PT85792B - PROCESS FOR THE PREPARATION OF CEFALOSPORIN COMPOUNDS AND ITS DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Abstract

Compounds of formula (I> <IMAGE> wherein R<1> and R<2>, which may be the same or different, each represents a hydrogen atom or a carboxyl blocking group; R<3> represents a hydrogen atom or an amino protecting group; R<4> and R<5> each represents a hydroxy or substrtuted hydroxy group or R<4> and R<5> together represent a cyclic protected diol group; Z is -S- or -SO- ( alpha - or beta -) and the dotted line bridging the 2-, 3-, and 4-positions indicates that the compound is a ceph- 2-em or ceph-3-em compound; and salts and solvates thereof.

Description

The present invention relates to improvements in or related to cephalosporins. More particularly, it refers to new cephalosporin compounds and their derivatives having valuable antibiotic activity.

The cephalosporin compounds in this specification are designated with reference to 'cefam' according to J. Amer. Chem. Soc., 1962, 84, 34CO, referring to the term 'cefam ¹ to the basic structure of cefam with a double bond.

Cephalosporin antibiotics are widely used in the treatment of diseases caused by pathogenic bacteria in humans and animals and are especially useful in the treatment of diseases caused by bacteria that are resistant to other antibiotics such as penicillin compounds, and in the treatment of sensitive patients to penicillin. In many cases it is desirable to use

- ¥

use a cephalosporin antibiotic that has activity against Gram-positive and Gram-negative microorganisms and a great deal of research has been carried out on the development of several types of broad-spectrum cephalosporin antibiotics.

So, for example, in our British Patent Specification N2. 1399086, we describe a new class of cephalosporin antibiotic derivatives containing a 7 ^ - (oximino ° <-terified) acylamino side chain, with the oximino group having the sin configuration. This class of antibiotic compounds is characterized by high antibacterial activity against a range of Gram-positive and Gram-negative organisms associated with a particularly high stability to the φ-lactemases produced by various Gram-negative organisms.

The discovery of this class of compounds has stimulated further research in this area in an attempt to find compounds that have better properties, for example against particular classes of organisms, especially Gram-negative organisms. This interest is reflected in the very large number of patent applications filed related to cephalosporin antibiotics having particular substituents on the 7-acylamino side chain and in the 3-position of the cephalosporin nucleus.

For example, British Patent Specification N ² . 1576625 contains a generic definition of cephalosporin antibiotics having a 7% - (oxy-non-esterified) side chain acetamido in which the etherifying group is an aliphatic hydrocarbon group that may have suitable substituents (including, among a large number of possibilities, a carboxy or protected carboxy group and a phenyl group substituted with up to three hydroxy groups), side chain which is yet or _su bstituida by a group which inter alia may be an aminothiazolyl group "However none of the specific compounds and exemplified contains an etherifying group carboxifenilalquilo. The group at position - 3 can also be chosen from a large number of alternatives, but the hydrogen atom is not included among them.

In our British Patent Specification N ² . 1604971 there is generally a wide range of cephalosporin antibiotics in which the Lateral position -7 can be chosen from inter alia a group 2- (2-aminothiazole-

4-yl) -2- (etherified oximino) acetamido, in which the etifying group, among many possible meanings, may be an alkyl group (for example methyl) substituted by phenyl and carboxy, although there is no specific example of compounds having a carboxyphenylalkyl group and the preferred etherifying group is specified as an unsubstituted methyl group. The group at position -3 can also be chosen from a large number of alternatives and the possible 3-substituents within the generic definition include a hydrogen atom.

In the UK Patent Specification N ² . 2017702 the etherifying group oximino, according to the generic definition inter alia is a radical ^ -Carboxyphenylmethyl. In the compounds specifically exemplified, the carboxyphenylmethyl group is always combined with an acetoxymethyl group at the 3-position.

UK Patent Specification ² .2104888 generically cephalosporin antibiotics wherein the side chain at the 7-position is a 2- (2-aminothiazol-4-yl) -2 (etherified oximino) acetamido group. The oximino etherifying group may inter alia be a carboxyphenylmethyl group in which the phenyl group can be replaced by a hydroxy group. The group at the -3 position is an isothiazolylthiomethyl or iminoalkylidenoditietane group.

European Patent specification N ² . 197409 generically cephalosporin antibiotics in which the side chain at the -7 posição position is a 2- (2-aminothiazol-4-yl) -2- (etherified oximino) acetamido group. The etherifying oxymin group may be inter alia a catechol carboxy tiloxyimino group. The substituent at position -3 can be chosen from a number of alternatives but these do not include the hydrogen atom.

