RU2056425C1 - Cephalosporin derivatives or their pharmaceutically acceptable acid-additive salts and methods of their synthesis - Google Patents

Abstract

FIELD: organic chemistry, antibiotics. SUBSTANCE: product: derivatives of cephalosporin of the formula given in description text at the definite radical values, and methods of their synthesis. EFFECT: improved method of synthesis. 4 cl, 3 tbl

Description

(1)
в которой R¹ и R² имеют значения, определенные ниже и ^⊕N ≡ Q представляет собой четвертичную аммонио-группу, определенную ниже, и к их солям и сложным эфирам. Изобретение также относится к способам получения соединений формулы (I), к фармацевтическим композициям, содержащим, по крайней мере, одно соединение формулы (I), и к промежуточным продуктам для их получения.The invention relates to 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (substituted) iminoacetamido] -3- [3- (quaternary ammonio) -1-propene-1- yl] -3-cephem-4-carboxylates of the formula I
R ¹ NH

(1)
in which R ¹ and R ² have the meanings defined below and ^⊕ N ≡ Q represents the Quaternary ammonio group, as defined below, and their salts and esters. The invention also relates to methods for producing compounds of formula (I), to pharmaceutical compositions containing at least one compound of formula (I), and to intermediates for their preparation.

в которой R¹ представляет собой амино или защищенный амино;
R² представляет собой водород, ацил, не обязательно замещенный арил, замещенный алкил, алкенил, алкинил, необязательно замещенный циклоалкил, циклоалкенил или О- или S-содержащее 5-членное гетероциклическое кольцо, замещенное оксо-группой (или группами);
R³ представляет собой водород или алкил;
R⁴ представляет собой водород, ацилоксиалкил, ацилтиоалкил, не обязательно замещенный пиридиниоалкил, не обязательно замещенный гетероциклилтиоалкил, алкил, галоген, гидроксил или не обязательно замещенный тиазолиоалкил; и
R⁵ представляет собой карбокси или защищенную карбокси;
при условии, что R⁵ представляет собой СОО, когда R⁴ представляет собой не обязательно замещенный пиридиниоалкил или не обязательно замещенный тиазолиоалкил;
и пунктирная линия показывает наличие или одинарной, или двойной связи,
Известны [1] цефемовые соединения формулы

в которой R¹ представляет собой амино или защищенный амино;
R² представляет собой не обязательно замещенную низшую алифатическую углеводородную группу, или циклоалкенил; и
группа формулы

представляет собой не обязательно замещенную гетероциклическую катионовую группу, содержащую более одного атома азота; и фармацевтически приемлемые соли их. Также раскрываются промежуточные соединения формулы:

CH

в которой R¹ и R² имеют определенные значения, R⁴ представляет собой защищенную карбоксильную группу, и Х^- кислотный остаток.Cephem and cefam compounds of the formula are known

in which R ¹ represents amino or protected amino;
R ² represents hydrogen, acyl, optionally substituted aryl, substituted alkyl, alkenyl, alkynyl, optionally substituted cycloalkyl, cycloalkenyl or an O- or S-containing 5-membered heterocyclic ring substituted with an oxo group (or groups);
R ³ represents hydrogen or alkyl;
R ⁴ represents hydrogen, acyloxyalkyl, acylthioalkyl, optionally substituted pyridinioalkyl, optionally substituted heterocyclylthioalkyl, alkyl, halogen, hydroxyl or optionally substituted thiazioalkyl; and
R ⁵ represents carboxy or protected carboxy;
with the proviso that R ⁵ is COO, when R ⁴ is an optionally substituted pyridinioalkyl or an optionally substituted thiazioalkyl;
and the dashed line indicates the presence of either a single or double bond,
Known [1] Cephem compounds of the formula

in which R ¹ represents amino or protected amino;
R ² represents an optionally substituted lower aliphatic hydrocarbon group, or cycloalkenyl; and
group of formula

represents an optionally substituted heterocyclic cationic group containing more than one nitrogen atom; and pharmaceutically acceptable salts thereof. Intermediates of the formula are also disclosed:

CH

in which R ¹ and R ² have certain meanings, R ⁴ represents a protected carboxyl group, and X ^{is an} acid residue.

CH $\genfrac{}{}{0ex}{}{\text{⊕}}{\text{2}}$ N

где R¹ амино или защищенный амино;
R² не обязательно замещенная низшая алифатическая углеводородная группа, цикло (низший) алкил или цикло (низший) алкенил;
R³ (низший) алкиламино, N-защищенный (низший) алкиламино, ди(низший) алкиламино, сульфо(низший) алкиламино, окси(низший) алкиламино, N-защищенный окси (низший) алкиламино, ацилокси (низший) алкил, (низший) алкокси (низший) алкокси (низший) алкил, ди (низший) алкиламино (низший) алкил, (низший) алкилтио (низший) алкил, (низший) алкилтио, (низший) алкокси, (низший) алкокси (низший) алкокси, окси (низший) алкокси, ацил (низший) алкил, окси (низший) алкилтио, ди(низший) алкиламино(низший) алкилтио, N-содержащая ненасыщенная 5-членная гетероциклическая группа, N-содержащая ненасыщенная 5-членная гетероциклическая тиогруппа, или N-содержащий ненасыщенный 5- или 6-членный гетероциклический тио(низший) алкил, который может быть замещен подходящим или подходящими заместителями; и
R⁴ водород или (низший) алкил; или соли их.Known [2] Cephem compounds of the formula:

CH $\genfrac{}{}{0ex}{}{\text{⊕}}{\text{2}}$ N

where R ^{1 is} amino or protected amino;
R ² is an optionally substituted lower aliphatic hydrocarbon group, cyclo (lower) alkyl or cyclo (lower) alkenyl;
R ³ (lower) alkylamino, N-protected (lower) alkylamino, di (lower) alkylamino, sulfo (lower) alkylamino, hydroxy (lower) alkylamino, N-protected hydroxy (lower) alkylamino, acyloxy (lower) alkyl, (lower ) alkoxy (lower) alkoxy (lower) alkyl, di (lower) alkylamino (lower) alkyl, (lower) alkylthio (lower) alkyl, (lower) alkylthio, (lower) alkoxy, (lower) alkoxy (lower) alkoxy, hydroxy (lower) alkoxy, acyl (lower) alkyl, hydroxy (lower) alkylthio, di (lower) alkylamino (lower) alkylthio, N-containing unsaturated 5-membered heterocyclic group, N-soda holding unsaturated 5-membered heterocyclic thio group, or N-containing unsaturated 5- or 6-membered heterocyclic thio (lower) alkyl, which may be substituted with suitable or suitable substituents; and
R ⁴ hydrogen or (lower) alkyl; or their salts.

где R¹ амино или защищенный амино;
R² (низший) алкил и Х водород или карбамоил.Known compounds of the formula

where R ^{1 is} amino or protected amino;
R ² (lower) alkyl; and X is hydrogen or carbamoyl.

CONH

где m равно 0 или 1;
Am не обязательно замещенный амино;
Т тиадиазолильный фрагмент (присоединенный к другим группам своими двумя атомами углерода);
R₂ водород, не обязательно замещенный алкил, циклоалкил или не обязательно замещенный карбамоил; и
R₁ не обязательно замещенный тиазолио, не обязательно замещенный пиразолио, три (низший) алкиламмонио или пиридинио группа формулы

в которой R^a замещенный (низший) алкил [причем, заместителем является циклоалкил, фенил, окси, алкокси, галоген, циано, карбамоил, карбоксил или сульфо] (низший) алкенил или карбоксизамещенный (низший) алкенил, (низший) алкилтио или карбокси замещенный (низший) алкилтио, амино или моно-замещенный амино [заместителем является (низший) алкил, (низший) алканоил или аминобензолсульфонил] ди (низший) алкиламино, замещенный карбамоил [заместителем является (низший) алкил окси (низший) алкил, (низший) алкокси, гидроксил или циано] ди (низший) алкилкарбамоил, тиокарбамоил, циклоалкил, фенил, гидроксил, (низший) алкокси, галоген, (низший) алкоксикарбонил, (низший) алканоилокси, (низший) алканоил, карбоксил, сульфо, циано, нитро или оксисульфо (низший) алкил;
R^b водород или карбамоил, или имеет то же значение, что и R^a и R^c- водород или имеет те же значения, что R^a; и их соли.Cephem compounds of the formula are known
Am t

CONH

where m is 0 or 1;
Am is not necessarily substituted amino;
T thiadiazolyl fragment (attached to other groups by its two carbon atoms);
R ₂ hydrogen, optionally substituted alkyl, cycloalkyl or optionally substituted carbamoyl; and
R ₁ optionally substituted thiazolio, optionally substituted pyrazolio, three (lower) alkylammonio or pyridinio group of the formula

in which R ^a substituted (lower) alkyl [wherein the substituent is cycloalkyl, phenyl, oxy, alkoxy, halogen, cyano, carbamoyl, carboxyl or sulfo] (lower) alkenyl or carboxy substituted (lower) alkenyl, (lower) alkylthio or carboxy substituted (lower) alkylthio, amino or mono-substituted amino [substituent is (lower) alkyl, (lower) alkanoyl or aminobenzenesulfonyl] di (lower) alkylamino, substituted carbamoyl [substituent is (lower) alkyl hydroxy (lower) alkyl, (lower) alkoxy, hydroxyl or cyano] di (lower) alkylcarbamo l, thiocarbamoyl, cycloalkyl, phenyl, hydroxy, (lower) alkoxy, halogen, (lower) alkoxycarbonyl (lower) alkanoyloxy (lower) alkanoyl, carboxyl, sulfo, cyano, nitro or oksisulfo (lower) alkyl;
R ^{b is} hydrogen or carbamoyl, or has the same meaning as R ^a and R ^c is hydrogen or has the same meanings as R ^a ; and their salts.

гетероциклическая группа, которая может также иметь галоген, или группа формулы:
R³SO₂HN

в которой R³ (низший) алкил; R² карбокси или защищенная карбокси и А низший алкилен, который может иметь заместитель, выбранный из групп: амино, защищенный амино, гидроксил, оксо и группы формулыN ≈ OR⁴, в которой R⁴ водород, цикло (низший) алкенил, (низший)-алкинил, (низший) алкенил [не обязательно замещенный группой карбокси или защищенной карбокси] (низший) алкил [не обязательно замещенный одной или более из групп карбокси или защищенной карбокси, амино, защищенной амино, циано, фосфоно, защищенной фосфоно и гетероциклической группы, которая сама по себе может быть замещенной] и их соли.Known 3-vinyl-Cephem compounds of the formula
R′- A CONH

a heterocyclic group, which may also have a halogen, or a group of the formula:
R ³ SO ₂ HN

in which R ³ (lower) alkyl; R ^{2 is} carboxy or protected carboxy and A is lower alkylene, which may have a substituent selected from the groups: amino, protected amino, hydroxyl, oxo and groups of the formula N ≈ OR ⁴ in which R ^{4 is} hydrogen, cyclo (lower) alkenyl, (lower) -alkynyl, (lower) alkenyl [optionally substituted with a carboxy or protected carboxy group] (lower) alkyl [optionally substituted with one or more carboxy or protected carboxy, amino, protected amino, cyano, phosphono, protected phosphono and heterocyclic groups, which itself can be replaced hydrochloric] and salts thereof.

в которой OR⁴ метокси, карбоксиметокси, трет-бутоксикарбонилметокси или 1-трет-бутоксикарбонилэтокси.Compounds of the formula

wherein OR ^{4 is} methoxy, carboxymethoxy, tert-butoxycarbonylmethoxy or 1-tert-butoxycarbonylethoxy.

O NH

в которой R водород или органическая группа, R^a простая этерифицирующая моновалентная органическая группа, связанная с кислородом через атом углерода, В группа

S или

S _→ O и Р органическая группа. В одном из воплощений Р может представлять собой наряду с другими винильную группу формулы
-CH= C

в которой R³ и R⁴ независимо могут представлять собой водород, нитрил, (низший) алкоксикарбонил, или замещенный или незамещенный и алифатический, циклоалифатический, аралифатический или ароматический. Однако 5-амино-1,2,4-тиадиазол-3-ильная группа не идентифицирована в качестве возможного R заместителя и нет никакого высказывания или предположения о том, что Р может быть четвертичной аммонио-замещенной пропенильной группой.A wide range of cephalosporins of the formula are known.
R

O NH

in which R is hydrogen or an organic group, R ^{a is a} simple esterifying monovalent organic group bonded to oxygen via a carbon atom, In a group

S or

S _ → O and P organic group. In one embodiment, P may be, along with others, a vinyl group of the formula
-Ch = c

in which R ³ and R ⁴ may independently be hydrogen, nitrile, (lower) alkoxycarbonyl, or substituted or unsubstituted and aliphatic, cycloaliphatic, araliphatic or aromatic. However, the 5-amino-1,2,4-thiadiazol-3-yl group is not identified as a possible R substituent and there is no suggestion or suggestion that P may be a quaternary ammonio-substituted propenyl group.

CONH

в которой R¹ (незамещенный) тиадиазолил;
R² карбокси(низший) алкил или защищенный карбокси (низший) алкил;
R³ водород, галоген или (низший) алкенил; и
R⁴ карбокси или защищенный карбокси.Known compounds of the formula
R′-

CONH

in which R ¹ (unsubstituted) thiadiazolyl;
R ² carboxy (lower) alkyl or protected carboxy (lower) alkyl;
R ^{3 is} hydrogen, halogen or (lower) alkenyl; and
R ⁴ carboxy or protected carboxy.

Although 1-propenyl is indicated as one of the possible values of R ³ , only compounds in which R ^{3 is} hydrogen, chlorine or vinyl are illustrated in the application.

в которой R⁵ наряду с другими может быть алкилом, винилом, цианометилом или защитной группой, такой как 2-метоксипроп-2-ил, и R³ и R⁴представляют собой алкильные группы (не обязательно замещенные группами окси, алкокси, амино, алкиламино или диалкиламино), или фенильные группы, или R³ и R⁴, взятые вместе с атомом азота, к которому они присоединены, могут образовывать насыщенное гетероциклическое кольцо из 5 или 6 членов, не обязательно содержащее еще один гетероатом, выбранный из азота, кислорода и серы, и не обязательно замещенное алкильной группой. Данные соединения полезны в качестве промежуточных продуктов при получении 3-тиовинилцефалоспориновых производных. В патенте нет никакого описания или предположения о наличии 5-амино-1,2,4- тиадиазол-3-ильного фрагмента вместо 2-аминотиазол-4-ильного заместителя, или четвертичного аммонио-замещенного пропенильного фрагмента в качестве 3-заместителя.Derivative Formulas Known

in which R ^5, along with others, may be alkyl, vinyl, cyanomethyl or a protecting group, such as 2-methoxyprop-2-yl, and R ³ and R ⁴ are alkyl groups (not necessarily substituted by hydroxy, alkoxy, amino, alkylamino groups or dialkylamino), or phenyl groups, or R ³ and R ⁴ , taken together with the nitrogen atom to which they are attached, can form a saturated heterocyclic ring of 5 or 6 members, not necessarily containing another heteroatom selected from nitrogen, oxygen and sulfur, and not necessarily substituted by an alkyl group oh. These compounds are useful as intermediates in the preparation of 3-thiovinylcephalosporin derivatives. The patent does not describe or suggest a 5-amino-1,2,4-thiadiazol-3-yl moiety instead of a 2-aminothiazol-4-yl substituent, or a quaternary ammonio-substituted propenyl moiety as a 3-substituent.

в которой R $\genfrac{}{}{0ex}{}{\text{a}}{\text{5}}$ и R $\genfrac{}{}{0ex}{}{\text{b}}{\text{5}}$ являются одинаковыми или различными и представляют собой водород или алкил, или взятые вместе, образуют алкиленовую группу, содержащую 2 или 3 атома углерода,
R $\genfrac{}{}{0ex}{}{\text{c}}{\text{5}}$ представляет собой группу, защищающую кислоту,
R₂ представляет собой защитную группу кислоты, такую, как сложноэфирную группу,
R₃ и R₄ являются одинаковыми или различными и представляют собой водород, алкил (не обязательно замещенный гидроксилом, алкокси, амино, алкиламино или диалкиламино) или фенильные группы, или
R₃ и R₄ взятые вместе с азотом, к которому они присоединены, могут образовывать 5- или 6-членное насыщенное гетероциклическое кольцо, не обязательно содержащее еще один гетеро-атом, выбранный из азота, кислорода и серы, и не обязательно замещенное алкильной группой. Эти соединения полезны в качестве промежуточных продуктов при получении 3-тиовинил-цефалоспориновых производных. Нет указания или предположения о наличии 5-амино-1,2,4-тиадиазол-3-ил фрагмента вместо 2-аминотиазол-4- ильного заместителя или четвертичной аммонио-замещенной пропенильной группы в качестве 3-заместителя.Known 3-vinylcephalosporin derivatives of the formula

in which R $\genfrac{}{}{0ex}{}{\text{a}}{\text{5}}$ and R $\genfrac{}{}{0ex}{}{\text{b}}{}$$\genfrac{}{}{0ex}{}{}{\text{5}}$ are the same or different and are hydrogen or alkyl, or taken together form an alkylene group containing 2 or 3 carbon atoms,
R $\genfrac{}{}{0ex}{}{\text{c}}{}$$\genfrac{}{}{0ex}{}{}{\text{5}}$ is an acid protecting group,
R ₂ represents a protective group of an acid, such as an ester group,
R ₃ and R ₄ are the same or different and represent hydrogen, alkyl (optionally substituted with hydroxyl, alkoxy, amino, alkylamino or dialkylamino) or phenyl groups, or
R ₃ and R ₄ taken together with the nitrogen to which they are attached can form a 5- or 6-membered saturated heterocyclic ring, optionally containing yet another hetero atom selected from nitrogen, oxygen and sulfur, and not necessarily substituted with an alkyl group . These compounds are useful as intermediates in the preparation of 3-thiovinyl-cephalosporin derivatives. There is no indication or suggestion that there is a 5-amino-1,2,4-thiadiazol-3-yl moiety in place of the 2-aminothiazol-4-yl substituent or a quaternary ammonio-substituted propenyl group as a 3-substituent.

в которой R $\genfrac{}{}{0ex}{}{\text{0}}{\text{1a}}$ (в одном из нескольких воплощений) может быть группой формулы

-

в которой R₅ наряду с другими может представлять собой водород, алкил, винил, цианометил, оксим-защищающую группу, такую как тритил, и др. или группу формулы

C -

OOR $\genfrac{}{}{0ex}{}{\text{c}}{\text{5}}$ в которой R $\genfrac{}{}{0ex}{}{\text{a}}{\text{5}}$ и R $\genfrac{}{}{0ex}{}{\text{b}}{\text{5}}$ являются одинаковыми или различными и могут представлять собой водород, алкил, или, взятые вместе, алкиленовый радикал с 2 или 3 атомами углерода, и
R $\genfrac{}{}{0ex}{}{\text{c}}{\text{5}}$ представляет собой водород или кислото-защищающий радикал;
R $\genfrac{}{}{0ex}{}{\text{o}}{\text{2a}}$ представляет собой водород или кислото-защищающий радикал, такой как метоксиметил;
R^o (в одном из нескольких воплощений) может быть метильной группой, замещенной 5- или 6-членным ароматическим гетероциклическим кольцом, содержащим единственный гетеро-атом, таким как 2- или 3-пиридил, 2- или 3-тиенил или 2- или 3-фурил; и
R₃ представляет собой группу формулы R₄SO₂O в которой R₄ может представлять собой алкил, тригалоидметил или не обязательно замещенный фенил.A wide variety of 3-vinylcephalosporin derivatives of the formula are known.
R $\genfrac{}{}{0ex}{}{\text{o}}{\text{1a}}$ -NH

in which R $\genfrac{}{}{0ex}{}{\text{0}}{\text{1a}}$ (in one of several embodiments) may be a group of the formula

-

in which R _5, along with others, may be hydrogen, alkyl, vinyl, cyanomethyl, an oxime protecting group such as trityl, etc. or a group of the formula

C -

Oor $\genfrac{}{}{0ex}{}{\text{c}}{}$$\genfrac{}{}{0ex}{}{}{\text{5}}$ in which R $\genfrac{}{}{0ex}{}{\text{a}}{\text{5}}$ and R $\genfrac{}{}{0ex}{}{\text{b}}{}$$\genfrac{}{}{0ex}{}{}{\text{5}}$ are the same or different and may be hydrogen, alkyl, or, taken together, an alkylene radical with 2 or 3 carbon atoms, and
R $\genfrac{}{}{0ex}{}{\text{c}}{}$$\genfrac{}{}{0ex}{}{}{\text{5}}$ represents hydrogen or an acid protecting radical;
R $\genfrac{}{}{0ex}{}{\text{o}}{\text{2a}}$ represents hydrogen or an acid protecting radical such as methoxymethyl;
R ^o (in one of several embodiments) may be a methyl group substituted with a 5- or 6-membered aromatic heterocyclic ring containing a single hetero atom, such as 2- or 3-pyridyl, 2- or 3-thienyl or 2- or 3-furyl; and
R ₃ represents a group of the formula R ₄ SO ₂ O in which R ₄ may be alkyl, trihalomethyl or optionally substituted phenyl.

SR которые не обладают антибактериальной активностью.These compounds are intermediates in the preparation of compounds in which the 3-substituent is a group of the formula
-Ch =

SR which do not have antibacterial activity.

Although it is contemplated that R ⁰ is a methyl group substituted with an N-containing heterocyclic ring, both in the intermediates and in the final products (thus yielding a heterocyclic substituted propenyl moiety), it is only said that the heterocyclic ring is attached via one of its carbon atoms. Thus, a quaternary ammonio-substituted propenyl group is not intended at all. This reference gives, as an example, R ^o in the intermediates and end products only methyl. In addition, in the intermediate and in the final products, the propenyl group must also contain another substituent (respectively —O ₃ SR ₄ or —SR). There is no indication or suggestion that there is a 5-amino-1,2,4-thiadiazol-3-yl moiety instead of a 2-amino-thiazol-4-yl substituent.

CH= CH-R³ в которой n равно 0 или 1, R⁵ водород, алкил, винил, цианометил или оксим-защитная группа, и R³ галоген.Known 3-vinylcephalosporin intermediate compounds of the formula
H ₂ N

CH = CH — R ³ wherein n is 0 or 1, R ^{5 is} hydrogen, alkyl, vinyl, cyanomethyl or an oxime protecting group, and R ^{3 is} halogen.

в которой R¹ представляет собой водород или общепринятую аминозащищающую группу, R² представляет собой водород, алкильную группу с прямой или разветвленной цепью, содержащую от 1 до 4 атомов углерода, циклоалкильное или циклоалкенильное кольцо, содержащее от 3 до 6 атомов углерода, или группу формулы

CH CH-R³,

- C ≡ C R³,

в которых R³ представляет собой водород, (низший) алкил или карбоксил; Х представляет собой галоген, гидроксил или (низший) алкокси; и R⁴ и R⁵каждый независимо представляет собой водород, метил или этил; или R⁴ и R⁵, взятые вместе с атомом углерода, к которому они присоединены, могут представлять циклоалкилиденовое кольцо, содержащее от 3 до 5 атомов углерода; и группа -^⊕N≡Q представляет собой четвертичную аммонио-группу; и к нетоксичным фармацевтически приемлемым солям и физиологически гидролизуемым сложным эфирам их. В объем данного изобретения включены также сольваты (включая гидраты) соединений формулы (I), а также таутомерные формы соединений формулы (I), например 2-иминотиазолин-4-ильная форма 2-аминотиазолл-4-ильного фрагмента. Согласно еще одному аспекту, данная заявка относится к способу получения соединений формулы (I) и к некоторым промежуточным продуктам при их получении.This application relates to new cephalosporin derivatives, which are strong antibacterial agents. More specifically, it relates to compounds of the formula
R′NH

in which R ¹ represents hydrogen or a conventional amino protecting group, R ² represents hydrogen, a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl ring containing from 3 to 6 carbon atoms, or a group of the formula

CH CH-R ³ ,

- C ≡ CR ³ ,

in which R ³ represents hydrogen, (lower) alkyl or carboxyl; X represents halogen, hydroxyl or (lower) alkoxy; and R ⁴ and R ⁵ each independently represents hydrogen, methyl or ethyl; or R ⁴ and R ⁵ taken together with the carbon atom to which they are attached may represent a cycloalkylidene ring containing from 3 to 5 carbon atoms; and the group - ^⊕ N≡Q represents a quaternary ammonio group; and non-toxic pharmaceutically acceptable salts and physiologically hydrolyzable esters thereof. Solvates (including hydrates) of compounds of formula (I), as well as tautomeric forms of compounds of formula (I), for example, the 2-iminothiazolin-4-yl form of the 2-aminothiazoll-4-yl moiety, are also included within the scope of this invention. According to another aspect, this application relates to a method for producing compounds of formula (I) and to certain intermediates in their preparation.

 As shown in the structural formula, the compounds of formula (I) have a “syn” or “Z” configuration with respect to the alkoxyimino group. Due to the fact that the compounds are geometric isomers, some anti-isomer may also be present. This invention includes compounds of formula (I) containing at least 90% of the syn syn isomer. Preferably, the compounds of formula (I) are “syn” isomers that are substantially free of the corresponding “anti” isomers. In addition to the geometric isomers possible with respect to the alkoxyimino group, the compounds of formula (I) (and intermediates of formulas VIII and IX) also form geometric isomers (cis and trans) in connection with the double bond of the propenyl group. Both cis (Z) and trans (E) isomers of these compounds are specifically included in the scope of the invention.

 Non-toxic pharmaceutically acceptable salts of the compounds of formula (I) include salts with mineral acids, such as hydrochloric, hydrobromic, phosphoric and sulfuric, or with organic carboxylic acids, or sulfonic acids, such as acetic, trifluoroacetic, citric, formic, maleic, oxalic, succinic, benzoic, tartaric, fumaric, mandelic, ascorbic, malic acid, methanesulfonic, benzenesulfonic, p-toluenesulfonic and other acids known and used in the field of penicillins and cephalosporins. The preparation of these acid addition salts is carried out using well-known techniques.

 Examples of physiologically hydrolyzable esters of the compounds of formula (I) include indanyl, phthalidyl, methoxymethyl acetoxymethyl, pivaloyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl and other physiologically known physiologically used in the field of penicillins and cephalosporites. Such esters are prepared using conventional techniques known in the art.

The compounds of formula (I) in which R ¹ is hydrogen exhibit high antibacterial activity against various gram-positive and gram-negative bacteria and are useful in the treatment of bacterial infections in animals, including humans. The compounds of formula (I) can be converted into parenteral formulations in a conventional manner, using known pharmaceutical carriers and excipients, they can be presented in unit dosage form or in multi-dose containers. The compositions may be in the form of solutions, suspensions or emulsions in oily or aqueous vehicles, they may contain conventional dispersing, suspending or stabilizing agents. The compositions may also be in the form of a dry powder for use immediately prior to use, for example with sterile, pyrogen-free water. The compounds of formula (I) can also be formulated as medical suppositories using a conventional suppository base such as cocoa butter or other glycerides. The compounds of the invention may, if necessary, be administered in combination with other antibiotics, such as penicillins and other cephalosporins.

 When the compositions are provided in the form of dosage units, they preferably contain from about 50 to 1500 mg of the active ingredient of the formula (I). The dose of the compounds of formula (I) depends on factors such as the weight and age of the patient, as well as on the specific nature and severity of the disease, and is within the competence of the doctor. However, the dose for an adult is usually in the range of about 500 to 5000 mg per day, depending on the frequency and method of use. When a drug is administered intramuscularly or intravenously to an adult, a total daily dose of approximately 750 to 3000 mg in divided doses will usually be sufficient, although higher daily doses of certain compounds may be desirable if infected with bacteria of the genus Pseudomonas.

The quaternary ammonio group of the formula - ^⊕ N≡Q may be acyclic, cyclic, or may be a combination of two, may contain one or more additional hetero atoms selected from nitrogen, sulfur and oxygen atoms.

- R⁷ в которой R⁶, R⁷ и R⁸ могут быть одинаковыми или различными и могут представлять, например, (низший) алкил или замещенный (низший) алкил, в котором заместителями являются, например, галоген, амино при условии, что амино-группа не может быть у альфа-углерода, гидроксил, при условии, что гидроксильная группа не может быть у альфа-углерода, (низший) алкокси при условии, что алкокси-группа не может быть у альфа-углерода, (низший) алкилтио, (низший) алкиламино, ди(низший)алкиламино, карбамоил, (низший) алкенил, фенил(низший) алкил, фенил или замещенный фенил (в котором заместителями могут быть, например, галоген, гидроксил, амино, (низший)алкиламино, ди(низший)алкиламино, ациламино, (низший)алкил, (низший) алкилтио, (низший)алкокси или аналогичные).An example of an acyclic quaternary ammonio group is a group of the formula
-

- R ⁷ in which R ⁶ , R ⁷ and R ⁸ may be the same or different and may represent, for example, (lower) alkyl or substituted (lower) alkyl, in which the substituents are, for example, halogen, amino, provided that amino the α-group cannot be on alpha-carbon, hydroxyl, provided that the hydroxyl group cannot be on alpha-carbon, (lower) alkoxy, provided that the alkoxy group cannot be on alpha-carbon, (lower) alkylthio, (lower) alkylamino, di (lower) alkylamino, carbamoyl, (lower) alkenyl, phenyl (lower) alkyl, phenyl or substituted enyl (wherein the substituents may be, for example, halogen, hydroxyl, amino, (lower) alkylamino, di (lower) alkylamino, acylamino, (lower) alkyl, (lower) alkylthio (lower) alkoxy or the like).

