol-4-yl) acetic acid (syn isomer).

IR Spectrum (nujol): 3430, 1660, 1590, 1400 and 1010 cm cm ·.

NMR Spectrum (DMSO-d 6): δ (ppm) - 5.23 (2H, s), 6.93 (1H, s), 7.30-7.77 (3H, m).

5) The following compound is prepared in a similar manner as described in Preparation 4-4: 2- (3,4-Dichlorobenzyloxyimino) -2- (2- (2,2,2-trifluoroacetamido) thiazol-4-yl) acetic acid (syn -isomer).

IR Spectrum (nujol): 1720, 1580, 1300, 1260, 1200, 1160 and 1150 cm -1. NMR Spectrum (DMSO-d 6): δ (ppm) - 5.40 (2H, s), 7.47-7.93 (4H, m).

Preparation 18

To a suspension of 21.0 g of N- (cinnamyloxy) phthalimide in 200 ml of ethanol is added 8.3 g of hydrazine hydrate at 60 ° C and the mixture is stirred for 1.5 hours at the same temperature. To the mixture is added 22 ml of concentrated hydrochloric acid and 220 ml of water and the resulting mixture is filtered.

The filtrate is evaporated to give precipitate which is filtered off. The filtrate is adjusted to pH 7.0 and to the solution containing 25-cinnamylhydroxylamine is added 300 ml of ethanol and 10.0 g of 2- (2-form amidothiazol-4-yl) glyoxylic acid. The mixture is stirred for 2 hours at pH 4.0-4.5. The reaction mixture is evaporated and adjusted to pH 2.0 after the addition of ethyl acetate. The organic phase is washed with an aqueous solution of sodium chloride, dried over magnesium sulfate.

DK 162391 B

147 barrels and evaporated to give 8.6 g of 2-cinnamyloxyimino-2- (2-formamidothiazol-4-yl) acetic acid (syn isomer).

IR Spectrum (nujol): 3400-3100, 1700 and 1550 cm cm ".

NMR Spectrum (DMSO-d 6): δ (ppm) - 4.85 (2H, d, J - 5Hz), 6.2-6.93 (2H, m), 7.2-7.72 (5H) , m), 7.6 (1H, s), 8.57 (1H, s), 12.7 (1H, broad s).

Claims (7)