We have now found that by choosing a group (Z) -2- (2-ainothiazol-4-yl) -2- (etherified oximino) acetamido

- 3 J t

in position-7 in combination with a hydrogen atom in position-3, and by choosing a substituted phenylmethoxyimino -carboxy group as the etherified oxy group, cephalosporin compounds having a particularly advantageous activity profile can be obtained (described in more detail below). below) against a large number of pathogenic organisms normally found and / or used as intermediates in the preparation of other active compounds.

Thus, we present cephalosporin compounds of general formula I

NHR ³

COOR ¹ (I)

In which

2

R and R, which can be the same or different, each represent a hydrogen atom or a carboxyl blocking group, R ³ represents a hydrogen atom or an amino protecting group, R4 and R5 each represent a hydroxy or hydroxy group substituted or R4 and R5 together represent 4 i

together a protected cyclic diol group

Z is ^ S or ^ S-fO (* - orJJ-), the dotted line connecting positions -2, -3 and -4 indicates that the compound is a cef-2-em or ce-3-em, and its salts and solvates (especially non-toxic hydrates).

The compounds of formula (I), in which R ¹ and / or R represents carboxyl blocking groups, the blocking group can be, for example, the residue of an ester-forming aliphatic alcohol or of a silanol or stanyl-forming phenol ester, said alcohol, phenol silanol or stananol preferably 1 to 20 carbon atoms) or a symmetric or mixed anhydride blocking group derived from a suitable acid. Particular examples of ρΛ or r ² include t-butyl, u.phenylmethyl and p-nitrobenzyl.

When R ³ is an amino protecting group, the protecting group can be for example a C7-2O aralkyl group (for example a triphenylmethyl or 4-methoxybenzyl group), an acyl group, such as an optionally substituted C-6 alkanoyl group ( for example a formyl or chloroacetyl group) or an optionally substituted alkoxycarbonyl group (for example a t-butoxycarbonyl or 2,2,2-trichloroethoxycarbonyl group), or a C7-10 carbonyl aralkyloxy group (for example a benzyloxycarbonyl group) or a group silyl (for example a tri-methylsilyl group.

In general, compounds of formula (I) in which R is a hydrogen atom are preferred.

When R4 and R5 represent a substituted hydroxy group it can be, for example, an acyloxy group / for example a formyloxy group or a group of the formula -0C0R6 (where R6 is a C1-8 alkyl group, for example a methyl group) /, a -0CO0 ₂ carbonate group R ⁶ (where R6 is as acidic), a silyloxy group / for example a (C1-4 alkyl) silyloxy group such as a trimethylsilyloxy or t-butyldimethylsilyloxy group, or a borate / - 0B (0r7) | / or phosphate / -0P (0) (OR7) 2 / (where R7 represents C1-4 alkyl).

When R4 and R5 together form a diol group

protected cyclic it may be an alkylidenedioxy group, preferably having 1-20 carbon atoms, for example a methylenedioxy, ethylenedioxy or isopropylenedioxy group which may contain one or more substituents, for example phenyl, C1-4 alkoxy, or oxo, for example groups methoxymethylenedioxy, diphenylmethylenedioxy or carbonyldioxy, a cyclic borate group, for example -OB (OH) O-, a cyclic phosphate group, for example -0P (0) (0H) 0-, or-OP (0) (0R7) 0- (where R7 is as defined above) or a silyl cyclic ether group, for example a di (C1-4 alkyl) silyldioxy group for example a dimethylsilyldioxy group »

In general, these silyloxy, borate or phosphate groups represent protected hydroxy groups that can be cleaved to obtain a compound of formula (I) having three free hydroxyl groups.

In general, R4 and R5 are each preferably an acetoxy group or in particular a hydroxy group.

The compounds of formula (I), Z is preferably; > S.

The cef-3-em compounds of the invention are particularly preferred.

When the compound is to be used in medicine, any ester of the carboxyl groups in the molecule must be a non-toxic metabolically labile function. Examples of non-toxic metabolically labile ester derivatives include acyloxy alkyl esters, for example, lower methyl or alkanoyloxy esters such as acetoxy methyl or -ethyl ester or pivaloyloxy methyl and carbonyloxyethyl alkoxy ester, for example esters of lower alkoxycarbonyloxyethyl such as the ethoxycarbonyloxyethyl ester.

In addition to the aforementioned ester derivatives, it should be understood that the present invention includes within its scope the active compounds of the invention in the form of other physiologically acceptable equivalents, i.e. physiologically acceptable compounds which, like the metabolically labile esters, are converted in vivo in the antibiotic compounds related to the invention.