-^⊕N

-^⊕N

,

-

,
R

R⁹, R

_,

,

_R9 и аналогичные, в которых R⁹ и R¹⁰ являются одинаковыми или различными и могут представлять собой, например, водород, галоген, амино, (низший)алкил, (низший)алкенил, (низший) алкилтио, карбокси, гидроксил, (низший)алкокси, (низший) алкокси (низший)алкил, галоид (низший)алкил, окси(низший)алкил, амино (низший)алкил, (низший) алкиламино (низший) алкил, ди(низший) алкиламино (низший) алкил, (низший)алкиламино, ди(низший) алкиламино, карбокси (низший)алкил, карбокси (низший) алкиламино, карбокси (низший) алкилтио, карбамоил N-(низший)алкилкарбамоил, формиламино, ациламино, ацилокси, фенил, пиридил, амидино, гуанидино и аналогичные. Когда структура гетероциклического кольца позволяет, R⁹ и R¹⁰ взятые вместе, могут представлять алкиленовую группу, содержащую от 3 до 5 атомов углерода, например пропилен.Examples of cyclic quaternary ammonio groups are fully unsaturated monocyclic heterocyclic ring systems and bicyclic heterocyclic ring systems in which at least one N-containing ring is completely unsaturated. Suitable cyclic quaternary ammonio ring systems include, for example, systems of formulas
- ^⊕ N

- ^⊕ N

- ^⊕ N

,

-

,
R

R ⁹ , R

_,

,

_R 9 and similar, in which R ⁹ and R ¹⁰ are the same or different and may be, for example, hydrogen, halogen, amino, (lower) alkyl, (lower) alkenyl, (lower) alkylthio, carboxy, hydroxyl, (lower ) alkoxy, (lower) alkoxy (lower) alkyl, halogen (lower) alkyl, hydroxy (lower) alkyl, amino (lower) alkyl, (lower) alkylamino (lower) alkyl, di (lower) alkylamino (lower) alkyl, ( lower) alkylamino, di (lower) alkylamino, carboxy (lower) alkyl, carboxy (lower) alkylamino, carboxy (lower) alkylthio, carbamoyl N- (lower) alkylcarbamoyl, formylam foreign, acylamino, acyloxy, phenyl, pyridyl, amidino, guanidino and the like. When the structure of the heterocyclic ring allows, R ⁹ and R ¹⁰ taken together can represent an alkylene group containing from 3 to 5 carbon atoms, for example propylene.

N

R¹²,

N

R¹²,

N

R¹²

N

,

N

,

N

N

,

N

R¹²,

N

R¹²,

N

N-(низший) алкил

N

R¹²,

и аналогичные, в которых R¹¹ может представлять собой, например, (низший) алкил, (низший) алкокси (низший) алкил, окси (низший) алкил, при условии, что окси не может быть у альфа-углерода, карбокси(низший) алкил, амино (низший) алкил с условием, что амино не может быть у альфа-углерода, (низший) алкенил, галоид (низший) алкил, аллил и аналогичные, и R¹² может представлять собой, например, водород, окси, галоген (низший) алкил, окси (низший) алкил, (низший) алкокси(низший) алкил, галоид(низший) алкил, амино (низший) алкил, (низший)алкокси, (низший) алкилтио, (низший) алкенил, амино, (низший) алкиламино, ди(низший) алкиламино, ациаламино, ацилокси, карбамоил, амидино (низший) алкил, фенил, пиридил, амидино, гуанидино и аналогичные.Examples of combined acyclic (cyclic quaternary) ammonio groups include, for example, groups of formulas

N

R ¹² ,

N

R ¹² ,

N

R ¹²

N

,

N

,

N

N

,

N

R ¹² ,

N

R ¹² ,

N

N- (lower) alkyl

N

R ¹² ,

and similar, in which R ¹¹ may be, for example, (lower) alkyl, (lower) alkoxy (lower) alkyl, hydroxy (lower) alkyl, provided that hydroxy cannot be in alpha-carbon, carboxy (lower) alkyl, amino (lower) alkyl with the proviso that amino cannot have alpha-carbon, (lower) alkenyl, halogen (lower) alkyl, allyl and the like, and R ¹² may be, for example, hydrogen, hydroxy, halogen ( lower) alkyl, hydroxy (lower) alkyl, (lower) alkoxy (lower) alkyl, halogen (lower) alkyl, amino (lower) alkyl, (lower) alkoxy, (lower) alkylthio, (lower ii) alkenyl, amino, (lower) alkylamino, di (lower) alkylamino, acylamino, acyloxy, carbamoyl, amidino (lower) alkyl, phenyl, pyridyl, amidino, guanidino and the like.

,

-^⊕N

R¹⁸,

и

в которых R¹³, R¹⁴ и R¹⁵ являются одинаковыми или различными и представляют собой (низший)алкил, (низший) алкенил, амино (низший) алкил при условии, что амино не может находиться у альфа-углерода, или окси (низший) алкил при условии, что гидроксильная группа не может находиться у альфа-углерода;
R¹⁶ представляет собой водород, (низший) алкил, (низший) алкокси, (низший) алкилтио, (низший) алкиламино, ди(низший) алкиламино, формиламино, (низший)алканоиламино, карбокси, гидроксил, карбокси(низший) алкил, карбокси (низший) алкилтио, окси (низший) алкил, галоид (низший) алкил, амино (низший) алкил, (низший) алкокси (низший) алкил, карбамоил или N-(низший) алкилкарбамоил, или R¹⁶ может представлять двухвалентную алкиленовую группу, имеющую от 3 до 5 атомов углерода.Preferred quaternary ammonio groups are groups of formulas
^⊕ -

,

- ^⊕ N

R ¹⁸ ,

and

in which R ¹³ , R ¹⁴ and R ¹⁵ are the same or different and are (lower) alkyl, (lower) alkenyl, amino (lower) alkyl, provided that amino cannot be found on alpha-carbon, or hydroxy (lower) alkyl, provided that the hydroxyl group cannot be on alpha carbon;
R ¹⁶ represents hydrogen, (lower) alkyl, (lower) alkoxy, (lower) alkylthio, (lower) alkylamino, di (lower) alkylamino, formylamino, (lower) alkanoylamino, carboxy, hydroxyl, carboxy (lower) alkyl, carboxy (lower) alkylthio, hydroxy (lower) alkyl, halogen (lower) alkyl, amino (lower) alkyl, (lower) alkoxy (lower) alkyl, carbamoyl or N- (lower) alkylcarbamoyl, or R ¹⁶ may represent a divalent alkylene group, having from 3 to 5 carbon atoms.

R ¹⁷ represents (lower) alkyl, (lower) alkoxy (lower) alkyl, halogen (lower) alkyl, allyl, hydroxy (lower) alkyl, provided that the hydroxyl group is not found on alpha carbon, amino (lower) alkyl at provided that the amino group is not found on alpha carbon, or phenyl (lower) alkyl;
R ¹⁸ represents hydrogen, (lower) alkyl, (lower) alkoxy, (lower) alkoxy (lower) alkyl, (lower) alkylthio, amino, (lower) alkylamino, di (lower) alkylamino, carboxy, hydroxyl, carboxy (lower) ) alkyl, hydroxy (lower) alkyl, amino (lower) alkyl, formyl amino, (lower) alkanoylamino, carbamoyl or N- (lower) alkylcarbamoyl;
n is an integer from 1 to 3 inclusive;
Z represents CH ₂ or, when n-2, Z may also be sulfur, oxygen or an NR ¹⁹ group in which R ¹⁹ is hydrogen or (lower) alkyl; and
R ²⁰ and R ²¹ are the same or different and represent hydrogen, (lower) alkyl, (lower) alkoxy, (lower) alkylthio, amino, (lower) alkylamino, di (lower) alkylamino, carboxy, hydroxyl, hydroxy (lower) alkyl, amino (lower) alkyl, (lower) alkoxy (lower) alkyl, carboxy (lower) alkyl, carboxy (lower) alkylamino, (lower) alkanoylamino, carboxy (lower) alkanoylamino, carbamoyl or N- (lower) alkylcarbamoyl.

 Particularly preferred quaternary ammonio groups are N- (lower) alkylpyrrolidino (and especially N-methylpyrrolidino) tri (lower) alkyl (ammonio) and especially trimethylammoniopyridinio, aminopyridinio, formylaminopyridinio, carbamoylpyridinio, amino (lower alkoxydio) lower) alkylpyridinio, N- (lower) alkylcarbamoylpyridinio, (lower) alkylenepyridinio, 2-methylthiazolo and 2-amino-5-thiazolo (4,5-c) pyridinio.

In the compounds of formula (I), particularly preferred values of R ² are (lower) alkyl (and especially methyl), cycloalkyl containing from 3 to 5 carbon atoms, 1-carboxycycloalk-1-yl containing from 3 to 5 carbon atoms, allyl, propargyl and carboxy (lower) alkyl (especially 2-carboxyprop-2-yl). The most preferred compounds of this invention are:
1) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] 3- [3- (trimethylammonio) -1-propen-1-yl] -3-cephem -4-car-boxilate,
2) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] 3- [3- (1-methylpyrrolidinio) -1-propen-1-yl] -3 -cefem-4-carboxylate,
3) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamino] 3- [3-pyridinio-1-propen-1-yl] -3-cefem-4 carboxylate.

4) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] 3- [3- (3-aminopyridinio) -1-propen-1-yl] -3 Cephem-4-carbo-xylate,
5) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] 3- [3- (3-formylaminopyridinio) -1-propen-1-yl] -3 cephem-4-carboxylate,
6) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] 3- [3- (3-aminomethylpyridinio) -1-propen-1-yl] -3 cephem-4-carboxylate,
7) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] 3- [3- (3-carbamoylpyridinio) -1-propen-1-yl] -3 cephem-4-carboxylate,
8) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] 3- [3- (4-carbamoylpyridinio) -1-propen-1-yl] -3 cephem-4-carboxylate,
9) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] 3- [3- (2-methylthiazolo) -1-propen-1-yl] -3 -cefem-4-carboxy-lat,
10) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] 3- [3- (2-amino-5-thiazolo [4,5-c] pyridinio ) -1-propen-1-yl] -3-cefem-4-carboxylate,
11) 7, [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] 3- [3- (4-hydroxymethylpyridinio) -1-propen-1-yl] -3 cephem-4-carboxylate,
12) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] 3- [3- (3-hydroxymethylpyridinio) -1-propen-1-yl] -3 cephem-4-carboxylate,
13) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] 3- [3- (4- {N-methylcarbamoyl} pyridinio) -1-propen-1 -yl] -3-cefem-4-carboxylate,
14) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] 3- [3- (2,3-propylenepyridinio) -1-propen-1-yl] -3-cefem-4-carboxylate,
15) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamido] 3- [3- (4-carbamoylpyridinio) -1-propen-1-yl] -3 cephem-4-carboxylate,
16) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxyiminoacetamido] -3- [3- (4-carbamoylpyridinio) -1-propen-1-yl] - 3-cephem-4-carboxylate,
17) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-allyloxyiminoacetamido] -3- [3- (4-carbamoylpyridinio) -1-propen-1-yl] - 3-cefem-4-carboxylate,
18) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-propargyloxyimino-acetamido] -3- [3- (4-carbamoylpyridinio) -1-propen-1-yl ] -cefem-4-carboxylate,
19) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] 3- [3- (4-carboxypyridinio) -1-propen-1-yl] -3 cephem-4-carboxylate,
20) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamido] 3- [3- (4-carboxypyridinio) -2-propen-1-yl] -3 -cefem-4-carboxylate,
21) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] 3- [3- (3-carbo-ximethylpyridinio) -1-propen-1-yl] -3-cepem-4-carboxylate, and
22) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] 3- [3- (4-carbo-ximethylthiopyridinio) -1-propen-1-yl] -3- cefem-4-carboxylate.

(

Римская цифра обозначает, является ли соединение конечным продуктом (I) или промежуточным соединением, или другим реагентом [все другие римские цифры] Арабские цифры и буквенные обозначения не используются в тех случаях, когда имеется в виду общий класс (род) соединений.The numbering system used here for various reagents, intermediates and final products is as follows:
[Roman numerals]

(

The Roman numeral indicates whether the compound is the final product (I) or an intermediate compound, or another reagent [all other Roman numerals] Arabic numerals and letter designations are not used in cases where the general class (genus) of compounds is meant.

Arabic numbers indicate the specific meaning of the substituent R ² . If the particular R ² group contains a carboxyl group that is protected by a conventional carboxyl protecting group, the prim icon (') is used after the Arabic numeral to indicate this. The prim icon is not used if the carboxyl group is unprotected. The prim icon is also used with a generic substituent (ie, R ²¹ ) when referring generally to an R ² group containing a protected carboxyl group.

The letter at the end of the compound number refers to the quotient of the quaternary ammonio group - ^⊕ N≡Q
For convenience, Arabic numbers and letters assigned to some of the preferred R ² groups and Quaternary ammonio groups are presented below.

Arabic R ²
number
1 methyl
2 ethyl
3 allyl
4 steamed
5 cyclopentyl
Letter _ ^⊕ N≡Q
A 1-methylpyrrolidinio
In pyridinio
C 2-amino-5-thiazolo [4,5-c]
pyridinio
D trimethylammonio
E 3-aminopyridinio
F 3-Formylaminopyridinio
G 3-carbamoylpyridinio
H 4-carbamoylpyridinio
I 3-aminomethylpyridinio
J 2-methylthiazolio
K 3-hydroxymethylpyridinio
L 4-hydroxymethylpyridinio
M 4- (N-methylcarbamoyl) pi-
ridinio
N 4-carboxypyridinio
O 2,3-propenylpyridinio
P 3-carboxymethylpyri-
dinio
Q 4-carboxymethylthiopi-
ridinio
In the initial evaluation of the compounds of the invention, the minimum inhibitory concentrations (MICs) of the compounds were determined using the method of double dilution of agar on Muller-Hinton agar against 32 strains of the tested organisms in six groups. The geometric values of the MIC determined in these tests are shown in Table 1.

(G + 1) -1a: Sensitive to penicillin S. aureus (5 strains)
(G + 1) -1b: Penicillin-resistant S. aureus (5 strains)
(G-1) -1a: Cephalotin-sensitive E. coli (2 strains), K1, pneumoniae (1 strain) and Pr. mirabilis (2 strains)
(G-1) -1b: Cephalotin-resistant E.coli (3 strains) and (2 strains)
(G-1) -11: M. morganii (1 strain), Ent. cloacae (2 strains) Sir. mazcescens
(G-1) -III: Ps. aezuginosa (7 strains)
Table 2 gives the protective dose (PD ₅₀ ) for the experiment in mice for a number of compounds of formula (I) against selected microorganisms. Table 3 shows the blood levels of various compounds of formula (I) for intramuscular administration of test compounds to mice at a dose of 20 mg / kg.

According to another aspect, this invention relates to processes for the preparation of compounds of formula (I). Preferred procedures are shown in Reaction Schemes 1a, 1b and 1c below, with an alternative technique shown in Reaction Scheme 2. The abbreviation "Ph" means a phenyl group. Thus, the (-CH / Ph) ₂ moiety is a benzhydryl group, which is a preferred carboxyl protecting group. When R ² contains a carboxyl group, it is desirable to protect the carboxyl group with a conventional carboxyl protecting group, such as a tert-butyl group, Y represents chlorine, bromine or iodine.

На схеме реакции 1а показаны два альтернативных способа реакции, начиная от соединения IX до соединения XII. Прямой путь, использующий третичный амин (XI) применим для получения всех соединений формулы (I). Косвенный путь, через соединение (X), использует в качестве реагента вторичный амин, и на следующей стадии осуществляется кватернизация. Вторичный амин RR'NH может быть ациклическим (например, диметиламин) или циклическим (например, пирролидин), и данный косвенный способ, следовательно, является пригодным для получения соединений формулы (I), в которых четвертичная аммонио-группа является ациклической или "смешанной" ациклической циклической. Данный косвенный способ не пригоден для получения соединений формулы (I), в которых четвертичный азот находится в полностью ненасыщенном гетероциклическом кольце (например, пиридинио, тиазолио, 2-амино-5-тиазоло[4,5-c]пиридинио, и аналогичные).Reaction Scheme 1a

Reaction Scheme 1a shows two alternative reaction methods, ranging from compound IX to compound XII. The direct route using the tertiary amine (XI) is applicable for the preparation of all compounds of formula (I). The indirect route, through compound (X), uses a secondary amine as a reagent, and in the next step, quaternization is carried out. The secondary amine RR'NH may be acyclic (eg, dimethylamine) or cyclic (eg, pyrrolidine), and this indirect method is therefore suitable for the preparation of compounds of formula (I) in which the quaternary ammonio group is acyclic or “mixed” acyclic cyclic. This indirect method is not suitable for the preparation of compounds of formula (I) in which quaternary nitrogen is in a completely unsaturated heterocyclic ring (for example, pyridinio, thiazolo, 2-amino-5-thiazolo [4,5-c] pyridinio, and the like).

CHO

Схема реакции 1b представляет собой видоизменение схемы реакции 1а, заключающееся в том, что 7-амино-группа исходного вещества (II) является защищенной в виде Шиффова основания в течение большинства из стадий реакции, и позднее в ходе синтеза добавляется требуемая 7-боковая кислотная цепь. В других отношениях общая процедура является сходной.Reaction Scheme 1b

Cho

Reaction Scheme 1b is a modification of Reaction Scheme 1a, namely, that the 7-amino group of the starting material (II) is protected as a Schiff base during most of the reaction steps, and later the required 7-side acid chain is added during the synthesis . In other respects, the general procedure is similar.

Схема реакции 1с является дальнейшим видоизменением схемы реакции 1b. Согласно схемам реакции 1а и 1b кватернизация 3-боковой цепи является последней стадией, а по схеме реакции 1с последней стадией является ацилирование 7-амино-группы. Взаимосвязь между схемами реакций 1а, 1b и 1с показана на следующей схеме.Reaction scheme 1c

Reaction scheme 1c is a further modification of reaction scheme 1b. According to reaction schemes 1a and 1b, the quaternization of the 3-side chain is the last stage, and according to reaction scheme 1c, the last stage is the acylation of the 7-amino group. The relationship between reaction schemes 1a, 1b and 1c is shown in the following scheme.

На схемах реакций 1а, 1b и 1с бензгидрильная группа показана в качестве предпочтительной карбоксилзащищающей группы. Специалистам в данной области техники должно быть понятно, что могут использоваться и другие карбоксилзащищающие группы, хорошо известные в технике. Ацилирующая кислота формулы (III) может использоваться в форме производного, такого как галоидангидрид кислоты, активированный сложный эфир, смешанный ангидрид кислоты и др. все из которых хорошо известны в технике. Мы предпочитаем использовать ее в форме хлорангидрида кислоты. Ацилирующая кислота формулы (III) также может иметь амино группу, защищенную любой из обычных аминозащищающих групп, например N-тритильной, N-формильной или аналогичной. Основанием, используемым для превращения иодида фосфония (VI или XV) для получения фосфорилида (VII или XVI) может быть гидроокись натрия, карбонат натрия, смола IRA-410 (OH^-), смола IRA (CO $\genfrac{}{}{0ex}{}{\text{-}}{\text{3}}$ ) или аналогичные, или смеси их. Хлорацетальдегидом, используемым для превращения фосфорилида VII в 3-хлорпропенил-3-цефемовое соединение VIII (или соединения XVI в соединение XVII) может быть коммерчески доступный 40-50% водный раствор, дистиллированный раствор (например 70%) или безводный альдегид. Обнаружили, что соединение VIII, полученное из соединения VII (схема 1а) в типичном случае имеет соотношение Z:E около 2:1 при пропенильной двойной связи. Соединение VIII, получаемое из соединения XVIII (схема 1b), с другой стороны, обычно почти исключительно состояло из Z изомера. Разница не может заключаться в используемом способе, а в условиях, используемых при реакции Виттига (VII в VIII или XVI и XVII). Также обнаружили, что использование соответствующего силильного реагента, такого как N, O-бис-(триметилоилил)ацетамид в реакции Виттига (VII в VIII в схеме 1а и XVI в XVII по схеме 1b) вызывало улучшение выходов и чистоты соединений VIII и XVII. Реакция предпочтительно осуществляется с использованием 2-5 эквивалентов силильного реагента. Когда хлорпропенил-цефем (VIII) вводился в реакцию с иодистым натрием в ацетоне, давая иодпропенил-цефем (IX), двойная связь в пропенильной группе изомеризовалась из Z в Е в ходе иодирования. Короткий период реакции сохранял в огромной степени конфигурацию исходного соединения VIII, хотя длительная реакция давала главным образом Е изомер соединения IX. Однако реакция в течение избыточного периода времени при высокой температуре дает более низкую чистоту соединения IX. Реакция в течение около 10 мин при 25^оС и в течение 2 ч при 5^оС дает чистое соединение IX с хорошим выходом. При использовании схемы реакции 1с нашли, что при иодировании соединения XIV иодистым натрием получается более чистое соединение, если раствор ацетона разбавляется четыреххлористым углеродом, когда иодирование в основном завершается, и часть реакции, относящаяся к изомеризации, проводится в смеси ацетона и четыреххлористого водорода. Когда иодирование хлорпропенилцефема (XVII) для получения иодпропенил-цефема (XIX) проводилось с помощью иодистого калия в диметилформамиде, изомеризация двойной связи из Z в Е протекала также быстро, как и иодирование. Вся реакция завершалась за 45 мин при комнатной температуре, давая чистое XIX без разбавления четыреххлористым углеродом в течение реакции.

In reaction schemes 1a, 1b and 1c, a benzhydryl group is shown as a preferred carboxyl protecting group. Those skilled in the art will appreciate that other carboxyl protecting groups well known in the art can be used. The acylating acid of formula (III) can be used in the form of a derivative, such as an acid halide, an activated ester, a mixed acid anhydride, etc. all of which are well known in the art. We prefer to use it in the form of an acid chloride. The acylating acid of formula (III) may also have an amino group protected by any of the usual amino protecting groups, for example N-trityl, N-formyl or the like. The base used to convert phosphonium iodide (VI or XV) to produce phosphorylide (VII or XVI) may be sodium hydroxide, sodium carbonate, resin IRA-410 (OH ^- ), resin IRA (CO $\genfrac{}{}{0ex}{}{\text{-}}{\text{3}}$ ) or similar, or mixtures thereof. The chloroacetaldehyde used to convert phosphorylide VII to 3-chloropropenyl-3-cephem compound VIII (or compound XVI to compound XVII) may be a commercially available 40-50% aqueous solution, distilled solution (e.g. 70%) or anhydrous aldehyde. It was found that compound VIII obtained from compound VII (Scheme 1a) typically has a Z: E ratio of about 2: 1 at the propenyl double bond. Compound VIII obtained from compound XVIII (Scheme 1b), on the other hand, usually almost exclusively consisted of the Z isomer. The difference cannot lie in the method used, but under the conditions used in the Wittig reaction (VII in VIII or XVI and XVII). It was also found that the use of an appropriate silyl reagent such as N, O-bis- (trimethyloyl) acetamide in the Wittig reaction (VII in VIII in Scheme 1a and XVI in XVII in Scheme 1b) caused an improvement in the yields and purity of compounds VIII and XVII. The reaction is preferably carried out using 2-5 equivalents of a silyl reagent. When chlorpropenyl-cephem (VIII) was reacted with sodium iodide in acetone to give iodopropenyl-cephem (IX), the double bond in the propenyl group was isomerized from Z to E during iodination. The short reaction period kept to a tremendous extent the configuration of the starting compound VIII, although the long reaction gave mainly the E isomer of compound IX. However, reaction for an excess period of time at high temperature gives a lower purity of compound IX. The reaction for about 10 minutes at 25 ° ^C and for 2 hours at ⁵ ° C gave the pure compound IX in good yield. Using reaction scheme 1c, it was found that by iodinating compound XIV with sodium iodide, a cleaner compound is obtained if the acetone solution is diluted with carbon tetrachloride, when iodination is mostly completed, and part of the reaction related to isomerization is carried out in a mixture of acetone and hydrogen tetrachloride. When iodination of chlorpropenylcefem (XVII) to obtain iodopropenyl-cephem (XIX) was carried out using potassium iodide in dimethylformamide, the double bond isomerization from Z to E proceeded as quickly as iodination. The whole reaction was completed in 45 minutes at room temperature, giving pure XIX without dilution with carbon tetrachloride during the reaction.

Схема реакции 2 является аналогичной схеме реакции 1а, за исключением того, что соединение XXIII (эквивалентное соединению IX схемы реакции 1а) превращается в его S-окись перед кватернизацией. Соединение XXV впоследствии восстанавливается, а остальная часть реакционной схемы 2 является такой же, как и схема реакции 1а. По схеме реакции 2 предпочитается защищать амино-группу 7-боковой цепи известной аминозащищающей группой, такой как тритильная группа (трифенилметильная).Compound XII was typically released without purification, and the final product (I) was purified by reverse phase column chromatography using a glass column containing a nozzle taken from PrepPak-500 / C ₁₃ coal briquette from Waters Associates
Reaction Scheme 2

Reaction Scheme 2 is similar to Reaction Scheme 1a, except that compound XXIII (equivalent to compound IX of Reaction Scheme 1a) is converted to its S-oxide before quaternization. Compound XXV is subsequently reduced, and the rest of reaction scheme 2 is the same as reaction scheme 1a. In Reaction Scheme 2, it is preferable to protect the amino group of the 7-side chain with a known amino protecting group such as a trityl group (triphenylmethyl).

The acylating acids of formula (III) used herein are either known compounds or are readily prepared using published procedures. A known example is the preparation of compounds of formula III in which R ² is methyl, ethyl, propyl and isopropyl. A well-known example is the preparation of a wide variety of compounds of formula (III) in which R ² is, for example, cyclopentyl, 2-cyclopenten-1-yl, allyl, 2-propynyl, 1-tert-butyloxycarbonyl-1-methylethyl, 1-tert- butyloxycarbonyl-1-cyclopentyl, 1-ethoxycarbonyl-1-methylethyl, tert-butyloxycarbonylmethyl, 1-tert-butyloxycarbonyl-2-methylpropyl, trityl and the like.

 Compound (II) (7-amino-3-chloromethyl-3-cephem-4-carboxylate), used as starting material in reaction scheme 1a, 1b and 1c, is a known compound.

 The tertiary amines of formula (XI) (and the secondary amines RR'NH) used in the preparation of the quaternary ammonium compounds of the present invention are either known compounds or can readily be obtained by those of ordinary skill in the art. Many of the amines are industrially and commercially available.

в которой R³ представляет собой водород или обычную амино-защищающую группу, R²-водород, алкильная группа с прямой или разветвленной цепью, содержащая от 1 до 4 атомов углерода, циклоалкильное или циклоалкенильное кольцо, содержащее от 3 до 6 атомов углерода, или группа формул

^-

^{C ≡ C -}

^или в которых R³ представляет собой водород, (низший) алкил или карбоксил, Х представляет собой галоген, гидроксил или (низший) алкокси, и R⁴ и R⁵каждый независимо представляет собой водород, метил или этил, или R⁴ и R⁵, взятые вместе с атомом углерода, к которому они присоединены, могут представлять циклоалкилиденовое кольцо, содержащее от 3 до 5 атомов углерода, и группа -^⊕N≡Q представляет собой четвертичную аммонио группу, и их нетоксичных фармацевтических приемлемых солей и физиологически гидролизуемых сложных эфиров, причем данный процесс предусматривает взаимодействие соединения формулы
B²HN

H= CHCH₂Z в которой R^2' имеет те же значения, что и R², или представляет собой группу формул

^{или -}

в которых Х, R⁴ и R⁵ имеют значения, определенные выше, В¹ представляет собой общепринятую карбоксилзащищающую группу, В² является водородом или общепринятой амино-защищающей группой, представляет хлор, бром или иод, и m равно нулю или единице, с третичным амином Q ≡ N (или последовательно с вторичным амином RR'NH и соединением формулы R"Z), и, если m равно 1, восстановление сульфоксида с помощью обычных средств, и последующее удаление всех блокирующих групп с помощью обычных средств.The present invention also provides a process for preparing compounds of the formula

in which R ³ represents hydrogen or a conventional amino protecting group, R ^{2 is} hydrogen, a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl ring containing from 3 to 6 carbon atoms, or a group formulas

^-

^{C ≡ C -}

^or in which R ³ represents hydrogen, (lower) alkyl or carboxyl, X represents halogen, hydroxyl or (lower) alkoxy, and R ⁴ and R ⁵ each independently represents hydrogen, methyl or ethyl, or R ⁴ and R ⁵ taken together with the carbon atom to which they are attached may represent a cycloalkylidene ring containing from 3 to 5 carbon atoms, and the group - ^⊕ N≡Q represents a quaternary ammonio group, and their non-toxic pharmaceutical acceptable salts and physiologically hydrolyzable esters, moreover, this process c provides for the interaction of the compounds of formula
B ² HN

H = CHCH ₂ Z in which R ^{2 '} has the same meanings as R ² , or is a group of formulas

^{or -}

in which X, R ⁴ and R ⁵ are as defined above, B ¹ is a conventional carboxyl protecting group, B ² is hydrogen or a common amino protecting group, is chloro, bromo or iodo, and m is zero or one, with a tertiary an amine Q ≡ N (or sequentially with a secondary amine RR'NH and a compound of the formula R "Z), and, if m is 1, the reduction of sulfoxide by conventional means and the subsequent removal of all blocking groups by conventional means.