1 S R-C-CONH -—- S V N-OR2 A-Nv / r4 1 0 »3 R where R ^ - represents a group of the general formula * 7- {R- 10 where R? represents amino, C 1-6 alkanoylamino, halo- g -alkanoylamino, G 1-6 alkanesulfonylamino, C 1-6 alkoxycarbonylamino, hydroxy or C 2. alkyl; R ^ represents C ^g alkyl alkyl, C £ .g alkenyl, C ^g alkyl-thio-C Cj ^ alkyl, carboxy-C ^ ^ ^ alkyl, C ^g alkoxycarbonyl-C ± mg-alkyl, phenylthio-G1-6 alkyl, phenyl-g-alkyl, halogen-substituted phenyl-C1-6 alkyl, halogenated and hydroxy-substituted phenyl-g-alkyl, phenyl-C3. 6 - alkenyl, g - alkanoyloxy-. g - alkyl, C g - alkoxy - g - alkyl; hydroxy-substituted phenoxy-Cj ^g-alkyl, thienyl-C ^. g-alkyl or isoxazolyl-C 1-6 alkyl; R 4 represents carboxy or a pharmaceutically tolerable esterified carboxy group; and R 2 represents propionyl oxymethyl; butyryloxymethyl; isobutyryloxymethyl; valeryloxymethyl; isovaleryloxymethyl; pivaloyloxymethyl; carbamoyloxymethyl; phenyl-carbamoy loxyme thyl; halo-C2- g - alkanoylcarbamoyloxyme thyl; benzoyl-oxymethyl, which can carry nitro; phenyl-g-alkanoyloxymethyl; hydroxymethyl; tetrazolylthiomethyl, which can carry C 2-6 alkenyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, hexyl or cyclohexyl; thiadiazolylthiomethyl which can carry ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, hexyl or cyclohexyl; triazolylthiomethyl, which can carry β-alkyl or C2-6 alkenyl; DK 162391 B or benzothiazolylthiomethyl; or and R4 is bonded together to form -COOCH2-; or pharmaceutically tolerable salts thereof, characterized in that a) a compound of the general formula II H2N-I-K'® '' x'-R4 II 0 in which R 1 and R 4 are as defined above, or a reactive derivative at the amino group or a salt thereof is reacted with a substituted acetic acid of the general formula R 1 -C-COOH wherein R 1 and II N-OR 2 R 2 have the meaning given above, or a reactive derivative at the carboxy group or a salt thereof or b) for the preparation of a compound of general formula Ia Rlb-C-CONH - \ i ia N-OR2 ^ -N ~ R4 ° 3 ττ where R4 represents a group of general formula DK 162391 B ν_0 ~ or a salt thereof, a compound of the general formula IV Rla-C-COHN ---- "S 1. Analogous Process for Preparing Syn-Isomers of 3,7-Disubstituted 3-Cephem-4-Carboxylic Acid Compounds of General Formula I Process according to Claim 1, 15, characterized in that R 1 - is a group of the general formula N - h 2n - H) - and has the meaning given in claim 1 (a) and that the reaction is carried out in the presence of a Vilsmeier reagent prepared by reacting phosphorus oxychloride with dimethylformamide, and under approximately neutral conditions, where phosphorus oxychloride is used in more than two molar equivalents for each amount of the substituted acetic acid and dimethylformamide. A process according to claim 1, characterized in that R 1 - is a group of the general formula HFT 10 wherein represents amino, and represents carbamoyloxymethyl, hydroxymethyl, thiadiazolylthiomethyl or triazolylthiomethyl, which may have q.6-alkyl. Process according to claim 3, characterized in that R 1 represents C 1-6 alkyl and R 1 represents carboxy. Process according to claim 4, characterized in that R 1 represents carbamoyloxymethyl or thiadiazolylthiomethyl. N-OR2a - R4 Va 0 TP wherein R 1, R 2 and R 2 have the meaning given above and R 2a represents -C 1-6 alkoxycarbonyl-C 1-6 alkyl, or a salt thereof, is subjected to elimination reaction of the carboxy protecting group, or 10 d) to prepare a compound of the general formula Id 1 / R -C-CONH-ii in 2 I J_ m N-OR 2 -N'v '^ CH 2 -OCONH 20 0 3 RJ wherein R 2 ·, R 2 and R 2 have the above or salts thereof, a compound of the general formula Vb R1-C-CONH - ^ N N-OR2 J-CH2-OCOHH-R4a ^ 0 I DK 162391 B wherein rA, rA and R meaning R4a represents halo-C2-6 alkanoyl, or a salt thereof, is subjected to elimination reaction by the amino protecting group; e) for the preparation of a compound of general formula Ie R 1 -C-CONH - S Lr 2 J-CH 2 -S-R 4 C 13 wherein R 1 -, R 2 and R 2 have the meaning given above and R 4 c has the meaning given below, or salts thereof, a compound of the general formula Vc 1 _ / S RC-CONH -r I-OR2 ^ CH2-R4b Vc * R3 wherein R * ·, R ^ and R ^ have the above represents a group which can be substituted by a group of R4c-S-, where R4c has the meaning given below, or a salt thereof is reacted with a compound of the general formula R4c-SH where R4c represents tetrazolyl, which may have C 2-6 alkenyl or ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, hexyl or cyclohexyl, thiadiazolyl which may have ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, hexyl or cyclohexyl, triazo [1-6] alkyl which may have C 1-6 alkyl or C 2-6 alkenyl, or benzotriazolyl, or a reactive derivative thereof by the mercapto group, or f) addition of a compound of the general formula If R ^ C-CONH —- ^ N 5. ii I IL * 2 J —'N ^ “f2 I I co — o where r! and has the above meaning, or salts thereof, a compound of the general formula Ve R 1 -C-CONH-S * N 10. I_Ve N-OR2 ^ -NCH2 ° H R3 wherein R * -, R ^ and are as defined above, or a salt thereof is treated with an acid. 5. IV f1-OR2 r4 Q> I R3 wherein R3 and R4 are as defined above and R4a represents a group of the general formula 10 wherein R4a represents C1-6 alkanoylamino, halogeno- C 1-6 alkanoylamino, C. g - alkanesulfonylamino or C 1-6 alkoxycarbonylamino; or a salt thereof is subjected to elimination reaction of the amino protecting group, or c) to prepare a compound of the general formula Ic R2-C-CONH -S S> i 2b in L 4 N-ORZ ° 1 N -R r »3 ΈΓ DK 162391 B wherein r1, r3 and R4 are as defined above and R2i> represents carboxy-C1-6 -alkyl, or a salt thereof, a compound of the general formula Va r -c-conh -rv Process according to claim 5, characterized in that R * represents thiadiazolylthiomethyl. Process according to claim 6, characterized in that R 1 represents methyl.