Derivatives of non-toxic salts that can be formed by reaction of the carboxyl group present in the compounds of formula (I) include salts of inorganic bases such as alkali metal salts (for example sodium and potassium salts) and alkaline earth metal salts (e.g. calcium salts), amino acid salts (e.g. lysine and arginine salts), organic base salts (e.g. procaine, phenylethylbenzylamine, dibenzylethylenediamine, ethanolamine, diethanolamine and Nmethylglucoseamine). Other non-toxic derivatives include acid addition salts, for example those formed with hydrochloric, hydrobromic, nitric sulfuric, phosphoric formic and trifluoroacetic acid. The salts may also be in the form of resinates formed with, for example, a cross-linked polyvinylbenzene copolymer resin containing quartenary amino or amino groups or sulfonic acid groups, with a resin containing carboxyl groups for example a polyacrylic acid resin. the soluble base salts (for example alkali metal salts such as sodium salt) of the compounds of formula (I) which can easily be used in therapeutic applications due to the rapid distribution of these salts in the body after administration. When, however, insoluble salts of compounds (I) are desired for a particular application, for example for use in preparations for storage, these salts can be obtained in a conventional manner, for example, with suitable organic amines.

The compounds according to the invention are syn isomers. The isomeric form is defined by the configuration of

-OCHCOOR ²

in relation to the carboxamido group. In this specification the sin configuration is represented structurally with

It should be noted that since the compounds according to the invention are geometric isomers, some mixing with the corresponding anti-isomer may occur.

It should also be noted that in the etherifying group oxime, the carbon atom adjacent to the oxy group is chiral and can therefore exist in the R or S configuration. The invention thus includes within its scope the individual forms R and S in this chiral carbon atom as their mixtures (including mixtures (diastereomeric). In general, compounds of formula (I) in which this chiral carbon atom has the -S configuration and R / S mixtures in which the -S isomer is preferred predominates.

The compounds according to the present invention can exist in tautomeric forms (for example with respect to the 2-aminothiazolyl group) and it should be noted that such tautomeric forms, for example the 2-iminothiazolinyl form, are included within the scope of the invention.

As indicated above, the compounds of the invention are active against a wide range of pathogenic organisms commonly found and / or have use as intermediates for the preparation of other active compounds. In general, when the compounds of the invention

groups are to be used as intermediaries

2

R and R will often be carbohydrate blocking groups; the R group will often be a protecting group

5 amino groups and the R and R groups will often be protected hydroxy groups such as silyloxy, borate or phosphate groups or together will be a protected cyclic diol group. Non-toxic derivatives in which R and / or R represent acyloxy groups such as acetoxy groups can serve as intermediates or as active compounds.

In general, the active compounds of the invention SE12 3 Ram compounds ceph-3-em formula (I) wherein R _T R and R are hydrogen, Z represents> S and R and R ^{4 5} , which may be the same or different represent C ^-C ^ hydroxy or acyloxy groups for example acetoxy groups.

The important active compounds according to the invention have the formula (Ia)

CONH

OCHCOOH

H

(Ia) in which R a is a hydroxy or acetoxy group;

R $ a is a hydroxy or acetoxy group;

and its non-toxic metabolically labile solvates, hydrates and esters.

A particularly preferred compound of the invention is:

Acid (6R, 7R, 2 'Z, S) —7— / 2— (2 — aminothiazole — 4 — il) —2— / car

boxi) (3,4-dihydroxyphenyl) methoxyimino / acetamido / cef-3-em4-carboxylic; and its non-toxic metabolically labile solvates, hydrates and esters.

We found that (6R, 7R, 2'Z, S) -7- / 2- (2 aminothiazol-4-yl) -2 - / (carboxy) (3 ₁ 4-dihydroxyphenyl) methoxyimino / acetamido / cef-3- em-4-carboxylic can advantageously and consistently be prepared and isolated with a high degree of purity in crystalline form and this form is an additional aspect of the invention. In particular, we prepared and isolated (6R, 7R, 2 'Z, S) -7- / 2- (2-aminothiazol-4-yl) -2- / carboxy) (3,4-dihydroxyphenyl) methoxyimino / acetamido / hydrated crystalline cef-3-in-4-carboxylic acid. This new material is not only superior in its crystallinity and superior purity, but is also obtained with high yields and has greater storage stability even at high temperature for long periods of time. These properties of the crystalline material make it of particular value in pharmaceutical use.

above-mentioned crystalline material can be characterized by the infrared spectrum and / or X-ray diffraction pattern.

Spectrum IV (Nujol) 3700-2100 (wide), 1760, 1720, 1660, 1555, 1520, 135C, 13_ 00 1290, 1240, 1215, 1170, 1155, 1120, 1030, 1000, 920, 860 and 755cm "\

X-ray Diffraction Pattern (given in d-spacings in Angstrbm units and percentages of intensities I).