CH= CH-CH₂-^⊕N≡Q в которой R¹ представляет собой водород или обычную амминозащищающую группу, R² представляет собой водород, алкильную группу с прямой или разветвленной цепью, содержащую от 1 до 4 атомов углерода, циклоалкильную или циклоалкенильную группу, содержащую от 3 до 6 атомов углерода, или группу формулы

CH-R³,

- C ≡ C R³,

или в которых R³ водород, (низший) алкил или карбоксил, Х галоген, гидроксил или (низший) алкокси, и R⁴ и R⁵ каждый независимо представляет собой водород, метил или этил, или R⁴ и R⁵ взятые вместе с атомом углерода, к которому они присоединены, могут представлять циклоалкиленовое кольцо, содеpжащее от 3 до 5 атомов углерода, и группа -^⊕N≡Q представляет собой четвертичную аммонио группу, и нетоксичных фармацевтически приемлемых солей и физиологически гидролизуемых сложных эфиров их, данный процесс предусматривает ацилирование соединения формулы

кислотой формулы

или ацилирующим производным указанной кислоты, где R^2' имеет те же значения, что и R² или представляет собой группу формул

или

- COOB¹ в которых Х, R⁴ и R⁵ имеют значения, определенные выше, В¹ представляет собой обычную карбоксил-защищающую группу, и В² водород или общепринятая амино-защищающая группа.The invention also provides a process for preparing compounds of the formula

CH = CH-CH ₂ - ^⊕ N ≡ Q in which R ¹ represents hydrogen or a conventional amino protecting group, R ² represents hydrogen, a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl group, containing from 3 to 6 carbon atoms, or a group of the formula

CH-R ³ ,

- C ≡ CR ³ ,

or in which R ^{3 is} hydrogen, (lower) alkyl or carboxyl, X is halogen, hydroxyl or (lower) alkoxy, and R ⁴ and R ^{5 are} each independently hydrogen, methyl or ethyl, or R ⁴ and R ⁵ taken together with an atom the carbon to which they are attached may represent a cycloalkylene ring containing from 3 to 5 carbon atoms, and the - ^⊕ N≡Q group is a quaternary ammonio group, and non-toxic pharmaceutically acceptable salts and physiologically hydrolyzable esters thereof, this process involves the acylation of the compound formulas

acid of the formula

or an acylating derivative of the specified acid, where R ^{2 '} has the same meanings as R ² or represents a group of formulas

or

- COOB ¹ in which X, R ⁴ and R ⁵ are as defined above, B ¹ is a conventional carboxyl protecting group, and B ^{2 is} hydrogen or a conventional amino protecting group.

The reactions are carried out in a non-aqueous organic solvent such as dimethyl sulfoxide, hexamethylphosphoramide, methylene chloride, chloroform, ethyl ether, hexane, ethyl acetate, tetrahydrofuran, acetonitrile and the like, or mixtures of such solvents. The reactions are conveniently carried out at a temperature from about -10 ^C to +50 ^C; usually prefer to carry out the reaction at room temperature. During the quaternization step per mole of compound IX, XIX, XXIII and XXIV, at least 1 mole of the tertiary amine should be used, typically about 25 to 100% excess tertiary amine is used.

Carboxyl protecting groups suitable for use as B ¹ in the above reactions are well known to those skilled in the art and include aralkyl groups such as benzyl, p-methoxybenzyl, p-nitrobenzyl and diphenylmethyl (benzhydryl); alkyl groups such as tert-butyl; haloalkyl groups such as 2,2,2-trichloroethyl and other known carboxyl protecting groups. Prefer to use carboxyl-protective groups, which are easily removed by treatment with acid. Particularly preferred carboxyl protecting groups are benzhydryl and tert-butyl.

Amino protecting groups suitable for use as ^B2 are also well known in the art and include a trityl group and acyl groups such as chloroacetyl, formyl and trichloroethoxycarbonyl. Amino protecting groups are preferred which are readily removed by treatment with an acid, for example a trityl group.

 When the cephalosporin core is used in the form of 1-hydroxy (m 1), the 1-oxide is obtained using known techniques such as oxidation with m-chloroperbenzoic acid, peracetic acid, sodium tungstate, etc. 1-oxide can subsequently be reduced using known procedures. for example, reduction of the corresponding alkoxysulfonium salt with an iodide ion in an aqueous medium. The alkoxysulfonium salt itself can easily be obtained by treating 1-oxide, for example with acetyl chloride.

в которой Z представляет собой хлор, бром или иод, R² представляет собой водород, алкильную группу с прямой или разветвленной цепью, содержащую от 1 до 4 атомов углерода, циклоалкильное или циклоалкенильное кольцо, содержащее от 3 до 6 атомов углерода, или группу формул

CH-R³,

- C ≡ C R³,

или в которых R³ представляет собой водород, (низший) алкил или карбоксил, Х представляет собой галоген, гидроксил или (низший) алкокси и R⁴ и R⁵каждый независимо представляет собой водород, метил или этил, или R⁴ и R⁵ взятые вместе с атомом углерода, к которому они присоединены, могут представлять циклоалкилиденовое кольцо, содержащее от 3 до 5 атомов углерода, и их солям и сложным эфирам. В сферу изобретения включены также соединения формулы XXVIII, в которой амино и/или карбоксильная группы защищены обычными аминозащищающими или карбоксил-защищающими группами.According to another aspect, the invention relates to new intermediates of the formula

in which Z represents chlorine, bromine or iodine, R ² represents hydrogen, a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl ring containing from 3 to 6 carbon atoms, or a group of formulas

CH-R ³ ,

- C ≡ CR ³ ,

or in which R ³ is hydrogen, (lower) alkyl or carboxyl, X is halogen, hydroxyl or (lower) alkoxy and R ⁴ and R ⁵ each independently represents hydrogen, methyl or ethyl, or R ⁴ and R ⁵ taken together with the carbon atom to which they are attached, can represent a cycloalkylidene ring containing from 3 to 5 carbon atoms, and their salts and esters. Compounds of formula XXVIII are also included in the scope of the invention in which the amino and / or carboxyl groups are protected by conventional amino protecting or carboxyl protecting groups.

CH= N

в которой R²² представляет собой водород или обычную карбоксил-защищающую группу, и R²³, R²⁴ и R²⁵ являются одинаковыми или различными и представляют собой водород, гидроксил, (низший) алкил или (низший) алкокси; или к их солям, сольватам, гидратам или сложным эфирам.According to another aspect, the invention relates to new intermediates of the formula
R

CH = N

in which R ²² represents hydrogen or a conventional carboxyl protecting group, and R ²³ , R ²⁴ and R ²⁵ are the same or different and represent hydrogen, hydroxyl, (lower) alkyl or (lower) alkoxy; or their salts, solvates, hydrates or esters.

CH= CH-CH₂-

Q в которой -^⊕N≡Q представляет собой четвертичную аммонио группу; или солям, сложным эфирам, сольватам или гидратам их. В том смысле, как они используются здесь, термины ациламино и ацилокси относятся к ацилированным амино или ацилированным гидроксильным группам, в которых ацильная часть представляет собой (низший)алканоил (например, формил, ацетил, пропионил, бутирил, изобутирил, изовалерил и др.), ароил (например, бензоил и др.), (низший) алкансульфонил (например, метилсульфонил, этансульфонил и др.) или арилсульфонил (например, бензолсульфонил, тозил и др.).According to another aspect, the invention relates to new intermediates of the formula

CH = CH-CH ₂ -

Q in which - ^⊕ N≡Q represents a quaternary ammonio group; or salts, esters, solvates or their hydrates. In the sense that they are used here, the terms acylamino and acyloxy refer to acylated amino or acylated hydroxyl groups in which the acyl moiety is a (lower) alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, isovaleryl, etc.) , aroyl (e.g., benzoyl, etc.), (lower) alkanesulfonyl (e.g., methylsulfonyl, ethanesulfonyl, etc.) or arylsulfonyl (e.g., benzenesulfonyl, tosyl, etc.).

 In the sense that they are used here, the terms (lower) alkyl, (lower) alkoxy, (lower) alkylthio (or similar) mean straight or branched chain alkyl, alkoxy, alkylthio (or similar) groups containing from 1 to 6 carbon atoms, inclusive. Similarly, the terms (lower) alkenyl and (lower) alkynyl refer to alkenyl or alkynyl groups containing from 2 to 6 carbon atoms.

 PRI me R 1.

7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2-метоксииминоацетамидо] -3- [3-(1-метилпирролидинио)-1-пропен-1-ил]-3-цефем-4-карбоксилат (1-1А).H ₂ N

7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (1-methylpyrrolidinio) -1-propen-1-yl] -3- cefem-4-carboxylate (1-1A).

To a solution of diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) -3-cefem -4- carboxylate (IX-I) (Z / E 2/1, 150 mg, 0.21 mmol) in ethyl acetate (2 ml) was added a solution of 1-methylpyrrolidine (36 mg, 0.42 mmol) in ethyl acetate (1 ml ) in one portion with stirring. The mixture was stirred for 15 minutes and diluted with isopropyl ether (10 ml) to form a precipitate, which was collected by filtration. A mixture of solid (130 mg), formic acid (1 ml) and concentrated hydrochloric acid (0.1 ml) was stirred at room temperature. After an hour, the reaction mixture was concentrated under reduced pressure, diluted with water (20 ml) and filtered. The aqueous solution was passed through the column in the reverse phase (nozzle carbon briquette PrepPAK-500 / C ₁₈ , 100 ml), was eluted with water and 10% methanol. Desired fractions were collected and concentrated in vacuo to a small volume and freeze-dried, giving 13 mg (12%) of the title compound (1-1A) (Z / E 1/1), melting at> 280 ^C (dec.).

IR: ν _max. KBr, cm ^-1 : 3400, 1760, 1660, 1610.

UV: λ _max. phosphate buffer (pH 7), nm: (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ 236/372), 288 (322).

(3,12) 3Н, и N

3,79 (1Н, синглет, 2-Н), 4,1 (2Н. дублет, J 2, CH₂N), 4,2 (3Н, синглет, ОСН₃) 5,36 (1Н, дублет, J 4,5, 6-Н), 5,95 (3Н, мультиплет, 7Н и 3-СН=СН), 6,66 (1/2Н, дублет, J 10, 3-СН цис), 7,0 (1/2Н, дублет, J 16, 3-СН транс).NMR: δ D ₂ O, ppm 2.31 (4H, multiplet, N

(3.12) 3H, and N

3.79 (1H, singlet, 2-H), 4.1 (2H, doublet, J 2, CH ₂ N), 4.2 (3H, singlet, OCH ₃ ) 5.36 (1H, doublet, J 4 5, 6-H), 5.95 (3H, multiplet, 7H and 3-CH = CH), 6.66 (1/2 H, doublet, J 10, 3-CH cis), 7.0 (1 / 2H, doublet, J 16, 3-CH trans).

 PRI me R 2.

CH^*=CH-CH₂-^⊕N

7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2-метоксииминоацетамидо] -3- [3-пиридинио-1-пропен-1-ил]-3-цефем-4-карбоксилат (1-1В).

CH ^* = CH-CH ₂ - ^⊕ N

7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3-pyridinio-1-propen-1-yl] -3-cefem-4- carboxylate (1-1B).

Mixture of diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) -3-cef- 4-carboxylate (IX-I) (E, 716 mg, 1 mmol), pyridine (153 mg, 2 mmol) in dimethyl sulfoxide (DMSO) (1 ml) was stirred for 1 h at room temperature. Ethyl acetate (20 ml) was added to the mixture to precipitate a solid (620 mg), which was added to formic acid (6 ml) containing sodium bisulfite (60 mg). The mixture was stirred at ⁴⁰ ° C for 30 min and concentrated to dryness. The residue was dissolved in water (40 ml), and insoluble matter was removed. The aqueous solution was loaded onto a reverse phase column (PrepPAC-500 (C ₁₈ , 100 ml) was eluted with water (300 ml) and 5% aqueous methanol (800 ml), and the eluate was monitored using UV (254 nm) and HPLC ( high pressure liquid chromatography). The fractions (5% aqueous methanol) containing the desired product were combined, concentrated to a small volume and lyophilized to give 40 mg (8%) of compound (1-1V), melting at> 200 ^C ( decomp.).

IR: ν _max . KBr, cm ^-1 : 3350, 1760, 1660, 1600.

UV: λ _max. Phosphate buffer (pH 7), nm: (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) 240 (352), 258 (366), 267 (279), 290 (469).

NMR: δ D ₂ O + DMSO-d ₆ , ppm 3.74 (2H, broad singlet, 2-H), 4.20 (3H, singlet, OCH ₃ ), 5.92 (1H, doublet, J 4.5, 7-H), 6.15 (1H, multiplet, 3-CH = CH), 7.04 (1H, doublet, J 16, 3-CH trans), 8.2 (2H, multiplet, Py-H _3.5 ), 8.62 (1H, multiplet, Ru-H ₄ ), 8.97 (2H, multiplet, Ru-H _2,6 ).

 PRI me R 3.

7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2-метоксииминоацетамидо] -3- [3-пиридино-1-1-пропен-1-ил]-3-цефем-4-карбо-ксилат (1-1Н).

7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3-pyridino-1-1-propen-1-yl] -3-cefem- 4-carbo-xylate (1-1H).

Chloropropenyl compound, diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-chloro-1-propen-1-yl) - 3- cefem-4-carboxylate (VIII-I) (Z 937 mg, 1.5 mmol) was added to a stirred solution of pyridine (237 mg, 3 mmol) in DMSO (3 ml) containing NaI (11 mg, 0.075 mmol). The mixture was allowed to stand overnight at room temperature in the dark. The mixture was diluted with ethyl acetate (30 ml) to separate the precipitate, which was then collected by filtration, washed with ethyl acetate (10 ml) and dried, giving 350 mg of a blocked product. The precipitate was treated for 30 minutes at 40 ^C. After removal of the formic acid the residue was purified by column chromatography in reverse phase (PrepPAK nozzle coal briquette-500 formic acid (3.4 ml) containing sodium bisulfite (34 mg) ₍₁₈ C, 100 ml) eluting with 5% aqueous methanol Fractions containing the desired product were combined based on HPLC analysis, evaporated under reduced pressure and lyophilized to give 41 mg (5.5%) of the target compound (1-1B) (Z / E) 4/1). m.p.> 200 ^{° C} (dec.).

IR: ν _max. KBr, cm ^-1 : 3300, 1760, 1660, 1600.

UV: λ _max. phosphate buffer (pH 7) nm (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ 237) 386, 250 (377), 258 (369), 265 (347), 280 (311).

NMR: δ D ₂ O, ppm 3.45 and 3.76 (each 1H, doublet, J 16, 2H), 4.18 (3H, singlet, OCH ₃ ), 5.34 (3H, multiplet, CH = CH = CH ₂ and 6-H) 5.92 (1H, doublet, J 4.5, 7-H), 6.58 (4 / 5H, doublet, J 11, 3-CH cis), 7.03 (1 / 5H, doublet, J 16 , 3-CH trans), 8.12 (2H, multiplet, Ru-H _3.5 ), 8.56 (1H, multiplet, Ru-H ₄ ), 8.82 (2H, multiplet, Ru-H _{2, 6} ).

 PRI me R 4.

CH^*=CHCH₂-

7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2-метоксииминоацетамидо] -3-[8- (2-амино-5-тиазоло[4,5-c] пиридинио)-1-пропен-1-ил]-3-цефем-4- карбоксилат (1-1С).

CH ^* = CHCH ₂ -

7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [8- (2-amino-5-thiazolo [4,5-c] pyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate (1-1C).

A stirred solution of diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl-2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) -3- cefem-4-carboxylate (IX-I) (E isomer, 714 mg, 1 mmol), 2-aminothiazolo [4,5-c] pyridine (prepared in accordance with the administration of R. Rakahashi et al. Farm Bull (Japan) 2 34 (1954)) and dry DMSO (1 ml) was stored at room temperature for 1 h. Ethyl acetate (20 ml) was added to the reaction mixture, giving a yellow powder (710 mg). Formic acid ( 7 mL) and sodium bisulfite (70 mg) and the mixture was stirred for 30 min at 40-45 ° ^C. After evaporation the residue was triturated with water (40 ml). The insolubles were filtered off and the filtrate chromatographed on a column of reverse phase (PrepPAK-500 / _C18, 100 ml) using water and 10% methanol as eluant. The fractions containing the desired product were combined, the solvent was distilled off under reduced pressure, and lyophilization gave the desired product (1-C1) as a colorless amorphous powder of the E isomer. Yield 110 mg (19%). Mp more than 200 ^about C (decomp.).

IR: ν _max. KBr, cm ^-1 : 3300, 1760, 1680, 1630, 1600.

UV: λ _max . phosphate buffer (pH 7), nm: (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) 245 (499), 285 (286).

NMR: δ DMSO-d + D ₂ O, ppm 3.86 (3H, singlet, OCH ₃ ), 4.98 (1H, doublet, J 4.5, 6-H), 5.2 (2H, multiplet, CH = CH-CH ₂ , 5.57 (1H multiplet, 3-CH = CH), 5.96 (1H, multiplet, 7-H), 7.16 (1H, doublet, J 16, 3-CH trans), 8.36 and 8.45 (each 1 -H, doublet J = 7, Ru-H), 8.92 (1H, singlet, Ru-H).

 PRI me R 5.

CH^*=CH-CH₂-^⊕N(CH₃)₃
7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2-метоксииминоацетамидо] -3- (3-триметиламмонио-1-пропен-1-ил)-3-цефем-4-карбокси- лат (1-1D).

CH ^* = CH-CH ₂ - ^⊕ N (CH ₃ ) ₃
7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-trimethylammonio-1-propen-1-yl) -3-cefem-4- carboxy lat (1-1D).

To a solution of diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) -3-cefem -4-carboxylate (IX-I) (Z / E 2/1, 490 mg, 0.68 mmol) in ethyl acetate (14 ml) was added a 0.1 M solution of trimethylamine in ether (13.6 ml) in one portion. The mixture was stirred for 10 minutes and evaporated to dryness, the residue was triturated with ether (20 ml). The resulting solid was added to trifluoroacetic acid (0.2 ml) containing one drop of anisole. After one hour and a half stirring, the mixture was evaporated to dryness under reduced pressure, and the residual oil was triturated with ether (20 ml). The resulting precipitate was collected by filtration and dissolved in water (20 ml). Insoluble substances were removed and the aqueous solution was eluted on a C ₁₈ column with a reverse phase (PrePAK-500 / C ₁₈ carbon briquette nozzle. Waters, 30 ml) using water as an eluent. Fractions containing the desired product were combined and concentrated to a small volume and lyophilized, giving 30 mg (9.2%) of the target compound (1-1D) (Z / E 1/1) as a colorless amorphous powder, melting at more than 150 ^about C (decomp.).

IR: ν _max. KBr, cm ^-1 : 3300, 1770, 1670, 1605.

UV: λ _max . Phosphate buffer (pH 7) (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ (236/389), 286 (343)
NMR: δ D ₂ O, ppm 3.45 and 3.7 (1H, J 16, 2-H), 3.81 (1H, singlet, 2-H), 4.1 (2H, doublet, J 8, -CH ₂ N) 4.21 (3H, singlet, OCH ₃ ), 5.39 (1H, doublet, J 4.5, 6-H), 5.95 (2H, multiplet, 3-CH = CH and 7-H), 6.61 ( 1 / 2H, doublet, J 11, 3-CH, cis), 7.05 (1) 2H, doublet, J 16, 3-CH, trans).

 PRI me R 6.

7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2-метоксииминоацетамидо] -3-[3- (3-аминопиридинио)-1-пропен-1-ил]-3-цефем-4-карбо-ксилат (1, 1Е).

7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (3-aminopyridinio) -1-propen-1-yl] -3- cefem-4-carbo-xylate (1, 1E).

Diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) -3-cefem-4 β-carboxylate (IX-I) (E, 716 mg, 1 mmol) was added to a stirred solution of 3-aminopyridine (188 mg, 2 mmol) in DMSO (1 ml). The mixture was stirred for 1 h and diluted with ethyl acetate (20 ml). The resulting precipitate was collected by filtration, washed with ethyl acetate and dried, giving 520 mg of a yellow powder. The mixture powder (500 mg), formic acid (5 ml) and sodium bisulfite (50 mg) was stirred for 30 min at 40 ^C. The mixture was concentrated in vacuo, dissolved in water (40 ml) and filtered to remove insolubles. The aqueous solution was chromatographed on a reverse phase column (PrepPAK-500 / C ₁₈ , 100 ml nozzle) using 7.5% aqueous methanol as eluent. The fractions containing the product were evaporated and lyophilized to give the title compound (1-1E) (7 mg, 1.4%), melting at over 185 ^{° C} (dec.).

IR: ν _max. KBr, cm ^-1 : 3400, 1765, 1675, 1620, 1600.

UV: λ _max. Phosphate buffer (pH 7), nm: (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) 246 (403), 290 (468)
NMR: δ D ₂ O, ppm 3.72 (2H, multiplet, 2-H), 4.14 (3H, singlet, OCH ₃ ), 5.35 (3H, multiplet, 6-H and CH = CH-CH ₂ , 5.9 (1H, doublet, J 4.5, 7-H), 6.11 H, multiplet, 3-CH = CH, 7.05 (1 H, doublet, J 16, 3-CH, trans), 8.1 (1 H, multiplet, Ru-H ₅ ), 8.54 (1H, broad singlet, Ru-H ₆ , 8.68, (1H, multiplet, Ru-H ₄ ), 9.4 (1H, multiplet, Ru-H ₂ ).

 Treatment of IX-I (716 mg, 1 mmol) in accordance with the described procedure with 3-tert-butoxycarbonylaminopyridine (324 ml, 2 mmol) gave 12 mg (2.3%) 1-1E.

 PRI me R 7.

CH^*=CHCH₂-^⊕N

7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2-метоксииминоацетамид] -3-[3- (3-амино-1-пиридинио)-1-пропен-1-ил]-3-цефем-4-карбоксилат (1-1Е).

CH ^* = CHCH ₂ - ^⊕ N

7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3- (3-amino-1-pyridinio) -1-propen-1-yl ] -3-cefem-4-carboxylate (1-1E).

Mixture of diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) -3-cef- 4-carboxylate (IX-I) (Z / E 2/1, 500 mg, 0.7 mmol) and 3-aminopyridine (66 mg, 0.7 mmol) in dimethyl sulfoxide (1 ml) was stirred for 20 min at room temperature. The mixture was diluted with ethyl acetate (10 ml) and ether (10 ml), the resulting precipitate was collected by filtration, washed with ether (10 ml) and dried. The quaternized salt was dissolved in formic acid (0.3 ml) and stirred for one and a half hours at room temperature. The mixture was concentrated to dryness under reduced pressure. The residue was dissolved in 2% hydrochloric acid (10 ml) and filtered. The aqueous layer was chromatographed on a reverse phase column (PrepPAC-500 / C ₁₈ 100 ml). After washing with water (500 ml), the column was eluted with a 5% aqueous methanol solution. The fractions containing the target compound were combined, concentrated in vacuo and freeze dried, giving 15 mg (4.2%) of the target compound (1-1E) (Z / E 1/1) as a colorless amorphous powder. Mp more than 160 ^about C (decomp.).

IR: ν _max. KBr, cm ^-1 : 3400, 1765, 1675, 1620, 1600
UV: λ _max . phosphate buffer (pH 7), nm: (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) 244 (434), 286 (333).

NMR: δ DMSO-d ₆ + D ₂ O, ppm 3.73 (2H, multiplet), 4.14 (3H, singlet, OCH ₃ ), 5.35 (3H, multiplet, 6-H and CH = CH-CH ₂ , 6.0 (2H, multiplet, 7- H and 3-CH = CH)), 6.6 (1 / 2H, doublet, J 11, 3-CH cis), 7.05 (1 / 2H, doublet, J 16, 3-CH trans), 8, 08 (1H, multiplet, Ru-H), 8.6 (2H, multiplet, Ru-H _4.6 ); 9.4 (1H, multiplet, Ru-H ₂ ).

 PRI me R 8.

7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2-метоксииминоацетамидо] -3-[3- (3-формиламинопиридино)-1-пропен-1-ил]-3-цефем-4-карбоксилат (1-1F).

7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (3-formylaminopyridino) -1-propen-1-yl] -3- cefem-4-carboxylate (1-1F).

Mixture of diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) -3-cef- 4-carboxylate (IX-I) (E, 716 mg, 1 mmol) and 3-formylaminopyridine (prepared according to the procedure of N. Enomoto et al. Bull. Chem. Soc. Japan, 45, 2665 (1972)) (244 mg, 2 mmol) in DMSO (2 ml) was stirred at room temperature for 1 h and poured into ethyl acetate (200 ml). The precipitate was collected by filtration, washed well with ethyl acetate and dried. The mixture was quaternized salt (500 mg) and sodium bisulfite (50 mg) in HCOOH (5 ml) was stirred at 40-50 ^{° C} for 80 min and evaporated to dryness in vacuo. The residue was dissolved in water (40 ml), neutralized with NaHCO ₃ and then filtered to remove insoluble matter. The pure filtrate was chromatographed on a reverse phase column, PrepPAC-500 / C ₁₈ (100 ml) using water and 5% methanol, 10% methanol, 20% methanol and 30% methanol. Fractions containing the desired compound were combined, concentrated in vacuo and lyophilized to give 16 mg (2.9%) of the target compound (1-1F / E) as a tan brown powder. Mp more than 170 ^about C (decomp.).

IR: ν _max . KBr, cm ^-1 : 3340 (wide) 1760, 1670, 1620 (wide), 1690
UV: λ _max. phosphate buffer (pH 7), nm: (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) 218 (428), 248 (362), 290 (474).

-CH₂), 6,98 (1Н, дублет, J 16, 3-СН транс), 8,8-7,9 (4Н, мультиплет, Ру-Н), 9,38 (1Н, широкий, NH

O).NMR: δ D ₂ O + NaHCO ₃ , ppm 3.68 (2H, broad, 2-H), 4.15 (3H, singlet, OCH ₃ ), 5.91 (1H, doublet, J 4.5, 7-H), 6.25 (1H, multiplet , CH =

-CH ₂ ), 6.98 (1H, doublet, J 16, 3-CH trans), 8.8-7.9 (4H, multiplet, Py-H), 9.38 (1H, broad, NH

O).

 PRI me R 9.

7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2-метоксииминоацетамид] -3-[3- (3-карбамоилпиридинио)-1-пропен-1-ил]-3-цефем-4-кар- боксилат (1-1G).

7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamide] -3- [3- (3-carbamoylpyridinio) -1-propen-1-yl] -3- cefem-4-carboxylate (1-1G).

To a solution of diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) -3-cefem -4-carboxylate (IX-I), (E, 716 mg, 1 mmol) in DMSO (2 ml) nicotinamide (244 mg, 2 mmol) was added and the mixture was stirred at ambient temperature for one and a half hours and poured into ethyl acetate (200 ml) with stirring. The resulting precipitate was collected by filtration. Quaternized salt (500 mg) was dissolved in HCOOH (5 ml) in the presence of sodium bisulfite (50 mL) and the mixture heated at 40-50 ^{° C} for 40 min under stirring and evaporated to dryness. The residue was dissolved in water (40 ml), and the insoluble solid was filtered off and washed with a small amount of water. The filtrate and water were combined and chromatographed on a reverse phase column, PrepPAC-500 / C ₁₈ (100 ml). After successive elution with water and 5% 10% and 20% aqueous methanol, the fractions containing the desired substance were combined, concentrated in vacuo and freeze dried, giving 21 mg (3.8%) of the target compound (1-1G) (E ) in the form of a yellow powder. Mp more than 175 ^{° C} (dec.).

IR: ν _max . KBr, cm ^-1 : 3340 (wide), 1760, 1670, 1600.

UV: λ _max. phosphate buffer (pH 7) nm (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) 235 (326), 274 (shoulder, 405), 290 (446).

), 5,88 (1Н, дублет, J 4,5, 7-Н), 6,15 (1Н, дублет-триплет, J 16 и 7,3-CH=

), 7,00 (1Н, дублет, J 16, 3-СН транс), 8,23 (1Н, мультиплет, Ру-Н₅), 9,03 (2Н, мультиплет, Ру-Н₄ и 6), 9,34 (1Н, синглет, Ру-Н₂).NMR: δ D ₂ O + NaHCO ₃ , ppm 3.68 (2H, broad, 2-H), 4.15 (3H, singlet, OCH ₃ ), 5.32 (1H, doublet, J 4.5, 6-H), 5.45 (1H, doublet , J 7, CH = CH-

), 5.88 (1H, doublet, J 4.5, 7-H), 6.15 (1H, doublet triplet, J 16 and 7.3-CH =

), 7.00 (1H, doublet, J 16, 3-CH trans), 8.23 (1H, multiplet, Ru-H ₅ ), 9.03 (2H, multiplet, Ru-H ₄ and 6), 9 34 (1H, singlet, Ru-H ₂ ).

 PRI me R 10.

CH=^*CHCH₂-^⊕N

CONH₂
7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2-метоксииминоацетамидо] -3-[3- (4-карбамоилпиридинио)-пропен-1-ил)-3-цефем-4-кар- боксилат (1-1Н).

CH = ^* CHCH ₂ - ^⊕ N

CONH ₂
7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (4-carbamoylpyridinio) propen-1-yl) -3-cefem- 4-carboxylate (1-1H).

To a stirred solution of diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) - 3-Cephem-4-carboxylate (IX-I) (E, 716 mg, 1 mmol) in dry DMSO (2 ml) was added ichonicotinamide (244 mg, 2 mmol). The mixture was stirred at room temperature for 1 h and then poured into ethyl acetate (200 ml). The resulting precipitate was collected by filtration, washed well with ethyl acetate and dried. A stirred mixture of quaternized material (400 mg) and sodium bisulfite (40 mg) in HCOOH (4 ml) was heated at 40-50 ^{° C} for 1 hour and evaporated to dryness under reduced pressure. The crude solid was dissolved in water (40 ml). After filtering the insoluble matter, the filtrate was chromatographed on a reverse phase column (PrepPAC / C nozzle ₁₈ , 100 ml) using water and 5% 10% 20% and 30% aqueous methanol as eluent. Fractions containing the desired compound were evaporated and lyophilized to give 21 mg (3.8%) of the target compound (1-1H) (E) as a pale yellow powder. Mp more than 180 ^about C (decomp.).

IR: ν _max. KBr, cm ^-1 : 3340 (wide), 1760, 1670, 1600.

UV: λ _max. Phosphate buffer (pH 7), nm: (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) 222 (362), 285 (452).

NMR: δ D ₂ O + NaHCO ₃ , ppm 3.68 (2H, broad, 2-H), 4.15 (3H, singlet, OCH ₃ ), 5.33 (1H, doublet, J 4.5, 6-H), 5.46 (2H, doublet , J 7, CH = C — CH ₂ ), 5.90 (1H, doublet, J 4.5, 7-H), 6.17 (1H, doublet triplet, J 16, and 7.3-CH = CH), 7.02 (1H, doublet, J 16, 3-CH trans), 8.43 and 9.09 (each 2H, doublet, J 7, Py-H).

 PRI me R 11.

CH=^*CHCH₂-^⊕N

7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2-метоксииминоацетамидо] -3-[3- (3-аминометилпиридинио)-1-пропен-1-ил-3-цефем-4- карбоксилат (1-11).

CH = ^* CHCH ₂ - ^⊕ N

7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (3-aminomethylpyridinio) -1-propen-1-yl-3-cefem -4-carboxylate (1-11).

Mixture of diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) -3-cef- 4-carboxylate (IX-I) (E, 716 mg, 1 mmol) and 3- (tert-butyloxycarbonylaminomethyl) pyridine (516 mg, 2 mmol) in DMSO (2 ml) was stirred at ambient temperature for 30 minutes. The mixture was poured into ethyl acetate (200 ml) and the precipitate was collected by filtration, washed well with ethyl acetate and dried. A mixture of the quaternized salt (500 mg), sodium bisulfite (50 mg) in HCOOH (5 ml) was stirred at 40-50 ^{° C} for 80 min and evaporated to dryness under reduced pressure. The remaining solid was dissolved in water (40 ml) and the mixture was neutralized with NaHCO ₃ . The insoluble matter was filtered off, the filtrate was chromatographed on a reverse phase column (PrePAK-500 carbon briquette nozzle (C ₁₈ , 100 ml), eluted with water, and accordingly 5% 10% 20% and 30% aqueous methanol. Fractions containing the desired compound , combined, evaporated and lyophilized, giving 10 mg (1.8%) of the target compound (I-II) (E) in the form of a tan powder.

IR: ν _max . KBr, cm ^-1 : 3380 (wide), 1760, 1650 (wide), 1620 (wide).

UV: λ _max. phosphate buffer (pH 7), nm: (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) 235 (wide, 260), 286 (370).

NMR: δ D ₂ O + NaHCO ₃ , ppm 3.68 (2H, broad, 2-H), 4.16 (3H, singlet, OCH ₃ ), 6.98 (1H, doublet, J 16, 3-CH trans), 8.05 (1H, multiplet, Ru-H ₅ ), 8.50 (1H, multiplet, Ru-H ₄ ), 8.80 (2H, multiplet, Ru-H _2,6 ).

 PRI me R 12.

C

=CHCH₂-^⊕N

CONH₂
7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2-метоксииминоацетамидо] -3-[3- (4-карбамоилпиридинио)-1-пропен-1-ил]-3-цефем-4- карбоксилат (I-IH).

C

= CHCH ₂ - ^⊕ N

CONH ₂
7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (4-carbamoylpyridinio) -1-propen-1-yl] -3- cefem-4-carboxylate (I-IH).

Mixture of diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) -3-cef- 4-carboxylate (IX-I) (E isomer, 4.1 g, 5.7 mmol) and isonicotinamide (1.4 g, 11 mmol) in dry DMSO (6 ml) was stirred for 2 hours at room temperature under control by thin layer chromatography (silica gel plate, CHCl ₃ : CH ₃ OH 3: 1). The reaction mixture was diluted with ethyl acetate (100 ml) to separate a yellow gum, which was treated with formic acid (40 ml) and sodium bisulfite (390 mg) at ⁴⁵ ° C for 30 min. The resulting solution was concentrated to dryness. The residue was dissolved in water (100 ml) and insoluble matters were removed by filtration. The combined filtrate and wash water were applied to the top of the column containing the nozzle in the reverse phase (PrepPAK-500 / C ₁₈ , 120 ml). The column was eluted with water. The eluate was collected in 300 ml fractions and controlled by UV (254 nm) and HPLC (Lichrosorb RP-18, 4 x 300 mm, 0.01 M ammonium phosphate buffer, pH 7.2, containing 20% methanol). Fractions Nos. 4 and 5 were combined and concentrated to a small volume. Lyophilization gave 250 mg (8.1%) of the title compound 1-1N melting at over 180 ^{° C} (dec.). Spectra showed that the product was identical to the substance obtained in example 10.

Preparation of hydrochloride. 10% hydrochloric acid (0.1 ml) was added to a suspension of compound 1-1H (98 mg, 0.18 mmol) in methanol (1 ml), and the mixture was stirred for 5 minutes. Acetone (100 ml) was added to the resulting yellow solution, resulting in a precipitate which was collected by filtration, washed with acetone (2 x 10 ml) and dried in vacuo to give a 1-1N hydrochloride salt as a colorless powder. The yield was 88 mg (79%). Mp more than 190 ^{° C} (dec.).

IR: ν _max. KBr, cm ^-1 : 3300, 1770, 1680, 1620.

UV: λ _max. phosphate buffer (pH 7), nm: (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) 227 (385), 286 (374).

), 5,93 (1Н, дублет, J 4,5, 7-Н), 6,28 (1Н, дублет-триплет, J 16 и 7,3-CH=

), 7,15 (1Н, дублет, J 16, 3-

), 8,43 и 9,1 (каждый 2Н, дублет, J 7, Ру-Н).NMR: δ D ₂ O, ppm 2.32 (1H, singlet, acetone-H), 3.79 (2H, broad singlet, 2-H), 4.17 (3H, singlet, OCH ₃ ), 5.34 (1H, doublet, J 4, 5, 6-H), 5.49 (2H, doublet, J 7, CH = CH-

), 5.93 (1H, doublet, J 4.5, 7-H), 6.28 (1H, doublet triplet, J 16 and 7.3-CH =

), 7.15 (1H, doublet, J 16, 3-

), 8.43 and 9.1 (each 2H, doublet, J 7, Ru-H).

 PRI me R 13.

CH=^*CHC

7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2-метоксииминоацетамидо] -3-[3- (2-метилтиоазолио)-1-пропен-1-ил]-3-цефем-4-карбо- ксилат (1-1J).

CH = ^* CHC

7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (2-methylthioazolo) -1-propen-1-yl] -3- cefem-4-carboxylate (1-1J).

To a mixture of diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) -3-cephem -4-carboxylate (IX-I) (E, 714 mg, 1 mmol) and 2-methylthiazole (prepared according to the procedure RPKurkjy, EV Brown, J. Am. Chem. Soc. 74, 5778 (1952)) (198 mg , 2 mmol) in dry CH ₂ Cl ₂ (10 mL) was added AgBF ₄ (90% pure, 217 mg, 1 mmol) at -20 ^C. The mixture was stirred for 30 min at room temperature and filtered. The precipitate was extracted with 1% CH ₃ -CHCl (3x20 ml). The combined extracts were washed with brine (2 x 5 ml), dried over MgSO ₄ and evaporated to dryness to give a yellow precipitate, which was triturated with isopropyl ether and filtered, to give 350 mg of a quaternized product. A mixture of this solid, sodium bisulfite (35 mg) and formic acid (3.5 ml) was stirred for 30 min at 40 ^C. The mixture was concentrated to remove the formic acid and the residue was diluted with water (40 mL). Insoluble materials were removed by filtration. The filtrate was placed on a reverse phase column (PrepPAK-500 / C ₁₈ , 100 ml). The column was eluted sequentially with water (200 ml), 5% aqueous methanol (400 ml) and 10% aqueous methanol (300 mm). Fractions containing the desired substance were combined based on HPLC analysis (Lichrosorb RP-18, 4 x 300 mm, 0.01 M ammonium phosphate buffer 7.2, containing 20% methanol). The combined solution was concentrated to a small volume and lyophilized, giving 40 mg (7.7%) of the target compound (1-1J) (E). Mp more than 195 ^{° C} (dec.).

IR: ν _max . KBr, cm - ¹ : 3300, 1760, 1660, 1600,
UV: λ _max. phosphate buffer (pH 7), nm: (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) 238 (442), 292 (421).

), 6,8 (1Н, дублет, J 16, 3-CH транс), 8,04 и 8,23 (каждый 1Н, дублет, J 4, тиазол-Н).NMR: δ D ₂ O + DMSO-d ₆ , ppm 3.06 (3H, singlet, thiazole-CH ₃ ), 3.74 (2H, broad singlet, 2-H), 4.19 (3H, singlet, OCH ₃ ), 5.92 (1H, doublet, J 4 5, 7-H), 6.1 (1H, multiplet, 3-CH =

), 6.8 (1H, doublet, J 16, 3-CH trans), 8.04 and 8.23 (each 1H, doublet, J 4, thiazole-H).

 PRI me R 14.

CH=^*CHCH₂-^⊕N

CH₂OH
7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2-метоксииминоацетамидо] -3-[3- (4-оксиметилпиридинио)-1-пропен-1-ил] -3-цефем-4-карбоксилата (1-1L). Смесь дифенил 7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2- метоксииминоацетамидо]-3-(3-иод-1-пропен-1-ил)-3-це- фем-4- карбоксилата (IX-I) (Е изомер, 1,07 г, 1,5 ммоль), 4-оксиметилпиридина (818 мг, 7,5 ммоль) в CH₃CN (4,5 мл) и метанола (3 мл) перемешивалась при комнатной температуре в атмосфере азота в течение 1 ч. После удаления растворителя упариванием остаточное масло растиралось с изопропиловым эфиром, собиралось фильтрацией и промывалось смесью изопропилового эфира и метанола (3:1, 10 мл), давая 1,28 г кватернизованного цефемового эфира в виде желтого порошка. Раствор кватернизованного сложного эфира (1,25 г) и бисульфита натрия (600 мг) в 85%-ном НСООН (10 мл) перемешивался при комнатной температуре в атмосфере азота в течение 1 ч. После добавления 85%-ного НСООН (5 мл) смесь перемешивалась при тех же условиях дополнительно в течение часа. Добавлялся толуол и смесь азеотропно упаривалась при пониженном давлении. Остаток растирался с ацетоном, давая 1,17 г неочищенного формата целевого соединения. Суспензия этого соединения (1,15 г) в воде (100 мл) фильтровалась для удаления нерастворимых веществ, которые промывались водой (10 мл х 2). Фильтрат и промывные воды объединялись и подвергались хроматографии на колонке с обратной фазой. Колонка, которая наполнялась насадкой, взятой из колонки с угольным брикетом (ПрепПАК-500/С₁₈ (Уотерс, 60 мл), проявлялась последовательно водой, 5%-ным метанолом и 10% -ным метанолом. Фракции, содержащие желаемое соединение, объединялись, концентрировались при пониженном давлении, и осаждались добавлением ацетона, давая 100 мг целевого соединения (1-1L) в виде желтого порошка. К суспензии порошка (90 мг) в метаноле (9 мл) добавлялся 1 М HCl в метаноле (0,5 мл) и смесь перемешивалась при комнатной температуре и концентриро- валась в вакууме. К концентрату добавлялся изопропанол для осаждения 77 мг хлоргидрата целевого соединения. Бледно-желтый порошок. Т.пл. более 190^оС (разл.)
ИК: ν_макс. KBr, см-¹: 1775, 1670, 1635, 1530.

CH = ^* CHCH ₂ - ^⊕ N

CH ₂ OH
7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (4-hydroxymethylpyridinio) -1-propen-1-yl] -3- cefem-4-carboxylate (1-1L). Mixture of diphenyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) -3-ce fem-4-carboxylate (IX-I) (E isomer, 1.07 g, 1.5 mmol), 4-hydroxymethylpyridine (818 mg, 7.5 mmol) in CH ₃ CN (4.5 ml) and methanol ( 3 ml) was stirred at room temperature in a nitrogen atmosphere for 1 h. After removal of the solvent by evaporation, the residual oil was triturated with isopropyl ether, collected by filtration and washed with a mixture of isopropyl ether and methanol (3: 1, 10 ml), giving 1.28 g of quaternized cefem ether in the form of a yellow powder. A solution of quaternized ester (1.25 g) and sodium bisulfite (600 mg) in 85% HCOOH (10 ml) was stirred at room temperature under nitrogen for 1 h. After addition of 85% HCOOH (5 ml) the mixture was stirred under the same conditions for an additional hour. Toluene was added and the mixture was azeotropically evaporated under reduced pressure. The residue was triturated with acetone, giving 1.17 g of a crude format of the target compound. A suspension of this compound (1.15 g) in water (100 ml) was filtered to remove insoluble substances, which were washed with water (10 ml x 2). The filtrate and washings were combined and chromatographed on a reverse phase column. The column, which was filled with a nozzle taken from a column of coal briquette (PrepPAK-500 / C ₁₈ (Waters, 60 ml), showed successively water, 5% methanol and 10% methanol. Fractions containing the desired compound were combined, concentrated under reduced pressure and precipitated by the addition of acetone to give 100 mg of the target compound (1-1L) as a yellow powder. To a suspension of the powder (90 mg) in methanol (9 ml) was added 1 M HCl in methanol (0.5 ml) and the mixture was stirred at room temperature and concentrated in vacuo. lyalsya isopropanol to precipitate 77 mg of the hydrochloride of the title compound. Pale yellow powder. mp: over 190 ^{° C} (dec.)
IR: ν _max. KBr, cm- ¹ : 1775, 1670, 1635, 1530.

UV: λ _max. Phosphate buffer (pH 7), nm: (ε) 230 (22600), 264 (shoulder, 16300).

-CH₂OH), 5,36 (1Н, дублет, J 4,5 Гц, 6-Н), 5,41 (2Н, дублет, J 7 Гц, CH=CH-

), 5,94 (1Н, дублет, J 4,5 Гц, 7-Н), 6,36 (1Н, дублет-триплет, J 16 и 7 Гц, CH=C

CH₂), 7,13 (1Н, дублет, J 16 Гц, C

=CH-CH₂), 8,08 и 8,83 (каждый 2Н, дублет, J 7 Гц, Ру-Н).NMR: δ D ₂ O, ppm 3.83 (2H, broad 2-H), 4.17 (3H, singlet, OCH ₃ ), 5.06 (2H, singlet, N

-CH ₂ OH), 5.36 (1H, doublet, J 4.5 Hz, 6-H), 5.41 (2H, doublet, J 7 Hz, CH = CH-

), 5.94 (1H, doublet, J 4.5 Hz, 7-H), 6.36 (1H, doublet triplet, J 16 and 7 Hz, CH = C

CH ₂ ), 7.13 (1H, doublet, J 16 Hz, C

= CH-CH ₂ ), 8.08 and 8.83 (each 2H, doublet, J = 7 Hz, Py-H).

 PRI me R 15.

CH

HCH₂-^⊕N

CONH₂
7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2- этоксииминоацетамидо]-3-[3- (4-карбамоилпиридинио)-1-пропен-1-ил] -3-цефем-4-кар- боксилат (1-2Н). К раствору 200 мг 7-амино-3-[3-(4-карбамоилпиридинио)-1-пропен-1- ил]-3-цефем-4-карбоксилата хлоргидрата (Е изомер) в 5 мл 50%-ном водном ацетоне добавлялось порциями 190 мг хлоргидрата 2-этоксиимино-2-(5-амино-1,2,4-тиадиазол-3-ил)ацетил- хлорида (приготовленного в соответствии с процедурой, описанной в японской патентной заявке (Кокаи) 57-24389 (2/8/82)), и смесь доводилась до рН 6,5-7,0 с помощью 2 норм Na₂CO₃ (около 1 мл). Реакционная смесь перемешивалась при 10^оС в течение часа, подкислялась до рН 21 н. соляной кислотой и упаривалась в вакууме. Остаток фильтровался и фильтрат хроматографировался на колонке НР-20, которая элюировалась последовательно 500 мл воды и 25% -ным водным изопропанолом. Фракции, содержащие желаемый продукт, объединялись и упаривались при пониженном давлении. Маслянистый остаток обрабатывался изопропанолом (20 мл), давая 263 мг (93%) целевого соединения (1-2Н), Т.пл. 170^оС (разл.). К перемешиваемой суспензии 225 мг (0,40 ммоль) указанного цвиттер-иона в 10 мл метанола добавлялся 1 мл 1н. HCl в метаноле, и смесь перемешивалась при комнатной температуре в течение 30 мин. Раствор фильтровался и концентрировался при пониженном давлении. К остатку добавлялось 15 мл изопропанолового спирта, и полученный в результате осадок собирался фильтрацией и сушился в вакууме, в результате чего получалось целевое соединение в виде его хлоргидрата. Выход 146 мг (57%). Т.пл. 160^оС (разл. ). Оцененная чистота 65%
ИК: ν_макс. KBr, см-^1: 3300, 1780, 1680, 1620.

CH

HCH ₂ - ^⊕ N

CONH ₂
7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamido] -3- [3- (4-carbamoylpyridinio) -1-propen-1-yl] -3- cefem-4-carboxylate (1-2H). To a solution of 200 mg of 7-amino-3- [3- (4-carbamoylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate hydrochloride (E isomer) in 5 ml of 50% aqueous acetone was added in portions of 190 mg of 2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetyl chloride hydrochloride (prepared in accordance with the procedure described in Japanese Patent Application (Coca) 57-24389 (2 (8/82)), and the mixture was adjusted to a pH of 6.5-7.0 with 2 norms of Na ₂ CO ₃ (about 1 ml). The reaction mixture was stirred at 10 ^about C for one hour, acidified to pH 21 N. hydrochloric acid and evaporated in vacuum. The residue was filtered and the filtrate was chromatographed on an HP-20 column, which was eluted successively with 500 ml of water and 25% aqueous isopropanol. Fractions containing the desired product were combined and evaporated under reduced pressure. The oily residue was treated with isopropanol (20 ml), giving 263 mg (93%) of the target compound (1-2H), so pl. 170 ^{° C} (dec.). To a stirred suspension of 225 mg (0.40 mmol) of the indicated zwitterion in 10 ml of methanol was added 1 ml of 1N. HCl in methanol, and the mixture was stirred at room temperature for 30 minutes. The solution was filtered and concentrated under reduced pressure. 15 ml of isopropanol alcohol was added to the residue, and the resulting precipitate was collected by filtration and dried in vacuum, resulting in the desired compound in the form of its hydrochloride. Yield 146 mg (57%). Mp 160 ^{° C} (dec.). Estimated Purity 65%
IR: ν _max. KBr, cm- ^1: 3300, 1780, 1680, 1620.

UV: λ _max. phosphate buffer (pH 7), nm (E): 227 (22300), 288 (22800).

-CH₃), 3,74 (2Н, широкий синглет, 2-Н), 4,45 (2Н, кв, J 7 Гц, OC

-CH₃), 5,36 (1Н, дублет: J 4,5 Гц, 6-Н), 5,46 (2Н, дублет, J 7 Гц, 3-CH=CH-C

) 5,92 (1Н, дублет, J 4,5 Гц, 7-Н), 6,20 (1Н, мультиплет, 3-CH=C

), 7,04 (1Н, дублет, J 16 Гц, 3-CH=C

), 8,43 (2Н, дублет, J 7 Гц, Ру-Н_А), 9,10 (2Н, дублет, J 7 Гц, Ру-Н_В).NMR: δ D ₂ O, ppm 1.44 (3H, triplet, J 7 Hz, OC

-CH ₃ ), 3.74 (2H, broad singlet, 2-H), 4.45 (2H, q, J 7 Hz, OC

-CH ₃ ), 5.36 (1H, doublet: J 4.5 Hz, 6-H), 5.46 (2H, doublet, J 7 Hz, 3-CH = CH-C

) 5.92 (1H, doublet, J 4.5 Hz, 7-H), 6.20 (1H, multiplet, 3-CH = C

), 7.04 (1H, doublet, J 16 Hz, 3-CH = C

), 8.43 (2H, doublet, J 7 Hz, Ru-H _A ), 9.10 (2H, doublet, J 7 Hz, Ru-H _B ).

 PRI me R 16. 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (4-carbamoylpyridinio) -1-propene -1-yl] 3-cephem-4-carboxylate (1-1H) (E isomer).

 This example shows the preparation of compound 1-1H through the last few steps of reaction scheme 1a or 1, in which intermediate 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] - 3- [3- (4-carbamoylpyridinio) -1-propen-1-yl -] - 3-cephem-4-carboxylate format (XXVII-1H) is isolated.

 A. Benzhydryl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyimino-acetamido] -3- [3- (4-carbamoyl-1-pyridinio) -1- propen-1-yl] -3-cefem-4-carboxylate format (E isomer) (XXVII-1H).

A solution of XII-1H Y ^⊖ = I ^⊖ , E isomer) (34 g of 75% purity) in a mixture of acetone and methanol (1/1, 1,200 ml) was placed on an Amberlite IRA-410 column (340 ml format). The column was eluted with the same solvent system. The first fraction (1 L) was evaporated to about 100 ml volume, and the brown residue was triturated with isopropyl ether (400 ml). The resulting powder was collected by filtration and dried in vacuo to give 29 g (75% purity as determined by HPLC) of the title compound XXVII-1H (E isomer) as a brown powder, mp over 150 ^{° C} (dec. )

IR: ν _max . KBr, cm ^-1 : 3300, 1780, 1680, 1630, 1600.

UV: λ _max. EtOH, nm: (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) 282 (186).

N⁺), 5,99 (1Н, дублет, J 4,5 Гц, 7-Н), 6,5 (1Н, мультиплет, 3-CH=C

), 6,92 (1Н, синглет, C

Ph₂), 7,1 (1Н, дублет, J 16 Гц, 3-C

), 7,35 (10Н, мультиплет, Ph-

), 8,36 (1Н, синглет, НСОО), 8,46 и 9,12 (2Н, каждый, дублет, J 8 Гц, Ру-Н).NMR: δ ppm acetone-d ₆ (CH ₃ OH-d ₄ 1 (1): 4.0 (3H, singlet, OCH ₃ ), 5.26 (1H, doublet, J 4.5 Hz, 6-H), 5.43 (2H, doublet, J 2, Hz, C

N ⁺ ), 5.99 (1H, doublet, J 4.5 Hz, 7-H), 6.5 (1H, multiplet, 3-CH = C

), 6.92 (1H, singlet, C)

Ph ₂ ), 7.1 (1H, doublet, J 16 Hz, 3-C

), 7.35 (10H, multiplet, Ph-

), 8.36 (1H, singlet, HCO), 8.46 and 9.12 (2H, each, doublet, J = 8 Hz, Py-H).

 B. 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] 3- [3- (4-carbamoyl-1-pyridinio) -1-propen-1- yl] -3-cefem-4-carboxylate (1-1H) (E isomer).

A mixture of XXVII-1H (E isomer) from step A (29 g, 75% purity) and 85% formic acid (290 ml) was stirred for 2 hours at room temperature. Evaporation of the mixture gave a brown oil, which was triturated with acetone (500 ml). The powder was collected by filtration, washed with acetone (2 x 100 ml) and dried in vacuum, yielding 24 g (50% purity as determined by HPLC) of the target compound. The brown solid was treated twice with 2 N. hydrochloric acid (1 l and 0.5 l). The aqueous extracts were combined and placed on a column filled with HP-20 Diaion (1.5 L). The column was washed with water (8 L) and eluted with 30% methanol (5 L). Fractions containing the desired product were evaporated to about 30 ml. The concentrate was treated with acetone (200 ml) to give a precipitate, which was collected by filtration and dried in vacuo, resulting in 10.1 g (85% purity) of the target compound (zwitterion form) as a yellow powder. Norms were added to a suspension of this product in methanol (100 ml). HCl in methanol (55 ml) at room temperature and the mixture was stirred for 30 minutes. The resulting clear solution was filtered to remove insoluble matter, concentrated to a volume of about 50 ml, and precipitated with isopropanol (200 ml). The resulting powder was collected, washed with isopropanol (50 ml) and dried in vacuo, giving 10.5 g (85% purity) of the title compound 1-1N (E isomer) (HCl salt), melting at 180 ^{° C} ( decomp.). Pale yellow powder.

 PRI me R 17. 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (4-carbamoylpyridinio) -1-propene -1-yl] 3-cephem-4-carboxylate (1-1H) (E isomer).

 This example shows the preparation of compound 1-1H through the last few steps of reaction scheme 1a and 1b, where intermediate XXVII-1H (format) is not isolated.

A solution of IX-I (E isomer) (27.6 g, 38.5 mmol) and isonicotinamide (22.8 g, 187 mmol) in a mixture of methanol (100 ml) and CH ₃ CN (120 ml) was stirred at room temperature in for 1 h in nitrogen atmosphere. After evaporation of the organic solvents, the oily residue was triturated with isopropyl ether to give 50.5 g of a mixture of the quaternized salt and isonicotinamide. A solution of the mixture (50.3 g) and sodium bisulfite (16 g) in 85% HCOOH (160 ml) was stirred at room temperature for 40 minutes and then at 40 ^{° C} for 1 hour under a nitrogen atmosphere. The mixture was evaporated in vacuo. The residual oil was mixed with toluene (50 ml), azeotropically evaporated and triturated with acetone (400 ml), giving 27.8 g of the crude target compound. This material was treated twice with 2 N hydrochloric acid (1 L and 0.5 L). The acid extracts were combined and placed on a column with HP-20 resin (1.5 L). The column was eluted with water (9 L) and 30% methanol (10 L). Fractions containing the desired compound were concentrated to give a yellow oil, which was triturated with acetone (300 ml), resulting in 9.35 g of the target compound in the form of a zwitterion. To a suspension of the product (9.3 g) in methanol (180 ml) was added 1 N. hydrochloric acid in methanol (55 ml) to obtain a clear solution. The solution was concentrated to a volume of about 100 ml and diluted with isopropanol to precipitate 9.50 g (75% purity) of the target compound 1-1H (E isomer) as its hydrochloride. Light yellow amorphous powder. Mp more than 195 ^{° C} (dec.).

 PRI me R 18. 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (4-carbamoylpyridinio) -1-propene -1-yl] 3-cephem-4-carboxylate (1-1H) (E isomer).

An example shows the preparation of compound 1-1H using the last step (7-N-acylation) of a 1 s reaction scheme. To an ice-cooled suspension of 7-amino-Cephem-hydrochloride XXII-H (E isomer) (5.0 g, 12.6 mmol) in 50% aqueous acetone (100 ml) was added sodium bicarbonate in small portions. The pH of the mixture was monitored by a pH meter throughout the reaction. To a cold neutralized solution (pH about 7) was added 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetyl chloride hydrochloride (4.02 g, 15.6 mmol) in small portions over a period of 1 h, and the pH of the reaction mixture was maintained between 6.8-7.5 by adding from time to time sodium bicarbonate. The reaction was also monitored by TLC. After all of the compound XXII-H was consumed, the mixture was acidified to pH 3 by adding 2 N. of hydrochloric acid. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with acetone (400 ml) to separate the precipitate, which was collected by filtration, to give 9.59 g of the crude compound as a pale yellow powder. HPLC Purity Evaluated 40% Suspension of Crude Product (9.5 g) in 2N hydrochloric acid (150 ml) was filtered, the filtrate was adsorbed on a column with HP-20 resin (500 ml). After washing with water (1.5 L), the column was eluted with 25% isopropyl alcohol, and the eluate was collected in 100 ml of the fraction. The desired fractions merged, acidified 2 N. hydrochloric acid (10 ml) and concentrated. The residual oil was triturated with isopropyl alcohol (200 ml) and the precipitate was collected by filtration. After drying over phosphorus pentoxide, 5.18 g of the target compound 1-1H (E isomer) was obtained as the hydrochloride in the form of a yellow amorphous powder. Mp more than 190 ^{° C} (dec.). Estimated Purity 75%
PRI me R 19. Purification and crystallization of compound 1-1H (E isomer).

 The compound hydrochloride 1-1H obtained in example 16, a pale yellow amorphous powder of 85% purity.

Procedure 1. 6 g of 85% pure hydrochloride was dissolved in 20 ml of water and filtered through a celite pad. An amber-colored filtrate (pH 2) was passed through a reverse phase column (prepPAK-500 / C ₁₈ charcoal briquette nozzle, Waters, 120 ml), which was eluted with water. The eluate was collected in 120 ml fraction controlled by HPLC. Fractions 3 through 5 were combined and concentrated to about 10 ml, precipitated with acetone (100 ml), giving 3.3 g of 1-1H in the form of a zwitterion (pale yellow amorphous powder, estimated purity 95%). Norms were added to a suspension of 95% pure powder (3.2 g) in methanol (32 ml). HCl in methanol (18 ml) and the mixture was stirred at room temperature until a clear solution was obtained. The solution was filtered and the filtrate was concentrated to about 10 ml. Isopropanol (100 ml) was added to the concentrate to separate a pale yellow precipitate, which was collected by filtration, washed with isopropanol (5 ml) and dried to give 2.6 g of HCl salt (amorphous powder, estimated purity 95%). A solution of 95% pure hydrochloride (1 g) in water (4 ml) was adjusted to pH 6.5 with NaHCO ₃ (200 mg) and stirred for 30 minutes. The crystals that precipitated during stirring were collected by filtration, washed with water (2 x 5 ml) and dried in vacuo to give 710 mg of 1-1H (in the form of a zwitterion) as pale yellow prisms. Mp more than 185 ^{° C} (dec.). Microanalysis showed that they were trihydrate.