12.5 (21); 9.97 (37); 9.51 (22); 6.79 (11); 6.33 (35); 5. 29 (10); 4.76 (30); 4.63 (100); 4.39 (54); 4.32 (5); 4.18 (15); 4.09 (31); 3.91 (24); 3.78 (69); 3.69 (17); 3.61 (9)

3.52 (12); 3.48 (21); 3.42 (6); 3.33 (37); 3.15 (36); 3.07 (22); 3.02 (4); 2.96 (36); 2.85 (9); 2.78 (3); 2.75 (3);

2.65 (11); 2.59 (49); 2.50 (6); 2.44 (9); 2.38 (6); 2.31 (3); 2.27 (4); 2.20 (5); 2.16 (9); 2.1C (10); 2.05 (4); 2.01 (9).

The compounds according to the invention have broad-spectrum antibiotic activity

gram-negative, including many strains producing B-lactamase. The compounds also have high stability to B-lactamases produced by a variety of Gram-positive and Gram-negative organisms.

The compounds according to the invention were found to have high activity against strains (including penicillinase producing strains) of Gram-negative bacteria such as Staphylococcus aureus, Staphyloccocus epidermidis and Streptococcus spectrum. This fact is linked to the excellent activity against the species of Pseudomonas, and also and also with high activity against several members of Enterobacteria (for example strains of Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis and the indole- Proteus posiLives such as Proteus vulqaris, Proteus morganii and Providence species) and strains of Haemophilus influenza and Acinetobacter calcoaceticus. This combination of high activity against Gram-positive organisms and high activity against Gram-negative organisms, more particularly against Pseudomanas, which the compounds of the invention possess is unusual and particularly advantageous.

The cephalosporin derivatives described herein have a desirably long serum elimination half-life in vivo.

The compounds of the invention can be used to treat various diseases caused by pathogenic bacteria in humans and animals such as infections of the respiratory system and infections of the urinary system.

The antibiotic compounds of the invention can be formulated for administration in any convenient way, by analogy with other antibiotics, and the invention thus includes within its scope pharmaceutical compositions comprising an antibiotic compound according to the invention adapted for use in human or veterinary medicine. These compositions can be presented

J »

for conventional use with the aid, if necessary, of pharmaceutical carriers or excipients.

The antibiotic compounds according to the invention can be formulated for injections and can be presented in unit dosage form, in ampoules or in multi-dose containers, if necessary with an added preservative. The compositions can also take forms such as suspensions, solutions or emulsions in oily or aqueous vehicles and can contain formulation agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, for example sterile water, without pyrogen, before use.

If desired, these powder formulations can contain a suitable non-toxic base in order to improve the water solubility of the active ingredient and / or ensure that when the powder is reconstituted with water, the pH of the resulting aqueous formulation is physiologically acceptable Alternatively to the base it can be present in the water in which it reconstitutes the powder. The base can be, for example, an inorganic base such as sodium carbonate, sodium bicarbonate or sodium acetate, or an organic base such as for example lysine or lysine acetate.

The composition may also be in a form suitable for absorption by the gastro-intestinal system, for example, tablets, capsules, syrups or suspensions for oral administration and suppositories.

Compositions for veterinary medicine can, for example, be formulated as intra-mammary preparations either as bases of action or both fast and long.

The compositions can contain 0.1% or more, for example 0.1-99% of the active material depending on the mode of administration. When the compositions comprise dosage units, each unit will preferably contain 1003,000 mg of the active ingredient, for example 200-2,000 mg. The daily dosage for treating adult humans will preferably range from 200 to 12,000 mg for example 1000-9 mg per day, depending inter alia on the nature of the infection and the route and frequency of administration. In general, intravenous or intramuscular administration is used, for example using 400 to 4000 mg per day of the active ingredient in the treatment of adult humans. It should be noted that in some cases, for example in the treatment of neonates, smaller dosage units may be desirable

The antibiotics according to the invention can be administered in combination with other therapeutic agents such as antibiotics, for example penicillins, cephalosporins or other B-lactam compounds.

The compounds of the invention can be prepared by various processes described below.

Thus, according to another embodiment of the invention there is shown the preparation of an antibiotic compound of general formula (I) as defined above or of a non-toxic salt, solvate or hydrate thereof, acylating a compound of formula (II).

H HZ

in which the dotted line is as defined above for formula (I) or a salt, for example an acid addition salt (formed with, for example, an inorganic acid such as hydrochloric, hydrobromic, sulfuric acid, nitric or phosphoric or with an organic acid such as methanesulfonic or tuluene-sulfonic acid or a 7-N-silyl derivative with an acid of formula (III

(III)

C.COOH \ 2 0j! HC00R ²

or with a corresponding acylating agent if necessary and / or desired in each or one of them, if

In which R your salt, and then carry out any of the following reactions, in any suitable sequence:

I) converting a Δ-isomer _the isomer II) to form a compound wherein Z is / S converting a carboxyl group into a metabolically labile ester function form a non - toxic salt or solvate, removing any boxilo groups and / or N- protectors, removal of any droxy groups.

The above reactions i) to vi) can be carried out in a conventional manner.

In the acylation process, the starting material of formula (II) is preferably a compound in which Z is ^ S and the dotted line represents a cef-3-em compound.

Acylating agents that can be used in the preparation of compounds of formula (I) include halogen

III)

IV)

V)

VI) car lock and

hi14 lock

acyl compounds, particularly acyl chlorides or bromides. Such acylating agents can be prepared by reacting an acid (III) or a salt thereof with a halogenating agent, for example phosphorus oxychloride, thionyl chloride or oxalyl chloride.

Acylations using acyl halides can be carried out in aqueous and non-aqueous reaction media, conveniently at temperatures between ~ 50 to + 50 ° C, preferably -40 to + 30 ° C, if desired in the presence of an acid binding agent. Suitable reaction media include aqueous ketones, aqueous alcohols such as aqueous ethanol, esters such as ethyl acetate, halogenated hydrocarbons such as methylene chloride, amides such as dimethylacetamide, nitriles such as acetonitrile, or mixtures of two or more of these solvents. Suitable acid-binding agents include tertiary amines (for example triethylamine or dimethylaniline) inorganic bases (for example calcium carbonate or sodium bicarbonate) and oxiranes such as 1,2-alkylene oxides (for example ethylene oxide or oxide of propylene) that bind to the hydrogen halide released in the acylation reaction.

The acids of formula (III) can be used as acylating agents in the preparation of compounds of formula (I). Acylations using acid (III) are desirably conducted in the presence of a condensing agent, for example carbodiimide such as N, N'-dicyclohexylcarbodiimide or N-ethyl-N'-y-dimethylaminopropylcarbodii mide; a carbonyl compound such as, for example, carbonyldi imidazole, or an isoxazolium salt such as, for example, N-ethyl-5-phenylisoxazolium perchlorate; or N-ethoxycarbonyl-2-ethoxi-1,2-dihydroquinoline.

Acylation can also be carried out with other amide-forming derivatives of acids of formula (III) such as, for example, an activated ester, a symmetrical anhydride or a mixed anhydride (for example formed with pivalic acid or with a haloformate, as eg lower alkyl haloformed) ► Anhydrides mixed with phosphorous acids (eg phosphoric or phosphorous acid), sulfuric acid or aliphatic or aromatic sulfonic acids (eg toluene-p-sulfonic acid) can also be formed. An activated ester can conveniently be formed in situ using, for example, 1-hydroxybenzotriazole in the presence of a condensing agent as set out above, alternatively the activated ester can be preformed.

Acylation reactions involving the above-mentioned free acids or their amide-forming derivatives are desirably carried out in an anhydrous reaction medium, for example methylene chloride, tetrahydrofuran dimethylformamide, acetonitrile, dimethylacetamide or dimethylsulfoxide.

An alternative activation process is, for example, reacting an acid of formula (III) with a preformed solution or suspension by adding a carbonyl halide, in particular oxalyl or phosgene chloride or a phosphoryl halide such as phosphorous to a solvent such as a halogenated hydrocarbon, such as methylene chloride containing a tertiary lower aryl amide, such as Ν, Ν-dimethylformamide. The activated form of the acid of formula (III) can then be reacted with a 7-amino compound of formula (II) in a suitable solvent or mixture of suitable solvents for example halogenated hydrocarbons for example dichloromethane, alcohols or alkanol for example an ethanol or methylated industrial alcohols esters such as ethyl acetate, esters eg tetrahydrofuran or dioxane, ketones eg acetone, amides eg dimethylacetamide, acetonitrile water and mixtures thereof.

Aailação The reaction may be conveniently effected at temperatures from -50 to + 5O ² C, preferably -40 to +30 C ² if desired in the presence of an acid-binding agent, for example as described above (e.g. dimethylaniline, triethylamine or sodium bicarbonate).

If desired, the acylation reactions mentioned above can be carried out in the presence of a catalyst such as 4-dimethylaminopyridine.

The acids of formula (III) and the corresponding acylating agents can, if desired and when appropriate, be prepared and used in the form of their acid addition salts. Thus, for example, acyl chlorides in the form of their hydrochloride salts, and acid bromides in the form of their hydrobromide salts can conveniently be used.

For use as starting materials for the preparation of compounds of general formula (I) according to the invention, compounds of general formula (III) and their amide-forming derivatives such as acyl halides and anhydrides are preferably used. corresponding to it, in its symmetric sin form or in the form of mixtures of corresponding anti isomers containing at least 90% of the sin isomer.