IR: ν _max. KBr, cm ^-1 : 1780, 1695, 1660, 1690, 1610.

UV: λ _max. phosphate buffer (pH 7), nm: (ε) 227 (22000), 290 (23000).

), 6,93 (1Н, дублет, J 16 Гц, 3-СН), 8,18 и 8,89 (каждый 2Н, дублет, J 7 Гц, Ру-Н).NMR: δ ppm DMSO-d ₆ + D ₂ O: 3.45 (2H, broad, singlet, 2-H), 3.9 (3H, singlet, OCH ₃ ), 4.99 (1H, doublet , J 4.5 Hz, 6-H), 5.16 (2H, doublet, J 7 Hz, CH ₂ N ⁺ ), 5.61 (1H, doublet, J 4.5 Hz, 7-H), 5 , 8 (1H, doublet of triplets, J 16 & 7 Hz, 3-CH = C

), 6.93 (1H, doublet, J 16 Hz, 3-CH), 8.18 and 8.89 (each 2H, doublet, J 7 Hz, Py-H).

Calculated for C ₂₁ H ₂₀ N ₈ O ₆ S ₂ · 3H ₂ O, C 42.14; H 4.38; N, 18.72; S 10.71
Found, C, 42.41; H 4.35; N, 18.86; S 11.00
Column, Lichrosorb RP-18, 4 x 300 mm: mobile phase, 0.01 M phosphate buffer (pH 7.2) (85/15 methanol: detection, UV (254 nm).

Procedure 2. After crystalline compound 1-1H was obtained using procedure 1, it is possible to obtain the crystalline zwitterion 1-1H form directly from the crude 1-1H hydrochloride by seeding with a certain amount of pure 1-1H crystals. A solution of 85% purity hydrochloride (250 mg) in water (1 ml) was treated with charcoal. The solution was adjusted to pH 6.5 with NaHCO ₃ (60 mg) and decolorized with charcoal. The filtrate was seeded with several pieces of crystals obtained from procedure 1, and was stirred overnight at room temperature. The precipitated crystals were collected by filtration, washed with water (2 x 2 ml) and dried under reduced pressure, giving 170 mg (80% yield) of pale yellow 1-1H prisms (in the form of a zwitterion), mp more than 185 ^C. (dec.), which was identical to that obtained by Procedure 1, (as shown by IR, UV and NMR). The crystalline zwitter-ionic form 1-1N compound was slightly soluble in water (6 mg / ml in saline at ²³ ° C).

 PRI me R 20.

CH

CH-CH₂-^⊕N

7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2-метоксииминоацетамидо] -3-[3- (3-оксиметилпиридинио)-1-пропенил]-3-цефем-4-кар- боксилат (1-1К) (Е изомер).

CH

CH-CH ₂ - ^⊕ N

7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (3-hydroxymethylpyridinio) -1-propenyl] -3-cefem-4- carboxylate (1-1K) (E isomer).

 A. diphenylmethyl iodide 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (3-hydroxymethylpyridinio) -1-propenyl] -3- cefem-4-carboxylate (E-isomer) (XII-1K).

To a solution of IX-I (E isomer, 1.79 g, 2.5 mmol) in 2.5 ml of methanol and 7.5 ml of CH ₃ CN was added 3-hydroxymethylpyridine (545 mg, 5 mmol), and the mixture was stirred at room temperature temperature for 3 hours. The reaction mixture was poured into ethyl acetate (100 ml) with vigorous stirring. The resulting precipitate was collected by filtration, washed with a small amount of ethyl acetate and dried, yielding 2.06 g (100%) of target compound XII-1K in the form of a tan powder. Mp 170-180 ^{° C} (dec.).

IR: ν _max. (KBr), cm ^-1 : 1780, 1725, 1675, 1615, 1530, 1385, 1225, 1040, 750, 700
UV: λ _max. (C ₂ H ₅ OH), nm: (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) 290 (196).

-OH), 5,28 (2Н, мультиплет, CH₂-N⁺), 5,23 (1Н, дублет, J 5 Гц, 6-Н), 5,90 (1Н, дублет, J 5 Гц, 7-Н), 6,34 (1Н, мультиплет, 3-CH= C

), 6,86 (1Н, дублет, J 16 Гц, 3-СН), 6,89 (1Н, синглет, CHPh₂), 7,35 (10Н, мультиплет, Ph-H), 7,9-8,9 (4Н, мультиплет, Ру-Н).NMR: δ (DMSO + D ₂ O), ppm. 3.7 (2H, broad singlet, 2-H), 3.91 (3H, singlet, OCH ₃ ), 4.70 (2H, singlet, Py-C

-OH), 5.28 (2H, multiplet, CH ₂ -N ⁺ ), 5.23 (1H, doublet, J 5 Hz, 6-H), 5.90 (1H, doublet, J 5 Hz, 7- H), 6.34 (1H, multiplet, 3-CH = C

), 6.86 (1H, doublet, J 16 Hz, 3-CH), 6.89 (1H, singlet, CHPh ₂ ), 7.35 (10H, multiplet, Ph-H), 7.9-8, 9 (4H, multiplet, Ru-H).

 B. 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] 3- [3- (3-hydroxymethylpyridinio) -1-propenyl] -3-cefem-4 -carboxylate (1-1K) (E isomer).

A mixture of XII-1K (E isomer, 2.0 g, 2.4 mmol) and sodium bisulfite (1 g) in 85% HCOOH (10 ml) was stirred for 2 hours at room temperature. The reaction mixture was concentrated to approximately 5 ml under reduced pressure. The oily residue was poured into acetone (100 ml) with vigorous stirring. The precipitate was collected by filtration, washed with a small amount of acetone and dried, yielding 1.1 g of a tan powder, which was purified by column chromatography (using a charcoal briquette as a nozzle (PrepPAK-500 / C ₁₈ , Waters), this yielded 283 mg (22%) of compound 1-1K as an amorphous powder, the powder crystallized from 4 normal H ₂ SO ₄ and acetone to give 144 mg of the desired compound 1-1K as colorless needles, mp 185-188 ^o C (decomp.).

-OH), 5,35 (1Н, дублет, J 4 Гц, 6-Н), 5,43 (2Н, дублет, J 6,5 Гц, СН₂-N⁺), 5,92 (1Н, дублет, J 4 Гц, 7-Н), 6,18 (1Н, дублет-триплет, J 16 Гц, J 6,5 Гц, 3-CH=C

-), 6,97 (1Н, дублет, J 16 Гц, 3-СН), 8,13 (1Н, д-д. J 8 Гц, J 16 Гц, Ру-Н), 8,60 (1Н, дублет, J 8 Гц, Ру-Н), 8,84 (1Н, дублет, J 6 Гц, Ру-Н), 8,90 (1Н, синглет, Ру-Н).IR: ν _max . (KBr), cm ^-1 : 1775, 1680 shoulder, 1660, 1630, 1225, 1045, 850
UV: λ _max . (phosphate buffer, pH 7), nm: (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ), 236.5 (283), 275 shoulder (280), 292.5 (330)
NMR: δ (D ₂ O), ppm 3.75 (2H, singlet, 2-H), 4.18 (3H, singlet, OCH ₃ ), 4.97 (2H, singlet, Py-C

-OH), 5.35 (1H, doublet, J 4 Hz, 6-H), 5.43 (2H, doublet, J 6.5 Hz, CH ₂ -N ⁺ ), 5.92 (1H, doublet, J 4 Hz, 7-H), 6.18 (1H, doublet of triplets, J 16 Hz, J 6.5 Hz, 3-CH = C

-), 6.97 (1H, doublet, J 16 Hz, 3-CH), 8.13 (1H, dd. J 8 Hz, J 16 Hz, Ru-H), 8.60 (1H, doublet , J 8 Hz, Ru-H), 8.84 (1H, doublet, J 6 Hz, Ru-H), 8.90 (1H, singlet, Ru-H).

 PRI me R 21.

CH

CH-CH₂-^⊕N

CONHCH₃
7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2- (Z)-метоксииминоацетамидо] -3- [3-(4-N-метилкарбамоилпиридинио)-1-пропенил] -3- цефем-4-карбоксилат (1-1М) (Е изомер).

CH

CH-CH ₂ - ^⊕ N

CONHCH ₃
7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (Z) -methoxyiminoacetamido] -3- [3- (4-N-methylcarbamoylpyridinio) -1-propenyl] - 3-Cephem-4-carboxylate (1-1M) (E isomer).

Mixture of diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propenyl) -3-cefem-4-carboxylate ( IX-I) (E isomer, 450 mg, 0.62 mmol) and 4-N-methylcarbamoylpyridine (obtained according to the method of M. Samejima, Yakugaku Zasshi 80, 1706 (1960) (215 mg, 1.58 mmol) in acetonitrile ( 2 ml) was stirred under nitrogen at room temperature for 5 hours, the mixture was evaporated under reduced pressure, and the residue was triturated with ether to give 530 mg of quaternary salt. A mixture of solid and sodium bisulfite (150 mg) in 85% formic acid ( 2 ml) was mixed eh for 4 hours and then heated ^at 40 ° C for 30 min. The mixture was evaporated under reduced pressure. The residue was triturated with acetone and the crude product was collected by filtration. The crude product was chromatographed on a column of HP-20 (1.5 x 18 cm) and the column was eluted with water and 30% aqueous methanol.The methanol eluate was evaporated under reduced pressure and the residue was freeze dried to give 140 mg of an amorphous powder, which was further purified by HPLC (Column: Lichrosorb RP-18, solvent: 15% methanol), and the eluate from HPLC was freeze-dried, d Away 60 mg (18%) of the target product 1-1M. Mp 180-183 ^about C (decomp.). Estimated Purity: 80%
IR: ν _max. (KBr), cm ^-1 : 1760, 1660, 1600.

UV: λ _max. (Phosphate buffer, pH 7), nm: ε 230 (22100), 286 (22100).

NMR: δ (D ₂ O), ppm. 3.08 (3H, singlet, CONHCH ₃ ), 3.72 2H, singlet, 2-H), 4.16 (3H, singlet, OCH ₃ ), 5.35 (1H, doublet, J = 4.5 Hz, 6-H), 5.95 (1H, doublet, J 4.5 Hz, 7-H), 7.00 (1H, doublet, J 16 Hz, 3-CH), 8.35 (2H, doublet, J 6 Hz, pyridin-H), 9.05 (2H, doublet, J 16 Hz, pyridin-H).

 PRI me R 22.

CH

CH-CH₂-^⊕N

7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2-метоксииминоацетамидо] -3-[3- (4-карбоксипиридинио)-1-пропенил]-3-цефем-4-карбо-ксилат (1-1N).

CH

CH-CH ₂ - ^⊕ N

7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (4-carboxypyridinio) -1-propenyl] -3-cefem-4- carbo-xylate (1-1N).

To a stirred suspension of isonicotinic acid (340 mg, 2.8 mmol) in dry DMF (3.5 ml) was added N, O-bis- (trimethylsilyl) acetamide (0.7 ml, 2.8 mmol) in a nitrogen atmosphere. To the resulting light solution was added diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propenyl) -3- cefem-4-carboxylate (IX-I) (E isomer, 720 mg, 1 mmol) as a single portion, and the red solution was stirred for 1.5 hours at room temperature. The reaction mixture was added dropwise to a stirred saturated sodium chloride solution (50 ml) containing sodium thiosulfate (150 mg). The yellow precipitate was collected by filtration, washed with water, and dried to obtain 722 mg of a pale yellow powder. Powder (700 mg) and sodium bisulfite (70 mg) were dissolved in 85% formic acid (5 ml) and the solution was left to stand at room temperature for 1.5 hours. The mixture was suspended in toluene (50 ml) and concentrated. The residue was triturated with acetone (70 ml) and the precipitate was isolated by filtration to give 421 mg of a yellow powder. This crude powder (400 mg) was suspended in water (2 ml), and sodium bicarbonate was added to the suspension. The resulting dark solution was adsorbed on a column with a nozzle (50 ml) from PrepPAK / C ₁₈ coal briquette (System Waters, 500), and the column was eluted with water (200 ml). The eluent was fractionated into 10 fractions (20 ml each), the desired fractions (fractions N 4-7) were combined, acidified to pH 32 N. hydrochloric acid and concentrated. The residue was triturated with acetone (30 ml), and the precipitate was collected by filtration to give 201 mg (37%) of target compound 1-1N as a yellow powder. E / Z 7/1; 80% purity. Mp more than 189 ^about C (decomp.).

IR: ν _max. (KBr), cm ^-1 : 1770, 1665, 1660.

UV: λ _max . (phosphate buffer, pH 7), nm: ε 227 (22500), 290 (22100)
NMR: δ (D ₂ O + NaHCO ₃ ) in ppm. 3.7 (2H, broad singlet), 4.15 (3H, singlet), 5.32 (1H, doublet, J 4 Hz), 5.39 (2H, doublet, J 6 Hz), 6.14 (1H doublet triplet, J 15.5 and 6 Hz), 7.03 (1H, doublet, J 15.5 Hz), 8.31 (2H, doublet, J 7 Hz), 8.94 (2H, doublet, J7 Hz).

 PRI me R 23.

CH

CH-CH₂-

7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2- (Z)-метоксииминоацетамидо] 3-[3-(2,3-циклопентенпиридинио)-1-пропенил] -3-цефем- 4- карбоксилат (1-10) (Е изомер)
Смесь дифенилметил 7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2- метоксииминоацетамидо] -3-)3-иод-1-пропенил)-3-цефем-4- карбоксилата (IX-I) (Е изомер, 450 мг, 0,62 ммоль) и 2,3-циклопентенпиридина (217 мг, 1,83 ммоль) в ацетонитриле (2 мл) перемешивалась в атмосфере азота в течение 4 ч при комнатной температуре. После упаривания при пониженном давлении смесь растиралась с простым эфиром, при этом получалось 560 мг четвертичной соли. Смесь твердого вещества и 85%-ной муравьиной кислоты (2 мл) перемешивалась в атмосфере азота в течение 3 ч при комнатной температуре и затем нагревалась при 40^оС в течение 30 мин. Смесь упаривалась при пониженном давлении, и растирание остатка давало 391 мг неочищенного продукта, который очи- щался хроматографией на колонке НР-20 (1,5 х 18 см). Колонка элюировалась водой и 30%-ным водным метанолом. Упаривание метанольного элюата при пониженном давлении с последующей сушкой вымораживанием давало 160 мг аморфного порошка, который в дальнейшем очищался с помощью HPLC (Колонка: Лихросорб, растворитель: 10%-ный метанол). Элюат HPL^Cсушился вымораживанием, давая 50 мг (15%) целевого продукта 1-10. Т.пл. более 190^оС (разл.). Оцененная чистота: 75%
ИК: ν_макс (KBr), см^-1: 1765, 1670, 1600.

CH

CH-CH ₂ -

7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (Z) -methoxyiminoacetamido] 3- [3- (2,3-cyclopentenpyridinio) -1-propenyl] -3 cephem-4- carboxylate (1-10) (E isomer)
Mixture of diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3-) 3-iodo-1-propenyl) -3-cefem-4-carboxylate ( IX-I) (E isomer, 450 mg, 0.62 mmol) and 2,3-cyclopentenpyridine (217 mg, 1.83 mmol) in acetonitrile (2 ml) was stirred under nitrogen for 4 hours at room temperature. After evaporation under reduced pressure, the mixture was triturated with ether to give 560 mg of a quaternary salt. A mixture of the solid and 85% formic acid (2 ml) was stirred under a nitrogen atmosphere for 3 hours at room temperature and then heated ^at 40 ° C for 30 min. The mixture was evaporated under reduced pressure, and trituration of the residue gave 391 mg of crude product, which was purified by chromatography on an HP-20 column (1.5 x 18 cm). The column was eluted with water and 30% aqueous methanol. Evaporation of the methanol eluate under reduced pressure, followed by freeze drying gave 160 mg of an amorphous powder, which was further purified by HPLC (Column: Lichrosorb, solvent: 10% methanol). The HPL ^C eluate was freeze dried to give 50 mg (15%) of the desired product 1-10. Mp more than 190 ^{° C} (dec.). Estimated Purity: 75%
IR: ν _max (KBr), cm ^-1 : 1765, 1670, 1600.

UV: λ _max (phosphate buffer, pH 7), nm: (ε) 235 (20,000), 283 (25,000).

NMR: δ (D ₂ O) + NaHCO ₃ ), ppm. 2.2-2.6 (2H, multiplet, -CH ₂ -), 3.1-3.6 (4H, multiplet, -CH ₂ -), 3.72 (2H, singlet, 2-H), 4 , 17 (3H, OCH ₃ ), 5.33 (1H, doublet, J 4.5 Hz, 6-H), 5.90 (1H, doublet, J 4.5 Hz, 7-H), 6.75 (1H, doublet, J = 16 Hz, 3-CH), 7.65-8.2 (3H, multiplet, pyridin-H).

 PRI me R 24.

CH=CH-CH₂-^⊕N

7-[2-(5-амино-1,2,4-тадиазол-3-ил)-2-(Z)-этоксииминоацетамидо] -3- [3-(4-карбоксипиридинио)-1-пропенил]-3-цефем-4-карбо- ксилат (1-2N, Е изомер).

CH = CH-CH ₂ - ^⊕ N

7- [2- (5-amino-1,2,4-tadiazol-3-yl) -2- (Z) ethoxyiminoacetamido] -3- [3- (4-carboxypyridinio) -1-propenyl] -3- cefem-4-carboxylate (1-2N, E isomer).

 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (Z) -ethoxyiminoacetamido] -3- [3- (4-carboxypyridinio) -1-propenyl] -3- cefem-4-carboxylate (1-2N, Z isomer).

IX-2 (from Preparation No. 21 (1.0 g, 1.37 mmol)) was added to a cooled mixture of BSA (1.0 ml, 4.12 mmol) and isonicotinic acid (506 mg, 4.12 mmol) and the mixture was mixed in a nitrogen atmosphere at room temperature for 2 hours. The mixture was poured into 10% Na ₂ S ₂ O ₃ (20 ml) to precipitate 1.3 g of the quaternary salt, which was collected by filtration, washed in water and dried. A mixture of solid and bisulfite sodium (0.3 g) in formic acid (98% 5 ml) was heated ^at 40 ° C for 1 hour and evaporated under reduced pressure. The residue was triturated with acetone and filtered to a d resulting in 900 mg of a crude product (E propenyl isomer, Z propenyl isomer 2: 1). Isomers were separated using HPLC (column: Lichrosorb, solvent: 15% methanol). Faster moving HPLC fractions were collected, evaporated with reduced pressure, the resulting E-propenyl isomer 1-2N (44 mg, 6% yield). Slow-moving fractions gave the Z-propenyl isomer 1-2N (32 mg 5% yield) when performing a similar procedure.

1-2N, E isomer
Mp more than 200 ^about C (decomp.)
IR: ν _max (KBr), cm ^-1 : 1765, 1660, 1620, 1380,
UV: λ _max (water), nm: (ε) 228 (22200) 291 (23600).

CH₃), 5,40 (1Н, дублет, J 4 Гц, 6-Н), 5,90 (1Н, дублет, J 4 Гц, 7-Н), 7,05 (1Н, дублет, J 15 Гц, 3-СН), 8,30 (2Н, дублет, J 6 Гц, Ру-Н), 8,95 (2Н, дублет, J 6 Гц, Ру-Н).NMR: δ (D ₂ O), ppm 1.45 (3H, triplet, J 6 Hz, CH ₂ CH8), 3.72 (2H, singlet, 2-H), 5.45 (2H, quartet, C

CH ₃ ), 5.40 (1H, doublet, J 4 Hz, 6-H), 5.90 (1H, doublet, J 4 Hz, 7-H), 7.05 (1H, doublet, J 15 Hz, 3-CH), 8.30 (2H, doublet, J 6 Hz, Ru-H), 8.95 (2H, doublet, J 6 Hz, Ru-H).

1-2N, Z isomer
T.pl.bolee 200 ^{° C} (dec.).

IR: ν _max (KBr), cm ^-1 : 1760, 1660 (shoulder), 1620, 1370
UV: λ _max (phosphate buffer, pH 7) in nm (ε) 225 (22400), 275 (16000).

), 3,50 (1Н, дублет, J 17 Гц, 2-Н), 3,75 (1Н, дублет, J 17 Гц, 2-Н), 5,38 (1Н, дублет, J 4 Гц, 6-Н), 5,95 (1Н, дублет, J 4 Гц, 7-Н), 6,62 (1Н, дублет, J 11 Гц, 3-СН), 8,35 (2Н, дублет, J 6 Гц, Ру-Н), 8,92 (2Н, дублет, J 6 Гц, Ру-Н).NMR: δ (D ₂ O), ppm 1.45 (3H, triplet, J 7 Hz, CH ₂ C

), 3.50 (1H, doublet, J 17 Hz, 2-H), 3.75 (1H, doublet, J 17 Hz, 2-H), 5.38 (1H, doublet, J 4 Hz, 6- H), 5.95 (1H, doublet, J 4 Hz, 7-H), 6.62 (1H, doublet, J 11 Hz, 3-CH), 8.35 (2H, doublet, J 6 Hz, Ru -H), 8.92 (2H, doublet, J = 6 Hz, Py-H).

 PRI me R 25.

CH

CH-CH₂-^⊕N

CONH₂
7-[2-(амино-1,2,4-тиадиазол-3-ил)-2-(про- пен-3-илоксиимино) ацетамидо] -3-[3-(4-карбамоилпиридинио)-1-пропенил] -3-цефем-4- карбоксилат (1-3Н) (Е изомер).

CH

CH-CH ₂ - ^⊕ N

CONH ₂
7- [2- (amino-1,2,4-thiadiazol-3-yl) -2- (propen-3-yloxyimino) acetamido] -3- [3- (4-carbamoylpyridinio) -1-propenyl] -3-cefem-4-carboxylate (1-3H) (E isomer).

To a solution of 35 mg (0.08 mol) of 7-amino-3- [3- (4-carbamoylpyridinio) -1- (E) -propenyl] -3-cefem-4-carboxylate hydrochloride in 2 ml of 50% aqueous 52 mg of 2- [5-amino-1,2,4-thiadiazol-3-yl)] - 2- (propen-3-yloxyimino) acetyl chloride hydrochloride (from Preparation 25) was added to acetone, and the mixture was brought to pH 6.5 -7.0 2 N Na ₂ CO ₃ . The mixture was stirred at room temperature for 1 h, acidified to pH 2 with 1N. hydrochloric acid and concentrated under reduced pressure. The residue was chromatographed on an HP-20 resin column, which was eluted with 300 ml of water and 30% methanol-water. The fractions containing the product were combined and evaporated under reduced pressure. The residue, 73 mg, was purified on a reverse phase column, the carrier of which was taken from PrepPAK-500 / C ₁₈ coal briquette (Waters, 30 ml). The column was eluted sequentially with water, 5% methanol, 10 and 20% methanol. The fractions containing the product were combined and lyophilized, giving 26 mg (62%) of the desired product 1-3H, So pl. 160 ^{° C} (dec.).

IR: ν _max (KBr), cm ^-1 : 3400, 1765, 1680, 1605, 1400.

UV: λ _max (phosphate buffer, pH 7), nm: (ε) 226 (24600), 288 (22800).

), 5,98 (1Н, дублет, J 5 Гц, 7-Н), 6,20 (1Н, мультиплет, 3-СН=СН), 7,09 (1Н, дублет, J 17 Гц, 3-СН), 8,50 (2Н, дублет, J 7 Гц, Ру-Н), 9,16 (2Н, дублет, J 7 Гц, Ру-Н).NMR: δ (D ₂ O), ppm. 3.75 (2H, singlet, 2-H), 5.41 (1H, doublet, J 5 Hz, 6-H), 5.50 (4H, multiplet, CH ₂ N ⁺ and CH = C

), 5.98 (1H, doublet, J 5 Hz, 7-H), 6.20 (1H, multiplet, 3-CH = CH), 7.09 (1H, doublet, J 17 Hz, 3-CH) 8.50 (2H, doublet, J = 7 Hz, Ru-H), 9.16 (2H, doublet, J = 7 Hz, Ru-H).

 PRI me R 26.

CH

CH-CH₂-^⊕N

7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2- пропаргилоксииминоацетамидо] 3-[3-(4-карбамоилпиридинио)-1-пропенил] -3-це- фем-4-карбоксилат (1-4Н) (Е изомер).

CH

CH-CH ₂ - ^⊕ N

7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-propargyloxyiminoacetamido] 3- [3- (4-carbamoylpyridinio) -1-propenyl] -3-cepem-4 -carboxylate (1-4H) (E isomer).

To a solution of 86 mg (0.19 mmol) of 7-amino-3- [3- (4-carbamoylpyridinio) -1- (E) -propenyl] -3-cefem-4-carboxylate (XXII-H) hydrochloride in 2 ml 50% aqueous acetone was added 63 mg of 2-propargyloxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl) acetyl chloride hydrochloride (from Preparation 26). The suspension was maintained at pH 6.5-7.0 with Na ₂ CO ₃ and then stirred at room temperature for 1 h. The reaction mixture was acidified to pH 21 N. hydrochloric acid and concentrated in vacuo.

The residue was diluted with 30 ml of water, neutralized with NaHCO ₃ and filtered. The filtrate was transferred to the top of the column, which was filled with the carrier in the reverse phase (30 ml) taken from the prepPAK-500 / C ₁₈ coal briquette (Waters). The column was eluted sequentially with water, 5, 10 and 20% methanol. The product containing fractions were combined and lyophilized to give 13 mg (12%) of the target compound 1-4H. Estimated purity 70% mp 160 ^about S.

IR: ν _max (KBr), cm ^-1 : 3400, 2120, 1765, 1680, 1610.

-C= CH), 5,40 (1Н, дублет, J 5 Гц, 6-Н), 5,50 (2Н, мультиплет, C

-N⁺), 5,98 (1Н, дублет, J 5 Гц, 7-Н), 6,20 (1Н, мультиплет, 3-CH=C

), 7,05 (1Н, дублет, J 17 Гц, 3-CH), 8,50 (2Н, дублет, J 7 Гц, Ру-Н), 9,16 (2Н, дублет, J 7 Гц, Ру-Н).UV: λ _max (phosphate buffer, pH 7), nm: (ε) 229 (24000), 288 (21200),
NMR: δ (D ₂ O), ppm. 3.78 (2H, singlet, 2-H), 5.15 (2H, doublet, J = 1 Hz, -C

-C = CH), 5.40 (1H, doublet, J = 5 Hz, 6-H), 5.50 (2H, multiplet, C

-N ⁺ ), 5.98 (1H, doublet, J 5 Hz, 7-H), 6.20 (1H, multiplet, 3-CH = C

), 7.05 (1H, doublet, J 17 Hz, 3-CH), 8.50 (2H, doublet, J 7 Hz, Ru-H), 9.16 (2H, doublet, J 7 Hz, Ru- H).

 PRI me R 27.

CH

CH-CH₂-^⊕N

CONH₂
7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2- циклопентилоксиимидо]-3-[3- (4-карбамоилпиридинио)-1-пропенил-3-цефем-4-карбо-ксилат (1-5Н) (Е изомер).

CH

CH-CH ₂ - ^⊕ N

CONH ₂
7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxyimido] -3- [3- (4-carbamoylpyridinio) -1-propenyl-3-cefem-4-carbo -xylate (1-5H) (E isomer).

To a stirred solution of 139 mg (0.31 mmol) of 7-amino-3- [3- (4-carbamoylpyridino) -1-propenyl] -3-cefem-4-carboxylate hydrochloride in 3.5 ml of 50% aqueous acetone 120 mg (0.44 mmol) of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxyiminoacetyl chloride hydrochloride was added in portions in an ice-cooled bath (from Preparation 27). The mixture was adjusted to pH 6.5-7.0 with 2N. Na ₂ CO ₃ (0.9 ml) and was stirred for 1 h at 10 ^about C. The reaction mixture was acidified to pH 21 N. hydrochloric acid and evaporated under reduced pressure. The residue was chromatographed on a column of HP-20 resin (20 ml) and eluted successively with 300 ml of water and a 30% methanol-water mixture. The fractions containing the product were combined and concentrated in vacuo. The residue was treated with 60 ml of acetone, giving 111 mg (83%) of the target compound 1-5 N. So pl. 160 ^{° C} (dec.). Estimated Purity 70%
IR: ν _max (KBr), cm ^-1 : 3400, 1770, 1680, 1605, 1530.

UV: λ _max (phosphate buffer, pH 7), nm: (ε) 224 (23300), 286 (24600).

), 4,48 (1Н, широкий синглет,

), 5,05 (1Н, дублет, J 5 Гц, 6-Н), 5,30 (2Н, мультиплет, CH₂N⁺), 5,67 (1Н, дублет-дублет, J 5 Гц и 7 Гц, 7-Н), 6,20 (1Н, мультиплет, 3-CH=CH), 7,08 (1Н, дублет, J 17 Гц, 3-СН), 3,34 (2Н, дублет, J 7 Гц, Ру-Н), 9,11 (2Н, дублет, J 7 Гц, Ру-Н), 9,38 (1Н, дублет, J 7 Гц, 7-NH).NMR: δ (DMSO-d ₆ ), ppm. 1.70 (8H, broad singlet, H

), 4.48 (1H, broad singlet,

), 5.05 (1H, doublet, J 5 Hz, 6-H), 5.30 (2H, multiplet, CH ₂ N ⁺ ), 5.67 (1H, doublet, doublet, J 5 Hz and 7 Hz, 7-H), 6.20 (1H, multiplet, 3-CH = CH), 7.08 (1H, doublet, J 17 Hz, 3-CH), 3.34 (2H, doublet, J 7 Hz, Py -H), 9.11 (2H, doublet, J 7 Hz, Py-H), 9.38 (1H, doublet, J 7 Hz, 7-NH).