The acids of formula (III) and their derivatives can be prepared by etherification of a compound of formula (IV). _

NHR ^J

in which R3 is as previously defined and R8 represents a hydrogen atom or a carboxyl blocking group, or a salt thereof, by selective reaction with a compound of the general formula (V).

T.CHC00R2

in which T is a bromine or iodine atom, a sulfate group or a sulfonate group, such as tosylate, followed by

The removal of any carboxyl blocking group R.

The etherification reaction is conveniently carried out in the presence of a base, for example potassium carbonate or sodium hydride, and is preferably carried out in an organic solvent, such as dimethylsulfoxide, a cyclic ether such as tetrahydrofuran or dioxane, or an amide Ν , Ν-disubstituted as for example dimethylformamide.

The separation of the isomers can be carried out before or after that etherification. In the circumstances described above, the configuration of the oxyimino group is not substantially altered by the etherification reaction.

When the compound of formula (IV) is used in the form of a free acid or a salt with a base, the etherification reaction is generally carried out in the presence of a strong base, such as potassium t-butoxide being added to the base enough to form a dianion. In addition, the reaction must be carried out in the presence of a base if an acid addition salt of the compound of formula (IV) is used, the amount of base being sufficient to quickly neutralize the acid in question.

The acids of formula (III) can also be prepared by reaction of a compound (VI).

iNHR ³ (VI)

1 ___ 1__CO.COOR ⁸

In which R3 and R8 are as defined above, with a compound of formula (VII).

(VII)

45 in which R, R and R are as defined above, followed by the removal of any carboxyl blocking group R, and when necessary the separation of the syn and anti isomers.

The reaction is conveniently carried out in a solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran or methanol, all optionally in the presence of water at a temperature of -20 ² to +50 ² C, preferably O ² _to 3 O ² C.

The acids of formula (III) can be converted to their acyl halides and anhydrides and acid addition salts by conventional processes, for example as described above.

Intermediates of formula (VII) can be prepared by treating compounds of formula (VIII).

(VIII) in which Y is an imido group, for example a succinimido or maleimido phthalimido group, with a hydrazine reagent such as hydrazine hydrate or an alkylhydrazine such as methylhydrazine. The reaction will generally be carried out in an inert solvent, for example a halogenated hydrocarbon such as low temperature methylene chloride, for example -70 ² to +30 ² C.

Intermediates of formula (VIII) can be prepared by alkylation with compounds of formula (IX)

Hal-ÇHCOOR ² / X ÍI I ^(IX) \ / \ ⁴ • 5

R ³

in which Hal is a halogen atom such as a chlorine or bromine atom, of a suitable hydroxyimine eg N-hydroxyphthalimide, N-hydroxysuccinimide, in the presence of a base such as triethylamine in a solvent such as acetonitrile to example -102 to + 3O2C.

The intermediate compounds of formula (IX) are either known compounds or can be prepared using processes analogous to those used for the preparation of known compounds.

The compounds of formula (II) used as starting materials in the acylation process are known from the literature e.g. British Patent Application No. ^s 2,159,817 or can be prepared according to the literature data.

An ester derived from cephalosporxna-A obtained according to the process of the invention α referred to above can be converted into the corresponding derivative -Δ, for example by treating the ester -Δ with a base, such as pyridine or triethylamine.

A reaction product cef-2-em can also be oxidized to obtain the corresponding cef-3-in 1-oxide for example by reaction with a peracid, for example peracetic acid or m-chloroperbenzoic acid, the resulting sulfoxide being subsequently reduced as described below to obtain the corresponding cef-3-sulfide desired.

When a compound in which Z is \ S-? 0 is obtained this compound can be converted into the corresponding sulfide by, for example, reducing the corresponding acyloxysulfonium or alkoxysulfonium salt prepared in situ by reaction with for example deacetyl chloride in the case of a salt of acetoxysulphenium, the reduction being carried out, for example, with sodium dithionite or by the iodide ion as in the solution of potassium iodide in a solvent for example acetic acid, acetone, tetrahydrofuran, dioxane, dimethylformamide or dimethylacetamide. The reaction can be carried out

temperature between -20 ² and + 50 ² C.

In the oxidation and reduction processes above _. 45 described, the groups R and R in the starting materials are desirably different from hydroxyl groups.

The metabolically labile ester derivatives of carboxyl groups in the compounds of formula (I) can be prepared by reacting a compound of formula (I) or a salt or derivative protected with the appropriate esterifying group such as acyloxyalkyl halide or alkoxycarbonyloxyalkyl halide (e.g. iodide) conveniently in an inert organic solvent such as, for example, dimethylformamide or acetone, followed, if necessary, by the removal of any protecting groups.