 PRI me R 28.

CH

CH-CH₂-^⊕N

7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2-метоксииминоацетамидо] -3-[3- (3-карбоксиметилпиридинио)-1-пропенил]-3-цефем-4-карбоксилат (1-1Р) (Е изомер).

CH

CH-CH ₂ - ^⊕ N

7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (3-carboxymethylpyridinio) -1-propenyl] -3-cefem-4- carboxylate (1-1P) (E isomer).

 A. Diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (3-carboxymethylpyridinio) -1-propenyl] 3- cefem-4-carboxylate (XII-1P, iodide, E isomer).

To a suspension of 3-carboxymethylpyridine hydrochloride (0.89 g, 5 mmol) in 10 ml of CH ₂ Cl _{2 was} added N, O-bis- (trimethylsilyl) acetamide (4.97 ml, 18 mmol) and the mixture was stirred at room temperature until until a clear solution is obtained. IX-I (1.79 g, 2.5 mmol) was added to the solution, and the mixture was allowed to stand at room temperature. After 3 hours, 3 ml of methanol was added to the cooled mixture and the solution was evaporated in vacuo, resulting in an oil which was triturated with ethyl acetate, which afforded 2.28 g of the target compound XII-1P in the form of a tan powder. Mp 161 ^{° C} (dec.).

IR: ν _max (KBr), cm ^-1 : 1780, 1720, 1675, 1630, 1530, 1385, 1225, 1045, 755, 700.

UV: λ _max (ethyl alcohol), nm: (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) 295 (188).

NMR: δ (DMSO + D ₂ O), ppm. 3.70 (2H, broad singlet, 2H), 3.90 (5H, singlet, OCH ₃ and Py-CH ₂ CO), 5.25 (3H, multiplet, -CH ₂ N ⁺ and 6-H), 5 92 (1H, doublet, J 4.5 Hz, 7-H), 6.35 (1H, multiplet, 3-CH = CH-), 6.90 (1H, doublet, J 16 Hz, 3-CH) 6.92 (1H, singlet, CHPh ₂ ), 7.35 (10H, multiplet, Ph-H), 8.8-8.0 (4H, multiplet, Py-H).

 B. 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] 3- [3- (3-carboxymethylpyridinio-1-propenyl] -3-cefem-4- carboxylate (1-1P) (E isomer).

A mixture of XII-1P (iodide) 2.28 g) and sodium bisulfite (1.1 g) in 85% HCOOH (10 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated to a volume of approximately 5 ml under reduced pressure. The oily residue was triturated with acetone (100 ml), resulting in 1.22 g of crude product, which was purified by column chromatography (HP-20, 420 ml), and 533 mg of the target compound 1-1P (38%) was obtained from IX-I) in the form of a pale yellow amorphous powder. Mp 165 ^{° C} (dec.).

IR: ν _max (KBr), cm ^-1 : 1770, 1670, 1600, 1530, 1385, 1140, 1040.

UV: λ _max (phosphate buffer pH 6.2), nm: (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) 234 (374), 277 shoulder (390), 290 (402),
NMR: δ (D ₂ O + NaHCO ₃ ), ppm 3.78 (2H, singlet, 2-H), 3.92 (2H, singlet, Py-CH ₂ CO), 4.22 (3H, singlet, OCH ₃ ), 5.40 (1H, doublet, J 4 Hz, 6-H), 5.44 (2H, doublet, J 6.5 Hz, -CH ₂ -N ⁺ ), 5.97 (1H, doublet, 4 Hz, 7-H), 6.20 (1H doublet triplet, J 16 and 6.5 Hz, 3-CH = CH), 7.08 (1H, doublet, J 16 Hz, 3-CH), 8.11 (1H, doublet doublet, J 8 and 7 Hz, Ru-H5), 8.53 (1H, doublet, J 8 Hz, Ru-H ₄ ), 8.82 (1H, doublet, J 7 Hz, Ru-H ₆ ), 8.86 (1H, singlet, Ru-N ₂ ).

 PRI me R 29.

CH

CH-CH₂-^⊕N

S-CH₂COOH
7-[2-(5-амино-1,2,4-тиадиазолил-3-ил)-2- метоксииминоацетамидо]-3- [3-(4-карбоксиметилтиопиридинио)-1-пропенил] -3-цефем- 4- карбоксилат (1-1Q) (E изомер).

CH

CH-CH ₂ - ^⊕ N

S-CH ₂ COOH
7- [2- (5-amino-1,2,4-thiadiazolyl-3-yl) -2-methoxyiminoacetamido] -3- [3- (4-carboxymethylthiopyridinio) -1-propenyl] -3-cefem-4- carboxylate (1-1Q) (E isomer).

 A. Diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (4-carboxymethylthiopyridinio) -1-propenyl] -3-cefem -4-carboxylate (XII-IQ, iodide, E isomer).

To a suspension of 4-carboxymethylthiopyridine (0.88 g, 5 mmol) in 10 ml of CH ₂ Cl ₂ , N, O-bis- (trimethylsilyl) acetamide (5 ml, 18 mmol) was added, the mixture was stirred at room temperature until until a clear solution is obtained. IX-I (E isomer, 1.79 g, 2.5 mmol) was added to the solution, and the mixture was allowed to stand at room temperature. After 3 hours, 3 ml of methanol was added to the cooled mixture and the solution was evaporated in vacuo to give an oily residue, which was triturated with ethyl acetate, to give 2.43 g of the target compound XII-1Q (iodide) as a tan powder. Mp 155 ^about C (decomp.).

IR: ν _max. (KBr), cm ^-1 : 1780, 1720, 1670, 1625, 1525, 1385, 1225, 1115, 1040, 755, 700
UV: λ _max. (ethyl alcohol), nm: (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) 312 (299).

), 6,87 (1Н, дублет, J 16 Гц, 3-СН), 6,91 (1Н, синглет, CHPh₂), 7,35 (10Н, мультиплет, Ph-H), 7,88 и 8,58 (каждый 2Н, дублет, J 6 Гц, Ру-Н).NMR: δ (DMSO-d ₆ + D ₂ O), ppm 3.70 (2H, broad singlet, 2H), 3.93 (3H, singlet, OCH ₃ ), 5.07 (2H, multiplet, CH ₂ -N ⁺ ), 5.23 (1H, doublet, J 5 Hz) 6-H), 5.90 (1H, doublet, J = 5 Hz, 7-H), 6.29 (1H, multiplet, 3-CH = C

), 6.87 (1H, doublet, J 16 Hz, 3-CH), 6.91 (1H, singlet, CHPh ₂ ), 7.35 (10H, multiplet, Ph-H), 7.88 and 8, 58 (each 2H, doublet, J = 6 Hz, Ru-H).

 B. 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] 3- [3- (4-carboxymethylthiopyridinio) -1-propenyl] -3-cefem-4 - carboxylate (1-1Q) (E isomer).

A mixture of XII-IQ (iodide, 2.43 g) and sodium bisulfite (1.1 g) in 85% HCOOH (10 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated to a volume of ≈ 5 ml under reduced pressure. The oily residue was triturated with acetone (100 ml), filtered and dried to give a crude product (1.39 g), which was purified by column chromatography (HP-20, 20 ml) to obtain 577 mg of the target compound I-IQ (39% of IX-I) as a pale yellow amorphous powder. Mp 188 ^{° C} (dec.).

IR: ν _max . (KBr), cm ^-1 : 1765, 1670, 1625, 1530, 1380, 1110, 1035.

UV: λ _max. (phosphate buffer, pH 6.2), nm: (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) 234 (459), 310 (678).

NMR: δ (D ₂ O + NaHCO ₃ ), ppm 3.79 (2H, broad singlet 2-H), 4 N. 10 (2H, singlet, S-CH ₂ ), 4.23 (3H, singlet, OCH ₃ ), 5.25 (2H, doublet, J 6.5 Hz, CH ₂ -N ⁺ ), 5.39 (1H doublet, J 4.0 Hz, 6-H), 5.97 (1H, doublet, J 4 Hz, 7-H), 6.18 (1H, doublet triplet, J 15.5 Hz and 6.5 Hz, 3-CH = CH), 7.05 (1H, doublet, J 15.5 Hz, 3-CH), 7.84 and 8.35 (each 2H, doublet, J 7 Hz, Py-H).

 PRI me R 30.

CH

CH-

-

7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2-метоксииминоацетамидо] -3-[3- (1-метилпирролидинио)-1-пропенил] -3-цефем-4-кар- боксилатсульфат (1-1А, сульфат).

CH

CH-

-

7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (1-methylpyrrolidinio) -1-propenyl] -3-cefem-4- carboxylate sulfate (1-1A, sulfate).

 A. Diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (1-methylpyrrolidinio) -1-propenyl] -3- cefem -4-carboxylate (XII-IA, iodide).

To a cold solution of diphenylmethyl 7- [2- (3-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3-iodo-propenyl] -3-cefem-4-carboxylate ( IX-I) (from Preparation 14) (21.5 g, 30 mmol) in ethyl acetate (300 ml) was added dropwise a solution of 1-methylpyrrolidine (2.55 g, 30 mmol) in ethyl acetate (30 ml over 1 h at from -5 to 0 ^о С, the resulting precipitate was collected by filtration and washed with chloroform (200 ml), resulting in 23.0 g (95.8%) of the target compound (IX-IA, iodide), melting at more than 175 ^o C (decomp.).

IR: ν _max. (KBr), cm ^-1 : 3330, 1780, 1730, 1685, 1615.

UV: λ _max . (ethyl alcohol), nm: (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ), 218 (435), 295 (188).

 B. Diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-5-yl) -2-methoxyiminoacetamido] -3- [3- (1-methylpyrrolidinio) -1-propenyl] -3- cefem -4-carboxylate (XII-IA, chloride).

The compound (XII-IA, iodide) (23 g, 28.7 mmol) was dissolved in a mixture of acetone and methanol (1: 1, 230 ml) and applied to an IRA-410 amberlite column (in the form of chloride, 230 ml), which pretreated with the same mixed solvent. The column showed a solvent, and the fractions containing the desired product were combined and concentrated to an oily residue, which was triturated with ethyl acetate (300 ml), to give 17.9 g (87.7% of the target compound (XII-IA, chloride), melting at 190 ^C. (dec.).

IR: ν _max. (KBr), cm ^-1 : 2380, 1780, 1680, 1620.

UV: λ _max . (ethyl alcohol), nm: (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) 220, (369), 290 (232).

 C. 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (1-methylpyrrolidinio) -1-propenyl] -3-cefem- 4-carboxylate sulfate (1-1A, sulfate).

A mixture of compound (XII-IA, chloride) (17.8 g, 25 mmol) in 85% formic acid (178 ml) was stirred at room temperature for 2 hours under nitrogen. The mixture was evaporated in vacuo and the oily residue was triturated with acetone to give 9.80 g of crude 1-1A. Concentration of the filtrate and acetone washes gave an additional 2.95 g of crude 1-1A. Two collections of crude material were combined and extracted with 2 N. hydrochloric acid (1 l and 0.5 l). The combined extracts were adsorbed on Diaion HP-20 resin (1.5 L column), which was eluted with water and 30% aqueous methanol. The desired fractions were collected and evaporated in vacuo to an oily residue, which was triturated successively with isopropanol (200 ml) and acetone (200 ml), yielding 7.09 g of a light yellow powder. This substance (6.80 g) was dissolved in water (20 ml) and then subjected to chromatography on a column with a nozzle of coal briquette PrepPAK-500 / C ₁₈ (90 ml), using water and 10% methanol as eluent. The eluate was collected in a 20 ml fraction controlled by HPLC. Column, Nucleocycle SSC-ODC-262.8 x 100 mm) mobile phase, 0.01 M phosphate buffer (pH 7.2) (methanol 90:10; detection, UV (254 nm)). Fractions 4 to 10 were combined, evaporated under reduced pressure and lyophilized to give 2.28 g of a yellow powder (E / Z 7/1, 70% purity). Fractions 11-85 were treated in the same manner as described above, yielding 3.27 g of yellow powder, (E / Z 5/1, 70% purity) (Collection 2). A portion of collection 1 (1.0 g) was purified by repeated chromatography on a nozzle of a coal briquette PrepPAK-500 / C ₁₈ (90 ml). The column was subsequently eluted with water and 5% aqueous methanol. The eluate containing the desired compound was concentrated and lyophilized, resulting in 638 mg (E / Z 7/1, 80% purity) of a yellow powder. The other part of collection 1 (1.14 g) was treated in the same way, giving 880 mg (E / Z 7/1, 80% purity) of a yellow powder. Two purified samples were combined, and a portion (1.45 g) was dissolved in 1 N. sulfuric acid (5 ml). The solution was diluted with acetone (315 ml) with stirring. Cream colored precipitate was collected by filtration, to give 1.48 g of the title compound (1-1A, sulfate) (E / Z 7/1, 80% pure) melting at over 185 ^{° C} (dec.).

IR: ν _max . (KBr), cm ^-1 : 3380, 3000, 1765, 1675, 1630, 1535, 1390, 1115.

UV: λ _max . (phosphate buffer, pH 7), nm: (ε) 286 (19900), 291.5 (22500).

), 3,15 (3Н, синглет, CH₃± N

), 3,62 (5Н, широкий, 2-Н и

), 3,83 (1Н, широкий, 2-Н), 4,13 (2Н, дублет, J 8 Гц, CH₂N⁺), 4,22 (3Н, синглет, ОСН₃), 5,39 (1Н, дублет, J 4,5 Гц, 6-Н), 5,96 (1Н, дублет, J 4,5 Гц, 7-Н), 6,00 (1Н, мультиплет, 3-CH=C

), 6,67 (1/8Н, дублет, J 10 Гц, 3-СН, цис), 7,04 (7/8Н, дублет, J 16 Гц, 3-СН, транс).NMR: δ (D ₂ O + NaHCO ₃ ), ppm 2.36 (4H, broad, N

), 3.15 (3H, singlet, CH ₃ ± N

), 3.62 (5H, broad, 2-H and

), 3.83 (1H, broad, 2-H), 4.13 (2H, doublet, J 8 Hz, CH ₂ N ⁺ ), 4.22 (3H, singlet, OCH ₃ ), 5.39 (1H doublet, J 4.5 Hz, 6-H), 5.96 (1H, doublet, J 4.5 Hz, 7-H), 6.00 (1H, multiplet, 3-CH = C

), 6.67 (1 / 8H, doublet, J 10 Hz, 3-CH, cis), 7.04 (7 / 8H, doublet, J 16 Hz, 3-CH, trans).

 PRI me R 31.

CH

CH-CH

N(CH₃)₃
7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2- метоксииминоацетамидо] -3-[3- триметиламмонио-1-пропенил]-3-цефем-4-карбоксилат (I-ID)
А. Дифенилметил 7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2-метоксиимино ацетамидо] -3- [3-триметиламмонио-1-пропенил]-3-це- фем-4-карбоксилат (XII-ID, иодид).

CH

CH-CH

N (CH ₃ ) ₃
7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3-trimethylammonio-1-propenyl] -3-cefem-4-carboxylate (I- ID)
A. Diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyimino acetamido] -3- [3-trimethylammonio-1-propenyl] -3-cef- 4-carboxylate (XII-ID, iodide).

To a solution of 13.0 g (19 mmol) diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodopropenyl) -3 - cefem-4-carboxylate (IX-I, from preparation 10) in 38 ml of dry ethyl acetate was added 1.75 ml (19.1 mmol) of 2.1 N. trimethylamine in ethyl acetate at -5 ^C, and the mixture was stirred for 1 h at -5 ^C. The resulting precipitate was filtered, washed well with CHCl ₃ and dried, to give 12.5 g (88%) of the title compound (XII -ID) as iodide.

IR: ν _max. (KBr), cm ^-1 : 3300, 1765, 1720, 1665.

UV: λ _max. (ethyl alcohol), nm: (ε) 300 (18400).

 B. Diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-trimethylammonio-1-propenyl) -3-cef-4 -carboxylate (XII-ID, chloride).

 Iodide (XII-ID, 12.5 g) was dissolved in 60 ml of a mixture of methanolacetone (1: 1) and passed through a column of ion exchange resin (IRA-410 (Cl-), 125 ml). The column was eluted with 300 ml of methanol: water (1: 1), and the eluate was evaporated in vacuo and triturated with 300 ml of isopropyl ether to give 10.4 g (91%) of the quaternary salt (XII-ID, chloride).

IR: ν _max. (KBr), cm ^-1 : 3300, 1765, 1710, 1665.

UV: λ _max. (ethyl alcohol), nm: (ε) 298 (15100).

 C. 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] 3- [3-trimethylammonio-1-propenyl] -3-cefem-4-carboxylate (I -ID, sulfate, E isomer).

A solution of 10.4 g (16.0 mmol) of XII-ID (chloride) in 20.8 ml of 85% formic acid was allowed to stand at room temperature for 3 hours and concentrated in vacuo. The residue was treated with 210 ml of isopropanol, and the precipitate was filtered off. The solid (10.1 g) was triturated with 210 ml of water and neutralized with sodium bicarbonate. The suspension was filtered off and the filtrate was chromatographed on an HP-20 column (300 ml), which was eluted successively with water (1000 ml), 10% methanol (200 ml) and 30% methanol (150 ml). Fractions containing the desired product were combined and concentrated under reduced pressure. The residue was purified by reverse phase chromatography. The column was filled with a charcoal briquette nozzle obtained from PrepPAK-500 / C ₁₈ (Waters, 200 ml). Elution successively with water (600 ml) and 30% methanol (200 ml), followed by concentration of the fractions containing the desired product, gave 2.52 g (18%) of the target compound. A solution of the zwitterionic product (1.5 g in 1 N sulfuric acid (5 ml) was added portionwise to 300 ml of acetone, and the resulting precipitate was filtered and dried. The I-ID yield as sulfate was 1.42 g (80 %). The E / Z ratio was approximately 10/1 based on HPLC.

IR: ν _max . (KBr), cm ^-1 : 3380, 1765, 1665.

UV: λ _max . (phosphate buffer, pH 7), nm: (ε) 237 (19500), 293 (22400).

), 7,23 (1Н, дублет, J 16 Гц, 3-СН).NMR: δ (D ₂ O), ppm. 3.25 (9H, singlet, N ⁺ -CH ₃ ), 3.94 (2H, singlet, 2-H), 4.14 (2H, doublet, J 7 Hz, CH ₂ N ⁺ ), 4.23 ( 3H, singlet, O-CH ₃ ), 5.42 (1H, doublet, J 4.5 Hz, 6-H), 6.00 (1H, doublet, J 4.5 Hz, 7-H), 6, 23 (1H, doublet of triplets, J = 7 & 16 Hz, 3-CH = C

), 7.23 (1H, doublet, J = 16 Hz, 3-CH).

 PRI me R 32.

CH

CH-CH

N

CONH₂
7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2-метоксииминоацетамидо] -3-[3- (4-карбамоилпиридинио)-1-пропенил]-3-цефем-4-кар- боксилат (I-IH, Е изомер).

CH

CH-CH

N

CONH ₂
7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (4-carbamoylpyridinio) -1-propenyl] -3-cefem-4- carboxylate (I-IH, E isomer).

To a mixture of 7-amino-3- [3- (4-carbamoyl-pyridinio) -1- (E) - propenyl] -3-cefem-4-carboxylic acid hydrochloride (XXII-H, 397 mg, 1 mmol) and NaHCO ₃ (168 mg, 2 mmol) in aqueous DMF (water, 3.5 ml and DMF, 7.5 ml) was added benzotrazol-1-yl-2- (5-amino-1,2,4-thiadazole-3- sludge) - 2-methoxyiminoacetate (479 mg, 1.5 mmol) (from Preparation 28). The mixture was stirred at room temperature for 3.5 hours. The reaction mixture was adjusted to pH 3-4 3 N. hydrochloric acid and was diluted with 200 ml of acetone, giving a precipitate, which was collected by filtration. The crude product was dissolved in a small volume of aqueous THF, and the solution was adjusted to pH 6.8 with NaHCO ₃ , treated with providing carbon, concentrated to a volume of ≈ 1 ml, and seeded with several pieces of crystalline I-IH. After stirring overnight, a crystalline precipitate was collected by filtration to obtain the target compound I-IH (in the form of a zwitterion). Yield 83 mg (16%). Mp more than 185 ^{° C} (dec.). The physico-chemical characteristics of this product were identical to those of Example 10.

 Preparation 1. Diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) 2-methoxyiminoacetamido] -3-chloromethyl-3-cefem-4-carboxylate (IV-I).

To a stirred suspension of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetic acid (III-I) (2.1 g, 10 mmol) in dry methylene chloride (50 ml) was added pentachloride phosphorus (2.09 g, 10 mmol) at ^-30 ° C, the mixture was stirred for 20 min at -15 to -20 ° ^C. to this solution was added a solution horangidrida acid hydrochloride of diphenylmethyl 7-amino-3- chloromethyl -3-cefem-4-carboxylate (II) (4.5 g, 10 mmol) in methylene chloride (50 ml) containing N, O-bis- (trimethylsilyl) acetamide (10 g, 50 mmol), at -30 ^o C. After stirring at ^-10 ° C for 1 h the mixture was concentrated was centered to remove methylene chloride and diluted with ethyl acetate (200 ml). The mixture was washed successively with 10% aqueous sodium bicarbonate (2 x 40 ml), water (2 x 20 ml) and brine (10 ml) and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the resulting oily residue (10 g) was dissolved in chloroform (20 ml) and chromatographed on silica gel (Waco gel C-200, 100 g containing 10 ml of 1 / 1.5 M pH 7 phosphate buffer) using 1 -3% methanol-chloroform mixture. Fractions containing the target compound were evaporated, yielding 5.7 g (95%) of compound IV-I as a yellow amorphous powder. Mp above 140 ^about C (decomp.).

IR: ν _{max. (} KBr), cm ^-1 : 3300, 1780, 1720, 1680, 1620.

UV: λ _max. (ethanol, nm: (ε) 245 (1800), 280 (9800).

), 4,42 (2Н, синглет, 3-СН₂), 5,22 (1Н, дублет, J 4,5 Гц, 6-Н), 5,92 (1Н, д-д. J 4,5 и 6, 7-Н), 6,93 (1Н, синглет, CHPh₂), 7,36 (10Н, мультиплет, Ph-H), 8,1 (2Н, шир. синглет, NH₂), 9,58 (1Н, дублет, J 6, 7-NH).NMR: δ (DMSO-d ₆ ), ppm 3.53 (2H, ABq, 2-H); 3.94 (3H, singlet, OC)

), 4.42 (2H, singlet, 3-CH ₂ ), 5.22 (1H, doublet, J 4.5 Hz, 6-H), 5.92 (1H, dd. J 4.5 and 6, 7-H), 6.93 (1H, singlet, CHPh ₂ ), 7.36 (10H, multiplet, Ph-H), 8.1 (2H, broad singlet, NH ₂ ), 9.58 ( 1H, doublet, J 6, 7-NH).

 Preparation 2. Diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) 2-methoxyiminoacetamido] -3-iodomethyl-3-cefem-4-carboxylate (V-I).

A mixture of IV-I from Preparation 1 (5.7 g, 9.5 mmol) and sodium iodide (4.3 g, 29 mmol) in dry acetone (50 ml) was stirred for 5 min at room temperature. The mixture was concentrated under reduced pressure, and the resulting oil was shaken with a mixture of ethyl acetate (100 ml) and water (10 ml). The organic layer was separated and washed successively with 10 wt. volume of sodium thiosulfate and saline. After drying, the ethyl acetate was removed in vacuo, giving 6.1 g (93%) of the title compound (VI) as a yellow amorphous powder, melting at above ¹²⁰ ° C (dec.).

IR: ν _max. (KBr), cm ^-1 : 3300, 1780, 1725, 1680, 1620.

Ph₂ 7,35 (10Н, мультиплет, Ph-H), 8,12 (2Н, шир. синглет, NH2), 9,65 (1Н, дублет, J 6, 7-NH).UV: λ _max. (ethanol), nm: (ε) 245 (17000) 282 (12000)
NMR: δ (DMSO-d ₆ ), ppm. 3.72 (2H, ABq 2-H), 3.94 (3H, singlet, OCH ₃ ), 4.23 (2H, singlet, 3-CH ₂ ), 5.21 (1H, doublet, J 4.5 6-H), 5.89 (1H, dd. J 4.5 and 6, 7-H), 6.94 (1H, singlet, C

Ph ₂ 7.35 (10H, multiplet, Ph-H), 8.12 (2H, broad singlet, NH2), 9.65 (1H, doublet, J 6, 7-NH).

 Preparation 3. Diphenylmethyl iodide 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3-triphenylphosphoniomethyl-3-cefem-4-carboxylate (VI-I )

A mixture of compound VI of Preparation Example 2 (690 mg, 1 mmol) and triphenylphosphine (786 mg, 3 mmol) in ethyl acetate (20 ml) was stirred overnight at room temperature. The solid that separated was collected by filtration, washed with ethyl acetate (2 x 10 ml) and dried, giving 950 mg (100%) of phosphonium iodide VI-I. Mp 186 ^{° C} (dec.).

IR: ν _max. (KBr), cm ^-1 : 3300, 1780, 1710, 1680, 1610.

UV: λ _max. (ethanol), nm: (ε) 268 (15000), 275 (13000), 300 (7300).

), 5,34 (1Н, дублет, J 4,5, 6-H), 5,9 (1Н, мультиплет, 7-Н), 6,3 (1Н, синглет), 7,3 (10Н, мультиплет, Ph-H), 7,8 (15Н, мультиплет, Ph-H).NMR: δ (DMSO-d ₆ ), ppm. 3.52 (2H, broad singlet, 2H), 3.94 (3H, singlet, OC

), 5.34 (1H, doublet, J 4.5, 6-H), 5.9 (1H, multiplet, 7-H), 6.3 (1H, singlet), 7.3 (10H, multiplet, Ph-H), 7.8 (15H, multiplet, Ph-H).

 Preparation 4. Diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxy-iminoacetamido] -3- [(triphenylphosphoranilidene) methyl] -3-cefem-4-carboxylate (VII-I).

A mixture of compound VI-I from preparation example 3 (952 mg, 1 mmol). Amberlite IRA-410 (OH-form, 500 mg) and normal. sodium hydroxide (4 ml) in methylene chloride (10 ml) was stirred for 1 h at room temperature. The mixture was filtered, and the separated organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting oil was triturated with ethyl acetate, the resulting yellow precipitate was collected by filtration, giving 740 mg (90% 0 VII-ITpl title compound. Above 180 ^{° C} (dec.).

IR: ν _max. (KBr), cm ^-1 : 3400, 1750, 1630.

UV: λ _max. (ethanol), nm: (ε) 268 (12000), 276 (10000) 384 (23000)
Preparation 5. Diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) 2-methoxyiminoacetamido] -3- (3-chloro-1-propen-1-yl) -3-cephem -4-carboxylate (VII-I).

Magnesium sulfate (3 g) and 40% chloroacetaldehyde (810 mg, 8.4 mmol) were added to the solution VII-I from preparation 4 (6.9 g, 8.4 mmol). The mixture was stirred for 1.5 hours at room temperature and then filtered. The filtrate was eluted on silica gel (Waco gel C-200, 100 g, containing 10 ml of 1 / 1.5 M phosphate buffer) on a column using CHCl ₃ and CHCl ₃ containing methanol. Fractions containing the desired product (0.5-1% methanol-chloroform) were evaporated in vacuo to give 1.6 g (30%) of the target compound VIII-I as a yellow amorphous powder, which was a mixture of Z and E isomers relative to chloropropenyl moiety (Z / E 2/1; according to NMR). Mp above 130 ^° C (decomposition).

IR: ν _max. (KBr), cm ^-1 : 3300, 1780, 1725, 1680, 1620.

UV: λ _max. (ethanol), nm: (ε) 240 (20,000), 286 (12,000).

Cl), 5,26 (1Н, дублет, J 4,5, 6-Н), 5,87 (1Н, дублетб J 4,5, 7-H), 6,28 (2/3Н, дублет, J 11, 3-C

цис-Н), 6,72 (1, 3Н, дублет, J 16, 3-C

, транс-Н), 6,81 (2, 3Н, синглет, C

Ph₂), 6,92 (1, 3Н, синглет, C

Ph₂), 7,4 (10Н, мультиплет, Ph-H).NMR: δ (DMSO-d ₆ + D ₂ O), ppm 3.56 and 3.8 (multiplet, 2H), 3.94 (3H, singlet, OCH ₃ ), 4.16 (doublet, J 4.5, C

Cl), 5.26 (1H, doublet, J 4.5, 6-H), 5.87 (1H, doublet J 4.5, 7-H), 6.28 (2 / 3H, doublet, J 11 3-C

cis-H), 6.72 (1, 3H, doublet, J 16, 3-C

, trans-H), 6.81 (2, 3H, singlet, C

Ph ₂ ), 6.92 (1, 3H, singlet, C

Ph ₂ ), 7.4 (10H, multiplet, Ph-H).

 Preparation 6. Diphenylmethyl 7-benzylidenamino-3- [(triphenylphosphoranilidene) methyl] -3-cefem-4-carboxylate (XVI).

To a solution of diphenylmethyl 7-benzylidenamino-3- [(triphenylphosphinio) methyl] -3-Cephem-4-carboxylate (XV prepared in accordance with the procedure described in Japanese Patent Application Publication (Cocai) 56-86187, 1981), ( 60 g, 70 mmol) in methylene chloride (350 ml) were added norms. sodium hydroxide (140 ml) and Amberlite IRA-410 (OH ^- form, 35 g) at 5 ^C. The mixture was stirred for 1 h at ⁵ ° C and filtered. The organic layer was separated, dried over magnesium sulfate, concentrated to approximately 100 ml volume and precipitated with ethyl acetate (500 ml). The resulting yellow solid was collected by filtration and dried in vacuo, giving 48 g (94%) of the title compound XVI, melting at 195-8 ^{° C} (decomposition).