The basic salts of the compounds of formula (I) can be obtained by reacting an acid of formula (I) with a suitable base. Thus, for example, sodium or potassium salts can be prepared using the respective acetate, 2-ethylhexanoate or bicarbonate salt. Acid addition salts can be prepared by reacting a compound of formula (I) or a metabolically labile ester derivative with the appropriate acid.

When a compound of formula (I) is obtained as a mixture of isomers, the sin isomer can be obtained by, for example, conventional processes such as crystallization or chromatography.

It should be noted that in some of the transformations mentioned above it may be necessary to protect any sensitive groups in the molecule of the compound in question to avoid undesirable side reactions. Examples of such protecting groups are given in Protective Groups in Organic Synthesis by Theodora k. Greene (John Víiley and Sons, 1981).

For example, during any of the above reaction sequences it may be necessary to protect the NH ₂ group from the molecular part of aminothiazolyl, for example by tritylation, acylation (for example chloroacetylation or formylation), protonation or other conventional process

national. The protecting group can then be removed by any convenient process that cannot break the desired compound, for example, in the case of a trityl group using an optionally halogenated carboxylic acid, for example acetic acid, formic acid, chloroacetic acid or trifluroacetic acid or using an inorganic acid, for example hydrochloric acid or mixtures of these acids, preferably in the presence of a protonic solvent such as water, or in the case of a chloroacetyl group, by treatment with thiourea.

Similarly, hydroxy groups on the molecular part of catechol may need to be protected during any of the above reaction sequences. Hydroxy protecting groups that can be removed under moderate conditions will generally be suitable for example, acetyl or silyl groups. These groups can be introduced in a conventional way and, when desired, removed so that the product does not rupture. For example, in the case of an acetyl group, the group can be removed by solvolysis with an aqueous solvent such as aqueous methanol or aqueous ethanol in the presence of a base such as sodium bicarbonate, ammonium hydroxide, ammonium carbonate or ammonium carbonate. . A trimethyl silyl group can be cleaved, for example by treatment with a dilute aqueous acid.

The carboxyl blocking groups used in the preparation of the compounds of formula (I) in the preparation of the necessary starting materials are desirably groups that can be easily eliminated at one stage of the reaction sequence, conveniently at the last stage. However, it may be convenient in some cases to use metabolically labile carboxyl blocking groups, such as acyloxymethyl or ethyl (eg acetoxymethyl or ethyl or pivaloyloxymethyl) and retain them in the final product to give a suitable ester drip of a compound of formula (I).

Suitable carboxyl blocking groups are well known in the art, including a list of representative carboxyl blocking groups in British Patent R2 1399086. Preferred carboxyl blocking groups include aryl lower alkoxy carbonyl such as p-methoxybenzyloxycarbonyl, Nitrobenzyloxycarbonyl and diphenylmethoxycarbonyl, lower alkoxycarbonyl such as t-butoxycarbonyl and lower haloalkoxycarbonyl groups, such as 2,2,2-trichloroethoxycarbonyl. The carboxyl blocking group can later be removed by any of the methods reported in the literature; thus, for example, acid hydrolysis or reduction, such as enzymatically catalyzed hydrolysis, is applicable in many cases.

When a particular enantiomer of a compound of formula (I) is desired, starting materials having the desired stereochemical configuration must be used in the above processes. Such intermediates can be obtained by conventional resolution processes. Thus, for example, enantiomeric intermediates of formula (VIII) can be obtained in which R is a hydrogen atom and in which the chiral carbon atom is in the (R) or (S) configuration by reacting a mixture of enantiomers with a resolving agent such as a chiral organic base (for example R - (+) - methylbenzylamine) in a solvent such as acetone or acetonitrile to obtain the corresponding diastereoisomeric salts. The salts can then be separated by known methods and the desired chiral daily intermediate of formula (VIII) can be regenerated by treatment with an aqueous acid solution, for example aqueous hydrochloric acid solution, for example at room temperature.

The crystalline form of (6R, 7R, 2'Z, S) -7- / 2- (2-aminothiazol-4-yl) -2 - / (carboxy) (3,4-dihydroxyphenyl) methoxyimino can be conveniently prepared / acetamido / cef-3-in-4-carboxylic acid in the form of its hydrate from an aqueous solution of the aforementioned cephalosporin salt or a solvate thereof.

Thus, according to a further embodiment of the invention, we present a process for the preparation of (6R, 7R, 2 'Z, S) -7- / 2- (2-aminothiazol-4-yl) -2 - / ( carboxy) (3,4-dihydroxyphenyl) methoxyimino / -acetamido / cef-3-in-4-carboxylic hydrate crystallizing said acid from an aqueous solution, preferably from an aqueous solution of its acid or base addition salt or a solvate thereof of said salts to obtain a hydrated crystalline product. Crystallization will normally be followed by isolation and drying of the product.