IR: ν _max. (KBr), cm ^-1 : 1770, 1620.

 Preparation 7. Diphenylmethyl 7-benzylidenamino-3- (3-chloro-1-propen-1-yl) -3-cefem-4-carboxylate (XVII).

To a stirred solution of compound XVI from preparation 6 (2.9 g, 4 mmol) in a mixture of methylene chloride (40 ml) and water (10 ml) was added anhydrous chloroacetaldehyde (800 mg) at room temperature. An additional 800 mg of chloroacetaldehyde was added to the mixture in three portions over a period of 1 hour, while the pH of the mixture was maintained between 6 and 9 by adding norms. sodium hydroxide. After 15 minutes, the aqueous layer was removed and the organic layer was dried over magnesium sulfate. Evaporation of the solvent gave a red oil, which was dissolved in a mixture of ethyl acetate and isopropyl ether (1/2, 80 ml). The solution was washed sequentially with saturated aqueous sodium bicarbonate (10 ml) and water (10 ml). After drying over magnesium sulfate, removal of solvent gave 3.3 g of a yellow oil. A solution of the oil in methylene chloride (50 ml) was filtered using silica gel (12 g, Vacogel C-200) containing 1 / 1.5 M phosphate buffer (1.2 ml, pH 6.4), and the silica gel was washed with methylene chloride (50 ml ) The filtrate and wash water were combined and evaporated to dryness. The residue was triturated with n-hexane to give 1.7 g (80%) of the target compound (XVII) as a yellow powder. The NMR spectrum showed that the chloropropenyl part of the molecule had a Z configuration. Mp above 50 ^about C (decomp.).

IR: ν _max. (KBr), cm ^-1 : 3400, 1775, 1720, 1630
UV: λ _max. (ethanol), nm: (ε) 253 (11000), 258 (11000), 26 (10000), 273 (8300), 281 (7000), 290 (6300).

-Cl), 5,42 (2Н, мультиплет 6Н и 3-CH=C

), 5,72 (1Н, дублет, J 4,5, 7-Н), 6,27 (1Н, дублет, J 11, 3-СН), 6,85 (1Н, синглет, CHPh2), 7,33 (10Н, мультиплет, Ph-H).NMR: δ (DMSO-d ₆ ), ppm 3.63 (2H, broad, singlet, 2-H), 4.0 (2H, multiplet, C

-Cl), 5.42 (2H, multiplet 6H and 3-CH = C

), 5.72 (1H, doublet, J 4.5, 7-H), 6.27 (1H, doublet, J 11, 3-CH), 6.85 (1H, singlet, CHPh2), 7.33 (10H, multiplet, Ph-H).

 Preparation of anhydrous chloroacetaldehyde.

Anhydrous calcium chloride was added to a cooled solution of 50% aqueous chloroacetaldehyde (50 ml) with stirring to separate it into two layers. The chloroacetaldehyde-hydrate layer (I) (upper) was separated and diluted with chloroform (100 ml), mixed with magnesium sulfate (20 g), heated to boiling under reflux for 5 min, and filtered. The solvent and water were removed azeotropically (bp. 56-64 ° ^C) (2), the residue was distilled to give anhydrous chloroacetaldehyde (3), b.p.. 70-82 ^about C / 760 mm Hg

IR: ν _max. (film), cm ^-1 : 1720).

 (1) R. P. Kurkjy, E. V. Brown, J. Amer. Chem. Soc. 74, 5778 (1952).

 (2) S. Trippett, D. M. Walker, J. Chem. Soc, 1961, 1266.

 (3) H.C. House, V.K. Jones, G.A. Frank, J. Org. Chem. 29, 3327 (1964).

 Preparation 8. Diphenylmethyl 7-amino-3- (3-chloro-1-propen-1-yl) -3-cephem-4-carboxylate (XVIII).

A solution of compound XVII from Preparation 7 (180 mg, 0.34 mmol) in ethyl acetate (10 ml) was added to a solution of Girard T [(carboxymethyl) trimethylammonium hydrazide] reagent (251 mg, 1.5 mmol) in methanol (10 ml) containing acetic acid (0.25 ml) at 5 ° ^C. After stirring for 30 min at ⁵ ° C, the mixture was concentrated to remove methanol and then added ethyl acetate (20 mL). The ethyl acetate solution was washed successively with water (2 x 5 ml), saturated aqueous sodium bicarbonate (5 ml) and brine (5 ml) and dried over magnesium sulfate. Evaporation of the solvent gave 145 mg (97%) of the target compound XVIII (Z isomer) as a yellow powder. Mp above 100 ^about C (decomp.).

IR: ν _max. (KBr), cm ^-1 : 3400, 1770, 1720.

UV: λ _max. (ethanol), nm: (ε) 252 (3700), 253 (3800), 260 (4000), 274 (4000), 285 (4000).

 Preparation 9. Diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) 2-methoxyiminoacetamido] -3- (3-chloro-1-propen-1-yl) -3-4 - carboxylate (VIII-I).

A mixture of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetic acid (III-I) (10, 1 g, 50 mmol) and phosphorus pentachloride (10.4 g, 50 mmol ) in dry methylene chloride (100 ml) was stirred at -7 to ^-15 ° C for 2 hours. The clear solution was poured into n-hexane (500 ml) to give a precipitate. The organic layer was discarded by decantation, and the remaining solid was triturated with n-hexane (100 ml). The yellow precipitate was collected by filtration and dried in vacuo, giving 12.5 g (99%) of acid chloride, melting at 80 ° ^C (decomposition).

IR: ν _max. (nujol), cm ^-1 : 1770.

An acid chloride (25 mg, 0.1 mmol) was added to a solution of compound XVIII (Z isomer) from Preparation 8 (44 mg, 0.1 mmol) in dry methylene chloride (5 ml) at room temperature with stirring. After 30 minutes, the mixture was concentrated under reduced pressure and diluted with ethyl acetate (20 ml) and saturated aqueous sodium bicarbonate (5 ml). The organic layer was washed with saturated aqueous sodium bicarbonate (5 ml), brine (5 ml), 10% HCl (5 ml) and brine (5 ml). The solvent was dried over magnesium sulfate and then evaporated to dryness, giving the product as a yellow foam. The foam was purified by chromatography on a silica gel column (Vacogel C-200, 1 g, containing 0.1 ml of 1 / 1.5 M phosphate buffer pH 6.4), eluting with a mixture of methylene chloride and methanol (100: 1) to give 31 mg (50%) of the target compound VIII-I (Z isomer) as a yellow powder. Mp above 150 ^about C (decomp.).

IR: ν _max. (KBr), cm ^-1 : 3400, 1775, 1675, 1630.

UV: λ _max. (ethanol), nm: (ε) 240 (17000), 280 (10000).

NMR: δ (DMSO-D ₆ ), ppm. 3.6 (2H, multiplet, 2-H), 3.92 (3H, singlet, O-CH ₃ ), 4.0 (2H, multiplet, CHCl), 5.27 (2H, multiplet, 6-H and 3-CH = CH), 5.83 (1H, dd. J 4.5 and 10, 7-H), 6.25 (1H, doublet, J 11, 3-CH), 6.83 (1H singlet, CHPh ₂ ), 7.33 (10H, multiplet, Ph-H), 8.0 (2H, broad singlet, NH ₂ ), 9.57 (1H, doublet, J 10, 7-NH).

 Preparation 10. Diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) -3- cefem-4-carboxylate (IX-I).

A solution of VIII-I from preparation example N 5 (Z / E 2/1, 480 mg, 0.77 mmol) in dry acetone (10 ml) containing Nal (346 mg, 2.3 mmol) was mixed for 30 min at ambient temperature. The reaction mixture was evaporated under reduced pressure. The resulting oil was partitioned between ethyl acetate (50 ml) and water (10 ml). The top layer was washed sequentially with 10% w / v aqueous sodium thiosulfate (10 ml) and brine (10 ml) and dried over magnesium sulfate. Evaporation of the solvent gave 540 mg (98%) IX-I title compound (Z / E 1-1) as a reddish amorphous solid, melting at above ¹²⁰ ° C (dec.).

IR: ν _max. KBr, cm ^-1 : 3300, 1780, 1720, 1680, 1620.

UV: λ _max. nm: (ε) 240 (21000), 290 (12000).

NMR: δ ppm (DMSO + D ₂ O) 3.67 (2H, multiplet, 2-H), 5.29 (1H, doublet, J 4.5, 6-H-, 5.95 (1H, doublet, J 4.5 7-H), 6.27 (1) 2H, doublet, J 11, 3-CH cis), 6.72 (1) 2H, doublet, J 16 3-CH transe, 6.87 and 6.96 ( each 1-2H, singlet, CHPh ₂ ), 7.4 (10H, multiplet, Ph-H).

 Preparation 11. Diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) -3- cefem-4-carboxylate (IX-I).

A mixture of VIII-I (Z isomer) from Preparation 9 (5.6 g, 9 mmol and sodium iodide (4 g, 27 mmol) in dry acetone (100 ml) was stirred for 1.5 hours at room temperature. The mixture was evaporated, and the resulting oil was diluted with ethyl acetate (90 ml). The ethyl acetate layer was washed with 10% w / v aqueous sodium thiosulfate (10 ml) and water (10 ml). Removal of the dried (magnesium sulfate) solvent gave a yellow oil which solidified with trituration with isopropyl ether Filtration of the precipitate gave 4.3 g (67%) of target compound IX-I in ide E isomer mp. above 165 ^{° C} (dec.)
IR: ν _max. KBr, cm ^-1 : 3400, 1780, 1725, 1680, 1610.

UV: λ _max. ethanol, nm: (ε) 240 (18000), 297 (11000).

NMR: δ ppm (DMSO-d ₆ + D ₂ O) 3.90 (3H, singlet, OCCH ₃ ), 5.25 (1H, multiplet, 6-H), 5.95 (1H, multiplet, 7-H), 6, 72 (doublet, J 16, 3-CH trans), 6.96 (1H, singlet, CH-Ph), 7.4 (10H, multiplet, Ph-H).

 Preparation 12. Benzhydryl 7-amino-3- [3-chloro-1-propen-1-yl] -3-cephem-4-carboxylate (Z-isomer) (XVIII).

 Compound XVIII is a common intermediate used in reaction schemes 1b and 1c.

 A. Benzhydryl chloride 7-benzylidenamino-3-triphenylphosphoniomethyl-3-cefem-4-carboxylate (XV).

To a suspension of 7-amino-3-chloromethyl-3-cephem-4-carboxylate-hydrochloride benzhydryl (11 hydrochloride) (200 g, 0.44 mol) in methylene chloride (940 ml) was added 1N. sodium hydroxide (440 ml) at room temperature. The mixture was shaken for 10 minutes and the organic layer was separated. Magnesium sulfate (75 g) and benzaldehyde (51 g, 0.48 mol) were added to the organic layer, the mixture was allowed to stand for 3 hours. The reaction mixture was filtered, and the insoluble matters were washed with methylene chloride (200 ml). Triphenylphosphine (126 g, 0.48 mol) was added to the combined filtrate and washings. The mixture was concentrated to about 400 ml and left to stand for 4 days. The resulting viscous oil was diluted with ethyl acetate (1 L) and triturated to separate the desired compound XV of a pale yellow crystalline powder, which was collected by filtration and dried in vacuo. Yield 322 g (96%). Mp 185-190 ^about C (decomp.).

IR: ν _max. KBr, cm ^-1 : 1780, 1720, 1630
UV: λ _max. methylene chloride, nm: (ε) 260 (24100).

 B. Benzhydryl 7-benzylidenamino-3 - [(triphenylphosphoranilidene) methyl] 3-cephem-4-carboxylate (XVI).

A mixture of XV (322 g, 0.42 mol) and 5 N. sodium carbonate (252 ml) in methylene chloride (1.6 L) was stirred vigorously for 15 minutes at room temperature. The organic layer was separated, dried over magnesium sulfate and concentrated to approximately 500 ml volume. The concentrate was added to acetone (1 L) with stirring, giving a pale yellow crystalline powder which was collected by filtration, giving 237 g (78%) of compound XVI, melting at 195-198 ^{° C} (dec.).

IR: ν _max. KBr, cm ^-1 : 1770, 1620.

UV: λ _max. methylene chloride, nm: (ε) 254 (23000), 389 (22000).

NMR: δ ppm (CDCl ₃ ) 2.56 and 3.16 (2H, ABq), 5.00 (1H, doublet, J 4 Hz), 5.23 (1H, doublet, J 4 Hz), 5.47 (1H, doublet J 22 Hz), 6.95 (1H, singlet), 7.2-7.8 (30H, multiplet), 8.55 (1H, singlet).

 C. Benzhydryl 7-amino-3-chloro-1-propen-1-yl-3-cephem-4-carboxylate hydrochloride (Z isomer) (XVIII hydrochloride).

To a refluxing solution of compound XVI (214 g, 0.294 mol) and N, O-bis- (trimethylsilyl) acetamide (40 ml, 0.15 mol) in dry methylene chloride (2.9 L) was added dropwise with stirring 50 % solution of chloroacetaldehyde (93 g, 0.59 mol) in chloroform over a period of 15 minutes After standing for 30 minutes, the mixture was concentrated to dryness. Methylene chloride (1.5 L), Girard T reagent (99 g, 0.59 mol) and 10% aqueous HCl (300 ml) were added to the residual oil, and the mixture was stirred for 1 h at room temperature. The organic layer was washed with water (200 ml) and saturated sodium chloride solution (200 ml, dried over magnesium sulfate, treated with charcoal (5 g) and filtered. The filtrate was cooled to ^-10 ° C and treated with 1N. HCl in methanol (300 ml The mixture was stirred for 30 min at room temperature and concentrated to approximately 300 ml, the Concentrate was diluted with ethyl acetate (400 ml) and seeded with a small amount of crystals of hydrochloride XVIII. After 2 hours, the separated crystals were collected by filtration, washed with ethyl acetate (200 ml) and su ilis in vacuo, giving 74 g (53%) of the title compound XVIII as its hydrochloride, melting at above 185 ^{° C} (dec.). Pale yellow needles.

IR: ν _max. KBr, cm ^-1 : 2830, 1780, 1720.

UV: λ _max. nm: (ε) 286 (8800).

Cl), 5,22 (1Н, дублет, J 4,5 Гц, 6-Н), 5,37 (1Н, дублет, J 4,5 Гц, 7-Н), 5,77 (1Н, мультиплет, 3-CH=C

), 6,45 (1Н, дублет, J 11 Гц, 3-С

), 6,88 (1Н, синглет, C

Ph₂), 7,33 (10Н, шир. синглет, Ph-

).NMR: δ ppm (DMSO-d ₆ ) 3.73 (2H, broad singlet, 2-H), 3.97 (2H, multiplet, C

Cl), 5.22 (1H, doublet, J 4.5 Hz, 6-H), 5.37 (1H, doublet, J 4.5 Hz, 7-H), 5.77 (1H, multiplet, 3 -Ch = c

), 6.45 (1H, doublet, J = 11 Hz, 3-C)

), 6.88 (1H, singlet, C)

Ph ₂ ), 7.33 (10H, broad singlet, Ph-

)

Calculated for C ₂₃ H ₂₁ N ₂ O ₃ SCl HCl, C 57.67; H 4.65; N, 5.87; S 6.72; Cl 14.85
Found, C 57.62; H 4.53; N, 5.70; S 6.64; Cl 14.89.

 Preparation 13. Benzhydryl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) - 2-methoxyiminoacetamido] -3- (3-chloro-1-propen-1-yl) -3- cepem-4-carboxylate (Z isomer) (VIII-I).

To a stirred solution of XVIII (Z isomer) (20 g, 42 mmol) in methylene chloride (420 ml) containing N, O-bis- (trimethylsilyl) acetamide (34 ml of 125 mmol) was added 2- (5-amino 1, 2,4-thiadiazol-3-yl) -2-metoksiiminoatsetilhlo-chloride (15.2 g, 59 mmol) in three portions over a period of 30 minutes at -10 to 0 ° ^C. The mixture was stirred for 30 min at 0- 5 ^{° C} and concentrated under reduced pressure. The residual brown oil was dissolved in ethyl acetate (420 ml), and the solution was washed successively with saturated aqueous sodium bicarbonate (3 x 15 ml), saturated aqueous sodium chloride (15 ml), 10% HCl (15 ml) and saturated aqueous sodium chloride (15 ml) ), and concentrated to approximately 50 ml volume. N-heptane (200 ml) was added to the concentrate; giving 28.5 g (90% purity) of target compound VIII-I (Z isomer) as a colorless powder. Mp above 150 ^about C (decomp.).

IR: ν _max. KBr, cm ^-1 : 3400, 1780, 1720, 1680, 1620.

UV: λ _max. ethanol, nm: (ε) 240 (20,000), 283 (12,000).

), 4,0 (2Н, мультиплет, C

Cl), 5,32 (1Н, дублет, J 4,5 Гц, 6-Н), 5,62 (2Н мультиплет, 3-CH=C

), 6,03 (1Н, дублет, J 4,5 Гц, 7-Н), 6,32 (1Н, дублет, J 11 Гц, 3-ОН), 6,87 (1Н, синглет, C

Ph), 7,33 (10Н широкий синглет, Ph-H).NMR: δ ppm (acetone-d ₆ ) 3.6 (2H, multiplet, 2-H), 3.95 (3H, singlet, OC

), 4.0 (2H, multiplet, C

Cl), 5.32 (1H, doublet, J 4.5 Hz, 6-H), 5.62 (2H multiplet, 3-CH = C

), 6.03 (1H, doublet, J 4.5 Hz, 7-H), 6.32 (1H, doublet, J 11 Hz, 3-OH), 6.87 (1H, singlet, C

Ph), 7.33 (10H broad singlet, Ph-H).

 Preparation 14. Benzhydryl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) - 2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) -3- cefem-4-carboxylate (E isomer) (IX-I).

A mixture of compound VIII-I (Z isomer) (28.5 g, 90% purity) and sodium iodide (19 g) in dry acetone (420 ml) was stirred for 10 min at room temperature and allowed to stand at ⁵ ° C for 2 hours. The mixture was concentrated under reduced pressure. Ethyl acetate (420 ml) and 10 w / v aqueous sodium thiosulfate solution (30 ml) were added to the residue, and the mixture was shaken. The organic layer was washed with water (30 ml), dried over magnesium sulfate and evaporated to about 50 ml volume. The concentrate was diluted with n-heptane (200 ml) to give 30.6 g (95% purity) of the title compound IX-I (E isomer) as a yellow powder, mp over 120 ^{° C} (dec.).

IR: ν _max. KBr, cm ^-1 : 3400, 1780, 1725, 1680, 1620
UV: λ _max. ethanol, nm: (ε) 306 (15000).

), 4,0 (2Н, дублет, J 8 Гц, C

I), 5,26 (1Н, дублет, J 4,5 Гц, 6-Н), 6,03 (1Н, д-д. J 4,5 и 8 Гц, изменившийся на дублет J 4,5 Гц при действии D₂O, 7-Н), 6,32 (1Н, д-т, J 15 и 8 Гц, 3-CH=C

), 6,79 (1Н, дублет, J 15 Гц, 3-С

), 6,98 (1Н, синглет, CHPh₂), 7,35 (10Н, мультиплет, Ph-H), 7,63 (2Н, шир. синглет, исчезнувший при действии D₂O, NH₂), 8,52 (1Н, дублет, J 8 Гц, исчезнувший при действии D₂O, 7-NH).NMR: δ ppm (acetone d ₆ ) 3.71 (2H, multiplet, 2-H), 3.97 (3H, singlet, OC

), 4.0 (2H, doublet, J = 8 Hz, C

I), 5.26 (1H, doublet, J 4.5 Hz, 6-H), 6.03 (1H, dd. J 4.5 and 8 Hz, changed to a doublet J 4.5 Hz under action D ₂ O, 7-H), 6.32 (1H, dt, J 15 and 8 Hz, 3-CH = C

), 6.79 (1H, doublet, J 15 Hz, 3-C

), 6.98 (1H, singlet, CHPh ₂ ), 7.35 (10H, multiplet, Ph-H), 7.63 (2H, broad singlet, which disappeared under the action of D ₂ O, NH ₂ ), 8, 52 (1H, doublet, J = 8 Hz, disappeared upon exposure to D ₂ O, 7-NH).

 Preparation 15. 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-4-carbamo-yl-1-pyridinio) -1 iodide -propen-1-yl] -3-cephem-4-carboxylate (E isomer) (XII-1H).

Methanol (100 ml) was added to a suspension of IX-I (E isomer) (30.5 g) and isonicotinamide (26 g, 212 mmol) in CH ₃ CN (120 ml) until the mixture became clear. The solution was stirred for 2 hours under nitrogen at room temperature and concentrated to about 100 ml under reduced pressure. The residual semi-solid was triturated with isopropyl ether (200 ml). The solvent was removed by decantation, and the residual yellow powder was washed with a mixture of isopropyl ether and methanol (3/1, 120 ml). Powder was collected by filtration and dried in vacuo, giving 36 g (75% pure by evaluating HPhC) of the title compound XII-IH (E isomer) as a pale yellow powder melting at above 150 ^{° C} (dec.).

IR: ν _max. KBr, cm ^-1 : 1780, 1720, 1680, 1620.

UV: λ _max. ethanol, nm: (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) 282 (170).

N⁺ 5,9 (1Н, д-д. J 4,5 и 8 Гц, изменившийся на дублет J 4,5 Гц при добавлении D₂O, 7-Н), 6,35 (1Н, мультиплет, 3-CH= CH) 6,89 (1Н, синглет, C

Ph) 6,9 (1Н, дублет, J 16 Гц, 3-C

), 7,35 (10Н, мультиплет, Ph-H), 8,06 (2Н, шир. синглет исчезающий при добавлении D₂O, N

), 8,21 (2Н, шир. синглет, исчезнувший при добавлении D₂O, NH₂), 8,36 и 9,07 (каждый 2Н, дублет, J 6 Гц, Py-

), 9,57 (1Н, дублет, J 8 Гц, исчезнувший при добавлении D₂O, 7-NH).NMR: δ ppm (DMSO-D ₆ ) 3.72 (2H, multiplet, 2-H) 3.90 (3H, singlet, OCH ₃ ), 5.25 (3H, multiplet, 6-H and C

N ⁺ 5.9 (1H, dd. J 4.5 and 8 Hz, which changed to a doublet J 4.5 Hz when D ₂ O, 7-H was added), 6.35 (1H, multiplet, 3-CH = CH) 6.89 (1H, singlet, C

Ph) 6.9 (1H, doublet, J 16 Hz, 3-C

), 7.35 (10H, multiplet, Ph-H), 8.06 (2H, broad singlet disappearing upon addition of D ₂ O, N

), 8.21 (2H, broad singlet, which disappeared with the addition of D ₂ O, NH ₂ ), 8.36 and 9.07 (each 2H, doublet, J 6 Hz, Py-

), 9.57 (1H, doublet, J = 8 Hz, disappeared with the addition of D ₂ O, 7-NH).

 Preparation 16. Benzhydryl 7-benzylidenamino-3- (3-chloro-1-propene 1-yl) -cefem-4-carboxylate (XVII) (Z isomer).

To an ice-cooled mixture of crystalline 7-amino-cephem intermediate XVIII (Z isomer) (13.4 g, 28 mmol) and benzaldehyde (8.3 g, 31 mmol) in ethyl acetate (150 ml) was added dropwise 0.5 N sodium hydroxide (56 ml, 28 mmol) over a period of 20 minutes to maintain the reaction mixture temperature below 10 ^C. The mixture was stirred with cooling for another 15 min, the organic layer was separated, washed with saturated aqueous sodium bicarbonate (100 ml x 2) and dried over magnesium sulfate. A small amount of charcoal was added to the dried solution, and the mixture was filtered. The filtrate was concentrated to dryness. The residual oil was dissolved in carbon tetrachloride (50 ml), and concentrated again. This procedure was repeated 3 times and the mixture was monitored by TLC in reverse phase to ensure that all of the starting 7-aminocephalosporin was converted to Schiff base. Removal of the solvent in vacuo gave 16.45 g of the title compound XVII (Z isomer) as a pale yellow powder (estimated purity 85%, mp 74 ^C (dec.), Which was used for the next step without purification.

IR: ν _max. KBr, cm ^-1 : 1780, 1725, 1635
UV: λ _max. methylene chloride, nm: (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) 257 (400).

NMR: δ ppm (CDCl ₃ ) 6.18 (1H, doublet, J = 11 Hz).

 Preparation 17. Benzhydryl iodide 7-benzylidenamino-3- [3- (4-carbamoyl-1-pyridinio) -1-propen-1-yl] -3-cefem-4-carboxylate (XXI-H) (E isomer )

To a cooled mixture of 3-chloropropenylcepheme XVII (Z isomer) (16.4 g) in acetone (5 ml) was added dropwise a solution of sodium iodide (6.3 g, 42 mmol) in acetone (30 ml) over 10 minutes in the atmosphere nitrogen, the mixture was stirred at room temperature. The reaction was controlled by the degree of UV absorption (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) (320 nm). When the degree reached less than 1.30 (after 45 minutes), the mixture was diluted with carbon tetrachloride (400 ml) and left to stand at room temperature. When the degree reached a value below 1.10 (after 3 hours), the mixture was concentrated to half its volume. The concentrate was treated with a small amount of charcoal and diatomaceous earth and filtered. The filter cake was washed with a 1: 1 mixture (100 ml) of methylene chloride and carbon tetrachloride. A solution of isonicotinamide (3.5 g, 28.7 mmol) in dimethylformamide (20 ml) was added to the combined solution of the filtrate and washings, and the mixture was concentrated under reduced pressure. The concentrate was allowed to stand at room temperature for 1.5 hours and it was washed with isopropyl ether (100 ml x 3). The residual brown semi-solid was dissolved in methylene chloride (50 ml), the solution was added dropwise with stirring to ethyl acetate (1.5 L). The resulting precipitate was collected by filtration and washed with ethyl acetate (200 ml). After drying over phosphorus pentoxide in vacuo, 17 g of the target compound XXI-H (E isomer) were obtained. Yellow amorphous powder. Mp 150-155 ^about C (decomp.). Purity estimated at 80% by NMR.

IR: ν _max. KBr, cm ^-1 : 1775, 1725, 1690, 1635
UV: λ _max. methylene chloride, nm: (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) 258 (335), 298 (255)
NMR: δ ppm (DMSO-d ₆ ) 3.4-3.8 (2H, broad), 5.35 (2H, broad), 5.41 (1H, doublet, J 4 Hz), 5.73 (1H, doublet , J 4 Hz), 6.93 (1H, singlet), 6.97 (1H, doublet, J 16 Hz), 7.3-7.5 (15H, broad singlet), 8.40 (2H, doublet , J 6.5 Hz), 9.15 (2H, doublet, J 6.5 Hz).

 Preparation 18. 7-amino-3- [3- (4-carbamoyl-1-pyridinio-1-propen-1-yl] -3-cefem-4-carboxylate (XXII-H) (E isomer).

Concentrated hydrochloric acid (5 ml) was added dropwise to a suspension of quaternized Cephem XXI-H (17 g) in 85% formic acid (25 ml), the mixture was stirred at room temperature for 1.5 hours and treated with a small amount of charcoal. The mixture was filtered and washed with 85% formic acid (5 ml). The filtrate was combined with wash water and poured into acetone (1 L) with stirring. The resulting precipitate was collected by filtration to give 9.52 g of a yellow-colored crude product. A small amount of charcoal was added to a suspension of the crude substance (9.5 g) in water (50 ml), and the mixture was filtered. The filtrate was added dropwise with stirring to isopropyl alcohol (700 ml). The resulting precipitate was collected by filtration, washed with a small amount of methanol (30 ml), and dried, yielding 7.58 g of the target compound XXII-H (E isomer) as hydrochloride. Light yellow powder. Purity estimated using UV 85% mp 173-188 ^about C (decomp.).

IR: ν _max. KBr, cm ^-1 : 1795, 1680, 1620, 1575, 1540.

UV: λ _max. phosphate buffer (pH 7), nm: (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) 294 (457).

NMR: δ ppm (D ₂ O + DCl) 3.82 (2H, singlet), 5.17 (1H, doublet, J 5 Hz), 5.33 (2H, doublet, J 7 Hz), 5.43 (1H, doublet, J 5 Hz), 6.37 (1H, dt J 16 and 7 Hz), 7.23 (1H, doublet, J 16 Hz), 8.34 (2H, doublet, J 7 Hz), 9, 00 (2H, doublet, J = 7 Hz).

 Preparation 19. 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetyl chloride hydrochloride (III-I as the acid chloride hydrochloride).

 A. 2-cyano-2-methoxyiminoacetamide.

To a stirred mixture of α-cyanoacetamide (252 g, 3 mol) and sodium nitrate (414 g, 6 mol) in water (600 ml) was added acetic acid (371 ml, 10 mole) at 5-10 ^{° C} for 1.5 hours. The mixture was allowed to mix for another 1.5 hours and brought it to pH 8.5 using 6 N. sodium hydroxide. To the mixture was added dimethyl sulfate (568 ml, 6 mole) at 15-20 ^{° C,} and the mixture was stirred at ⁴⁵ ° C for 1.5 hours. The reaction mixture was adjusted to pH 8.5 using 6N. sodium hydroxide and allowed to stand at ⁵ ° C overnight to precipitate separation, which were collected by filtration, washed with cold water and air dried, giving 292 g (77%) of the title compound as brown needles melting at ^about 170-172 FROM.

IR: ν _max. KBr, cm ^-1 : 3400, 3188 (1720 (shoulder), 1715, 1690, 1615, 1570.

UV: λ _max. water, nm: (ε) 238.5 (8290), 268 (shoulder, 3870)
NMR: δ ppm (DMSO-d ₆ ) 4.20 (3H, singlet, OCH ₃ ), 7.85 (2H, broad NH ₂ ).

Analysis for C ₄ H ₅ N ₃ O ₂
Calculated, C 37.80; H 3.97; N, 33.06.

 Found, C, 37.43; H 3.75; N 32.51.

 B. 2-Methoxyiminopropanedinitrile.

A stirred mixture of 2-cyano-2-methoxyiminoacetamide (88.9 g, 0.7 mol), sodium chloride (70 g) and phosphorus oxychloride (97 ml, 1.05 mol) in dry 1,2-dichloroethane (350 ml) heated under reflux for 16 hours. Insoluble matter was filtered off through a decalite filter and washed with dichloroethane. The filtrate and wash water were combined and poured into a stirred ice-water mixture (1.5 L) to decompose the excess phosphorus oxychloride. The organic phase was washed with 10% sodium bicarbonate (500 ml), water (500 ml x 3) and saturated sodium chloride solution (500 ml) and dried over magnesium sulfate. The filtrate was distilled under reduced pressure to give 61.5 g (81%) of the title compound, boiling at 62 ^C / 24 mmHg (Lit. T. boil 47-48 ^about C / 12 mm Hg).

IR: ν _max. liquid film, cm ^-1 : 3020, 2960, 2245, 2020, 1530, 1080.

NMR: δ ppm (CDCl ₃ ) 4.35 (3H, singlet, OCH ₃ ).

 C. 2-Cyano-2-methoxyiminoacetamidinium acetate.

To a solution of ammonium chloride (28.4 g, 0.53 mol) in 28% aqueous ammonia (355 ml) and ethanol (180 ml) was added dropwise a solution of 2-methoxyiminopropanedinitrile (58.0 g, 0.53 mol) in ethanol (120 mL) at -15 to ^-10 ° C over a period of 30 minutes with stirring. The mixture was stirred at ^-10 ° C overnight and then at ambient temperature (20-25 ° ^C) for one day. The reaction mixture was partitioned between water (350 ml) and methylene chloride (350 ml), and the aqueous phase was saturated with sodium chloride and extracted again with methylene chloride (300 ml). The organic extracts were combined, dried over magnesium sulfate and evaporated in vacuo. A solution of the residue in ethyl acetate (1.6 L) was adjusted to pH 3-4 with acetic acid to precipitate the title compound as crystals, which were collected by filtration and washed with ethyl acetate. Yield 67.6 g (69%). Mp 152-4 ^{° C} (dec.). (Lit. mp. 150-155 ^about C (decomp.)).

IR ν _max. KBr, cm ^-1 : 3160, 2900, 2360, 2235, 2000, 1665, 1495, 1415.

UV: λ _max. ethanol, nm: (ε) 243 (8500), 265 (shoulder, 5380), 305 (shoulder, 1400).

NMR: δ ppm (DMSO-d ₆ ), 1.88 (3H, singlet, CH ₃ COOH), 4.15 (3H, singlet, OCH ₃ ), 7.60 (4H, broad).

Calculated for C ₄ H ₆ N ₄ O CH ₃ COOH, C 38.71; H 5.41; N, 30.09
Found C, 38.71; H 5.59; N 29.51
D. 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetonitrile.

To a suspension of 2-cyano-2-metoksiiminoatsetamidiniyatsetata (125 g, 0.672 mol) in methanol (1.25 L) were added dropwise triethylamine (234 ml, 1.68 mol) at ^-10 ° C, and subsequently bromine (41.6 ml, 0.806 mol) over 20 minutes at -15 to ^-10 ° C, and the mixture was stirred for 20 min. To the mixture was added dropwise a solution of potassium thiocyanate (KSCN) (78,3 g, 0.806 mol) in methanol (550 mL) over 1 hour at -15 to -10 ° ^C. After stirring at 0-5 ^{° C} for For 1 h, the mixture was poured into a mixture of ice and water (12 L) to form a crystalline precipitate, which was collected by filtration, washed with water and dried in air, giving 120 g (98%) of the target compound. Mp 263-5 ^about C (decomp.) Mp. the compound prepared by us is higher by about ⁵⁰ ° C than known (m.p. 210-15 ^{° C} (dec.)) but spectral and microanalytical data are consistent with structure.

IR: ν _max. KBr, cm ^-1 : 3435, 3260, 3120, 2960, 2245, 2020, 1630, 1545, 1455, 1415.

UV: λ _max. ethanol, nm: (ε) 246 (13300), 310 (3470).

NMR: δ ppm (DMSO-D ₆ ) 4.21 (3H, singlet, OCH ₃ ), 8.30 (2H, broad. H ₂ ).

Analysis for C ₅ H ₅ N ₅ O.

 Cooking 20.

 Calculated, C 32.78; H 2.75; N, 38.23; S 17.50.

 Found, C 32.76; H 2.31; N, 38.02; S 17.50.

 E. 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminacetic acid (III-I).

A mixture of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetonitrile (18.3 g, 0.1 mol) in 4N sodium hydroxide (250 ml) was heated at 50-55 ^{° C} with stirring for 3 hours. The reaction mixture was adjusted to pH 1 with phosphoric acid and washed with ethyl acetate (100 ml), saturated with sodium chloride and extracted three times with ethyl acetate and tetrahydrofuran ( 51, 300 ml x 2 and 200 ml x 1). The extracts were combined, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with isopropyl ether to give pale yellow crystals of the target acid. Yield 16.8 g (83%). Mp 184-5 ^about C (decomp.). (Lit. M.p. 180-182 ^C. (dec.)).

IR: ν _max. KBr, cm ^-1 : 3460, 3260, 3140, 1725, 1620, 1605, 1545
UV λ _max. water, nm: (ε) 234 (13200), 288 (shoulder, 3620).

 F. 2- (5-amino-1,2,4-thiadisol-3-yl) -2-methoxyiminoacetyl chloride hydrochloride.

To a suspension of 2- (5-amino-1,2,4-thiadiazole-3 -) - 2-methoxyiminoacetic acid (III-I) (40.4 g, 0.2 mol) in dry methylene chloride (400 ml) was added pentachloride phosphorus (41.6 g, 0.2 mol) in one portion at -50 ° ^C. The mixture was stirred for 4 hours at -20 to ^-5 ° C and poured into a mixture of n-heptane and isopropyl ether (2: 1, 2 l). A yellow precipitate was collected by filtration, washed with the same solvent mixture, and dried with potassium hydroxide under reduced pressure to give 46.0 g (90% of the desired acid chloride).

IR: ν _max. nujol, cm ^-1 : 1775.

CH₂-Cl
Дифенилметил 7-[2-2-(5-амино-1,2,4-тиадиазол-3-ил)-2-(Z)- этоксииминоацетамидо] -3-(3-хлор-1-пропенил)-3-цефем-4-карбо- ксилат (VIII-2-2, Z изомер).Cooking 20

CH ₂ -Cl
Diphenylmethyl 7- [2-2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (Z) -ethoxyiminoacetamido] -3- (3-chloro-1-propenyl) -3-cephem -4-carboxylate (VIII-2-2, Z isomer).

To a mixture of O-bis- (trimethylsilyl) acetamide (2.3 ml, 9 mmol) and crystalline diphenylmethyl hydrochloride 7-amino-3- [3-chloro-1- (Z) propen-1-yl] -3-cef- 4-carbo-xylate (XVIII) (1.338 g, 2.8 mmol) (from Preparation Example 12) in methylene chloride (10 ml) was added 2- (5-amino-1,2,4-thiadiazol-3-yl) hydrochloride -2- (Z) -ethoxy-imino acetyl chloride (800 mg, 2.95 mmol) portionwise under stirring at ^-10 ° C, the mixture was allowed to stand at ⁰ ° C for 2 hours. The mixture was diluted with ethyl acetate (200 mL), washed water and evaporated under reduced pressure. Trituration of the residue with isopropyl ether gave the desired product VIII-2 as an amorphous powder. Yield 1.70 g (95%). Mp above 150 ^about C (decomp.).

 Cooking 21.

IR: ν _max. (KBr), cm ^-1 : 3300, 1780, 1720, 1690, 1380, 1220.

UV: λ _max. (ethanol), nm: (ε) 285 (11000).

), 4,25 (2Н, квартет, J 7 Гц, C

CH₃), 5,90 (1Н, д-д-. J 4 и 8 Гц, 7-Н), 6,26 (1Н, дублет, J 11 Гц, 3-СН), 6,85 (1Н, синглет, CHPh₂ 9,53 (1Н, дублет, J 8 Гц, 7-Н).NMR: δ (DMSO-d ₆ ), ppm. 1.26 (3H, triplet, J 7 Hz, CH ₂ C

), 4.25 (2H, quartet, J 7 Hz, C

CH ₃ ), 5.90 (1H, d-d. J 4 and 8 Hz, 7-H), 6.26 (1H, doublet, J 11 Hz, 3-CH), 6.85 (1H, singlet CHPh ₂ 9.53 (1H, doublet, J = 8 Hz, 7-H).

CH₂I
IX-2 *Смесь Е и Z изомеров
Дифенилметил 7-[2-(5-амино-1,2,4-тиадиазол-3-ил)-2-(Z)- этоксииминоацетамидо]-3-)3-иод-1-пропенил)-3-цефем-4-карбокси- лат (IX-2).Cooking 21

CH ₂ I
IX-2 * Mixture of E and Z isomers
Diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (Z) - ethoxyiminoacetamido] -3-) 3-iodo-1-propenyl) -3-cefem-4 -carboxylate (IX-2).

A mixture of compound VIII-2 (1.90 g, 3 mmol) (from preparation 20) and sodium iodide (1.4 g, 9 mmol) in acetone (20 ml) was stirred for 10 min at room temperature, and then left to stand at ⁵ ° C for 3 hours. The mixture was evaporated under reduced pressure, diluted with ethyl acetate (100 ml), washed with 10% sodium thiosulfate and water, and evaporated under reduced pressure. Trituration of the residue with isopropyl ether gave 1.82 g (84%) of the desired product IX-2 as a light brown amorphous powder.

IR: ν _max. (KBr), cm ^-1 : 3290, 1770, 1720, 1670, 1530, 1370, 1220.

UV: λ _max. (ethanol), nm: (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) 304 (199).

 Cooking 22.

CH=N

Дифенилметил 7-бензилиденамино-3-[(E)-3-(4-карбамоилпиридинио)-1- пропенил]-3-цефем-4-карбоксилат (XXI-H иодид) (Е изомер).

CH = N

Diphenylmethyl 7-benzylidenamino-3 - [(E) -3- (4-carbamoylpyridinio) -1-propenyl] -3-cefem-4-carboxylate (XXI-H iodide) (E isomer).

To a cooled solution of 3-chloropropenylcepheme (XVII, Z isomer, 42.8 g, 90 mmol) (from Preparation 16) in dry dimethylformamide (80 ml), potassium iodide (20 g, 120 mmol) was added in one portion, the mixture was mixed at room temperature. The reaction was monitored by the degree of UV absorption (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ (255 nm) E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ (320 nm)). When the degree became lower than 1.10 (after 45 minutes), the mixture was diluted with 800 ml of methylene chloride, treated with activated carbon (4 g), and filtered. The filter cake was washed with 100 ml of methylene chloride. Isonicotinamide (14, 64 G) was added to the combined filtrate and washing, the mixture was concentrated under reduced pressure. The concentrate was stored at room temperature for 1.5 hours and washed with a mixture of toluene and n-heptane (1: 1, 600 ml). The residual brown semi-solid was dissolved in methylene chloride (100 ml), and the solution was added dropwise to ethyl acetate (3 L) with vigorous stirring. After drying over phosphorus pentoxide in vacuo, 57.37 g (88%) of the quaternized target product XXI-H was obtained in the form of iodide. Yellow amorphous powder. Mp 150-155 ^about C (decomp.). This product was identical to the product obtained by iodination with sodium iodide (preparation 17).

 Cooking 23.

XVIII *Z
Дифенилметил 7-амино-3-(3-хлор-1-пропенил)-3-цефем-4-карбоксилат хлоргидрат (Z изомер (ZVIII, хлоргидрат).HCl • H ₂ N

XVIII * Z
Diphenylmethyl 7-amino-3- (3-chloro-1-propenyl) -3-Cephem-4-carboxylate hydrochloride (Z isomer (ZVIII, hydrochloride).

A 25% solution of chloroacetaldehyde (69 g, 0.22 mmol) in chloroform was added to a solution of compound XVI (80 g, 0.11 mol) in methylene chloride (1.1 L) containing N, O-bis- (trimethylsilyl) acetamide ( 16.2 ml, 0.06 mol) at ^-10 ° C in one portion and the mixture allowed to stand overnight at 5 ^C. The mixture was concentrated to about 0.3 l, diluted with a mixed solvent of ethyl acetate and isopropyl ether (1/2, 0.6 L), was treated with silica gel (Vacogel C-100, 60 g) and filtered through a decalite filter. The filter cake was washed with the same solvent system (0.2 L). The combined filtrate and washings were concentrated to approximately 0.2 L, treated with Girard T reagent (60 g, 0.26 mol) and 4 N. HCl (220 ml), and were seeded with several crystals of hydrochloride XVIII. After stirring for 3 hours, the resulting crystals were collected by filtration, washed with water (0.5 L) and ethyl acetate (0.5 L), and dried in vacuo to give 37 g (70%) of the desired compound of hydrochloride XVIII, melting at temperature above 185 ^C. (dec.). Pale yellow needles. This product was identical to the product obtained in preparation example 12.

CH₂-Cl
XVIII *Z
Хлоргидрат дифенилметил 7-амино-3-(3-хлор-1-пропенил)-3-цефем-4- карбоксилата (Z изомер) (XVIII, хлоргидрат).Cooking 24

CH ₂ -Cl
XVIII * Z
Diphenylmethyl 7-amino-3- (3-chloro-1-propenyl) -3-Cephem-4-carboxylate hydrochloride (Z isomer) (XVIII, hydrochloride).

To a solution of chloroacetaldehyde (25% solution in chloroform, 628 mg, 2 mmol) in methylene chloride (10 ml), N, O-bis- (trimethylsilyl) acetamide (0.135 ml, 0.5 mmol) and XVI (728 mg, 1 mmol) were added. ) successively at 5 ° ^C. The mixture was allowed to stand overnight at 5 ^C. The mixture was evaporated and diluted with ethyl acetate and isopropyl ether (1/2, 10 mL). Insoluble matters were removed by filtration, and the filtrate was concentrated to approximately 5 ml. The concentrate was processed 4 N. HCl (2 ml), was seeded with hydrochloride XVIII and was stirred for 1 h at room temperature. The crystals were collected by filtration, washed with ethyl acetate (10 ml) and water (10 ml) and dried in vacuo, giving 384 mg (80%) of the title compound hydrochloride XVIII, melting at above 185 ^{° C} (dec.). Pale yellow needles. This product was identical to the product obtained according to example preparation 12.

 Preparation 25. Hydrochloride 2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (propen-3-ylo-ximimino) acetyl chloride (III-3 in the form of its hydrochloride acid chloride).

 A. Methyl 2- (5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-propen-3-yloxyimino) acetate.

A mixture of 685 mg (3.37 mmol) of N- (propen-3-yloxy) phthalimide (prepared according to the procedure described by E. Grochosaki J. Jurczak, Synthesis 1976 682) and 175 mg (3.35 mmol) of hydrazine hydrate in 5 ml of ethanol was stirred for 1 h at room temperature. The resulting precipitate was filtered off, and the filtrate and washings were combined. 967 mg (3.37 mmol) methyl 2- (5-tert-butoxycarbonyl-amino-1,2,4-thiadiazol-3-yl) -2-oxoacetate was added to the solution, and the mixture was left to stand for 1 h at room temperature and concentrated using a rotary evaporator. The residue was purified by silica gel chromatography. The column was eluted with n-hexane-ethyl acetate (4: 1), and the fractions containing the main product were combined and evaporated under reduced pressure. Yield 514 mg (46%). Mp 83-86 ^about S.

IR: ν _max. (KBr), cm -1: 3100, 1745, 1710, 1610.

UV: λ _max. (ethanol), nm: (ε) 223 (9700), 242 (10000).

=CH), 5,90 (1Н, мультиплет, -C

=CH), 9,50 (1Н, широкий синглет, NH).NMR: δ (CDCl ₃ ), ppm. 1.55 (9H, singlet, BOC-H), 4.40 (2H, doublet, J = 5 Hz, O-CH ₂ ), 5.21 (2H, multiplet, C

= CH), 5.90 (1H, multiplet, -C

= CH), 9.50 (1H, broad singlet, NH).

 C. 2- (5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2- (propene 3-yloxyimino) acetic acid (J. Csendes et al. Anthibiotics, 36, 1020 (1983)) .

A solution of 770 mg (2.3 mmol) of methyl 2- (5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2- (propen-3-yloxyimino) acetate and 3.5 ml of 2 N. a solution of sodium hydroxide (7.0 mmol) in 15 ml of methanol was heated under reflux for 30 minutes The reaction mixture was concentrated in vacuo and diluted with 10 ml of ethyl acetate-water (1: 1). The aqueous layer was separated, acidified to pH 26 N. HCl and was extracted with ethyl acetate (10 ml x 2). The ethyl acetate solution was dried over magnesium sulfate and concentrated using a rotary evaporator, giving 596 mg (81%) of the target compound. Mp 134-135 ^C (m.p. 135-136 ° ^C).

IR: ν _max. (nujol), cm ^-1 : 3150, 1745, 1710, 1550.

UV: λ _max. (ethanol), nm (ε) 223 (11000), 242 (11300).

=CH), 6,0 (1Н, мультиплет, C

=CH₂).NMR: δ (DMSO-d ₆ ), ppm. 1.55 (9H, singlet, BOC-H), 4.77 (2H, doublet, J = 5 Hz, O-CH ₂ ), 5.22 (2H, multiplet, C

= CH), 6.0 (1H, multiplet, C

= CH ₂ ).

C. 2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (propen-3-yloxyimino) - acetic acid (III-3) [3]
A solution of 570 mg (1.74 mmol) of 2- (5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2- (propen-3-yloxyimino) acetic acid in 6 ml of trifluoroacetic acid was allowed to stand in for 1 h at ambient temperature. Evaporation followed by trituration with 30 ml of isopropyl ether gave 376 mg (95%) of the target compound. Mp 109 ^{° C} (dec.).

IR: ν _max. (nujol), cm ^-1 : 3180, 1710, 1545, 1460
UV: λ _max. (ethanol), nm: (ε) 245 (13500).

=CH), 6,0 (1Н, мультиплет, C

=CH₂).NMR: δ (DMSO-d ₆ ), ppm. 4.77 (2H, doublet, J = 5 Hz, O-CH ₂ ), 5.20 (2H, multiplet, C)

= CH), 6.0 (1H, multiplet, C

= CH ₂ ).

 D. 2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (propen-3-yl-hydroxyimino) -acetyl chloride hydrochloride.

A solution of 350 mg (1.54 mmol) III-3 and 410 mg (1.97 mmol) of phosphorus pentachloride in dichloromethane (5 ml) was stirred for 1 hour at 25 ^C. The reaction mixture was poured into 60 ml of n-hexane, and the precipitate was filtered off. Yield 323 mg.

IR: ν _max. (nujol), cm ^-1 : 1765.

 Cooking 26.

 2- (5-amino-1,2,4-thiadiazol-3-yl) -3-propargyloxyiminoacetyl chloride hydrochloride (III-4 in the form of its acid chloride hydrochloride).

 A. Methyl 2- (5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-propargyloxyiminoacetate.

A suspension of 870 mg (4.32 mmol) N-propargiloksiftalimida and 200 mg (4.0 mmol) of hydrazine hydrate in 5 ml ethanol was stirred at ²⁵ ° C for 1 h and filtered. 1.0 g (3.86 mmol) of methyl 2- (5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-oxoacetate was added to the combined filtrate and washings. (J. Csendes et al. I. Anthibrotics, 36, 1020 (1983)). The solution was allowed to stand for 1 h and concentrated under reduced pressure. Purification by chromatography on silica gel followed by evaporation afforded 319 mg (27%) of the expected product. Mp 72-75 ^about S.

IR: ν _max. (KBr), cm ^-1 : 3200, 2380, 1745, 1710, 1610.

UV: λ _max. (ethanol), nm: (ε) 235 (12200).

NMR: δ (DMSO-d ₆ ), ppm. 1.56 (9H, singlet, BOC-H), 3.55 (1H, triplet, J 2 Hz, C≡CH), 4.85 (2H, doublet, J 2 Hz, -CH ₂ C≡CH), 8.9 (1H, broad singlet, NH).

 B. 2- (5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-propargyloxyiminoacetic acid.

A solution of 490 mg (1.4 mmol) of methyl 2- (5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-propargyloxyiminoacetate and 2.2 ml of 2 N. an aqueous solution of sodium hydroxide (4.4 mmol) in 14 ml of methanol was heated under reflux for 30 minutes. The reaction mixture was concentrated under reduced pressure, 10 ml of a mixture of ethyl acetate and water (1: 1) was added to the solution. The separated aqueous layer was acidified to pH 2 with 6 N. HCl and was extracted with ethyl acetate (2 x 10 ml). Drying over magnesium sulfate followed by evaporation of the organic layer afforded 149 mg (89%) of the desired product. Mp 135 ^C. (dec.).

IR: ν _max. (nujol), cm ^-1 : 3350, 1720, 1670, 1550.

UV: λ _max. (ethanol), nm (ε) 233 (11500).

C≡CH), 9,0 (1Н, синглет, NH).NMR: δ (DMSO-D ₆ ), ppm. 1.55 (9H, singlet, BOC-H), 3.55 (1H, triplet, J 2 Hz, C≡CH), 4.89 (2H, doublet, J 2 Hz, C

C≡CH) 9.0 (1H, singlet, NH).

C. 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-propargyloxyiminoacetic acid (III-4) [3]
A solution of 410 mg (1.26 mmol) of 2- (5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-propargiloksiiminouksusnoy acid in 5 ml of trifluoroacetic acid was allowed to stand for 1 hour at 25 ^C. Evaporation followed by trituration of the residue with 25 ml of isopropyl ether gave 204 mg (72%) of the target compound. Mp 156-158 ^{° C} (dec.).

IR: ν _max. (nujol), cm ^-1 : 3300, 1480, 1730, 1610.

UV: λ _max. (ethanol), nm: (ε) 234 (12000).

C≡CH), 8,10 (2Н, шир. синглет, NH₂).NMR: δ (DMSO-d ₆ ), ppm. 3.52 (1H, triplet, J 2 Hz, C≡CH), 4.86 (2H, doublet, J 2 Hz, C

C≡CH), 8.10 (2H, broad singlet, NH ₂ ).

 D. 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-propargyloxyiminoacetyl chloride hydrochloride.

A mixture of 175 mg (0.07 mmol) III-4 and 182 mg (0.88 mmol) of phosphorus pentachloride in dichloromethane (2 ml) was stirred for 1 h at -5 ^C. The reaction mixture was poured into 30 ml of n-hexane , and the precipitate was filtered off. Yield 65 mg (34%).

IR: λ _max (nujol), cm ^-1 : 1770.

 Preparation 27. 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxyiminoacetyl chloride hydrochloride (III-5 as its hydrochloride acid chloride).

 A. Methyl 2- (5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxyiminoacetate.

 A suspension of 860 mg (3.7 mmol) of N- (cyclopentyloxy) phthalimide and 185 mg (3.7 mmol) of hydrazine hydrate in 5 ml of ethanol was stirred for 1 h at ambient temperature and filtered. The filtrate and washings were combined and added to 1.06 g (3.7 mmol) of methyl 2- (5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-oxoacetate. The solution was allowed to stand for 1 h at room temperature and it was concentrated in vacuo. The residue was purified by silica gel chromatography. Elution with a mixture of n-hexane and ethyl acetate (4: 1) followed by evaporation gave the desired product. Yield 906 mg (81%).

Mp 115-118 ^about S.

IR: ν _max. (KBr), cm ^-1 : 3200, 1745, 1710, 1550.

UV: λ _max. (ethanol), nm (ε) 217 (1800), 252 (7600).

), 3,88 (3Н, синглет, ОСН₃), 4,90 (1Н, шир. синглет,

), 8,70 (1Н, шир. синглет, NH).NMR: δ (CDCl ₃ ), ppm 1.51 (9H, singlet, BOC-H), 1.60 (8H, broad singlet, H

), 3.88 (3H, singlet, OCH ₃ ), 4.90 (1H, broad singlet,

), 8.70 (1H, broad singlet, NH).

 B. 2- (5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxyiminoacetic acid.

A solution of 500 mg (1.34 mmol) of methyl-2- (5-tert-butoxycarbonyl-amino 1,2,4-thiadiazol-3-yl) -2-cyclopentyloxyiminoacetate and 2N. a solution of sodium hydroxide (2 ml, 4 mmol) in 15 ml of methanol was heated under reflux for 30 minutes. The reaction mixture was evaporated, and 10 ml of a mixture of ethyl acetate and water (1: 1) was added to the solution. The aqueous layer was separated, acidified to pH 26 N. HCl and was extracted with ethyl acetate (10 ml x 2). The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 377 mg (78%) of the target compound. Mp 185 ^{° C} (dec.).

IR: ν _max. (KBr), cm ^-1 : 3160, 1710, 1550.

UV: λ _max. (ethanol), nm: (ε) 238 (13300).

), 4,82 (1Н, мультиплет

).NMR: δ (DMSO), ppm 1.51 (9H, singlet, BOC-H), 1.70 (8H, broad singlet, H

), 4.82 (1H, multiplet

)

 C. 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxyiminoacetic acid (III-5, Z isomer) (known).

A solution of 348 mg (0.97 mmol) of 2- (5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-cyclopentyoxyiminoacetic acid in 2 ml of trifluoroacetic acid was allowed to stand for 1 h at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was triturated with 5 ml of isopropyl ether and 10 ml of hexane, giving 215 mg (86%) of the target compound. Mp 162-165 ^о С (decomp.) (Lit.): Mp 160-165 ^{° C} (dec.)).

IR: ν _max. (nujol), cm ^-1 : 3290, 3200, 1710, 1615, 1600.

UV: λ _max. (ethanol), nm: (ε) 238 (13300).

NMR: δ (DMSO-d ₆ ), ppm. 1.17-2.10 (8H, multiplet), 4.60-4.98 (1H, multiplet), 8.22 (2H, singlet).

 D. 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxyiminoacetyl chloride hydrochloride.

 A solution of 190 mg (0.74 mmol) of III-5 and 219 mg (1.0 mmol) of phosphorus pentachloride in dichloromethane (5 ml) was stirred for 1 h at room temperature. The reaction mixture was poured into 50 ml of n-hexane. The resulting precipitate was collected by filtration. Yield 122 mg (60%).

IR: ν _max. (nujol), cm ^-1 : 1760.

 Preparation 28. Benzotriazol-1-yl-2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetate.

A mixture of 1-hydroxybenzotriazole (2.7 g, 20 mmol) and dicyclohexylcarbodiimide (4.12 g, 20 mmol) in 65 ml of DMF was stirred at room temperature. After 15 minutes to the stirred mixture at ⁰ ° C was added III-I (4,04 g, 20 mmol) compound, and stirring was continued for 3 hours. The reaction mixture was filtered to remove insoluble urea, and the filter cake washed with a small volume of DMF. The filtrate and washings were combined and poured into 800 ml of ice water. The precipitate was collected by filtration to give 5.24 g (82%) of the target compound as a light gray powder. Mp 189-192 ^about C (decomp.).

IR: ν _max. (KBr), cm ^-1 : 1815, 1620, 1540, 1415, 1090, 1060, 1005, 945, 865, 740.

UV: λ _max. (ethanol), nm: (E $\genfrac{}{}{0ex}{}{\text{one\%}}{\text{1cm}}$ ) 246 (580), 283 shoulder (228).

Claims (3)

1. Derivatives of cephalosporin of the general formula I

where R ¹ is methyl, ethyl, propenyl, propynyl, cyclopentyl;
Group

represents a quaternary ammonio group selected from the group consisting of

where Y is hydrogen, amino, carbamoyl, aminomethyl, hydroxymethyl, N-methylcarbamoyl, carboxy, carboxymethyl, formylamino or carboxymethylthio group,
or their pharmaceutically acceptable acid addition salts. 2. A method of obtaining derivatives of cephalosporin of the General formula

where R ¹ is methyl or ethyl;
Group

represents a quaternary ammonio group as defined in claim 1 of the formula

or their pharmaceutical acceptable acid addition salts, wherein the compound of general formula II

where R ¹ has the indicated meanings;
B is a diphenylmethyl protecting group;
Z is chlorine, iodine, is reacted with a tertiary amine of formula III
N≡Q ′,
where N≡Q ′, has values corresponding to the indicated values for the group

or in the case where Y is amino, carboxy or carboxymethyl, the tertiary amine contains a protecting group in the above groups,
at (-5) ^o C or room temperature in an organic solvent, followed by removal of the protective groups and isolation of the target compound in free form or in the form of a pharmaceutically acceptable acid addition salt. 3. The method of obtaining derivatives of cephalosporin of General formula 1B

where R ¹ is ethyl, propenyl, propynyl, cyclopentyl;
Group

means a group of the formula

or their pharmaceutically acceptable acid addition salts,
characterized in that the hydrochloride derivative of aminocepheme of General formula IV

where is the group

has the specified value
are reacted with a thiazole derivative hydrochloride of the general formula V

where R ¹ has the indicated meanings,
followed by isolation of the target compound in free form or in the form of a pharmaceutically acceptable acid addition salt.

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