Suitable basic salts include, for example, basic inorganic salts, such as alkali metal salts and alkaline earth metal salts and organic basic salts, as described above. A particularly suitable basic salt is sodium salt.

The starting acid addition salts can be formed with an organic or inorganic acid. Organic acids that can be used include carboxylic acids. and sulphonic acids, for example formic, trifluoroacetic and methanesulfonic acid. Organic acids that can be used include inorganic acids such as hydrochloric acid, hydrobromic acid or sulfuric acid.

According to a further aspect of the invention the desired material can be crystallized from a solution of an acid or basic salt of the acid (6R, 7r, 2'Z _t S) -7- / 2- (2-aminothiazole- 4-yl) -2 - / (carboxy) (3,4-dihydroxyphenyl) methoxyimino / acetamido / cef-3-em-4-carboxylic, or a solvate thereof, in an aqueous medium adjusting the pH value to 1.0 to 4.0.

For example, a hydrate can be crystallized from an aqueous solution of a basic salt by adding an organic or inorganic acid to a pH value in the ranges mentioned above. Suitable acids that can be used in crystallization include, for example, hydrochloric acid and sulfuric acid. Alternatively, the desired hydrate can be crystallized from an aqueous solution of an acid addition salt or by adding an organic or inorganic base

1

at an appropriate pH value in the above ranges. Bases that can be used include, for example, carbon hydroxides, bicarbonates or acetates of alkali metals or alkali or earth metals, for example, sodium hydroxide, sodium carbonate, sodium bicarbonate or sodium acetate »aqueous medium may contain a water-miscible organic solvent such as an alcohol, for example ethanol or isopropanol, an ether, for example tetrahydrofuran or dioxane, an amide for example N, N-dimethylformamide or Ν, Ν-dimethylacetamide, a ketone for example acetone, or a nitrile, for example acetonitrile.

Crystallization is desirably carried out at room temperature, for example from 0 to 30 ² and preferably from 15 to 25 ² C. The crystalline product can be recovered by filtration and dried in a conventional manner, for example by careful drying under reduced pressure »

The following Examples illustrate the invention. Nujol and Sorbsil are registered trademarks. Eorbsil U30 is a silica gel produced by Joseph Crosfield and Son of Warrington; Cheshire, England. Unless expressly stated otherwise, NMR spectra have been recorded on DlSSO-dg. X-ray diffraction measurements were made on a Siemens D-500 diffractometer using CuK radiation · X-ray intensities were measured in increments of 20 from 0.2.2 during 5-second intervals using a scintillation counter , between the values of 22 and 90 ² . The results were entered into a computer for processing

Intermediate 1

2- (3,4-Dioxicarbonylphenyl) -2- (phthalimidooxy) acetic acid

A solution of N-hydroxyphthalimide (14.6 g) and triethylamine (25 ml) in acetonitrile (50 ml) was added to a stirred suspension of 2- (3,4-dioxicarbonylphenyl) -2-chloroacetic acid (20, 5 g) in acetonitrile -2 to ² ° C for 20 minutes. After a further 1 hour to about ² 0 C was added rapidly hydrochloric acid solution concentra25

(7.5 ml) in water (100 ml) »Water (100 ml) was added slowly. Water (100 ml) was added slowly and the oil initially released crystallized, aided by nucleation. The mixture was filtered and the filter cake was washed with water and ethyl acetate: petroleum ether (eg 4C-602C) and dried to obtain the title compound (30 g), mp 183 to 1852C .

^ 5.84 (s, 0CH), 7.53 (s, 5-H and 6-H catechol), 7.69 (s, 2-H catechol), and 7.85 (s, phthalimido protons).

Intermediate 2 (a) (S) -2- (3,4-Dioxycarbonyl-phenyl) -2- (phthalimidooxy) acetic acid (R) - (+) -X-Methylbenzylamine

A solution of P .- (+) -cZ-methylbenzylamine (16.3 ml) in acetone (100 ml) was quickly added to a magnetically stirred solution of intermediate 1 (45 g) in acetone (1.25 liters) ) at 212C in a nitrogen atmosphere. After 30 minutes, the mixture was filtered and the precipitate was washed well with acetone to obtain the title compound (16.57) g.

/ tf / 2 ¹ ₊ 242 ° ( _c 1.07, EtOH), ^ rl, 46 (d, J 7Hz, CH ₃ CH), 5.48 (s, OCH), 7.3 to 7.6 (m , aromatic protons) and 7.30 (s, phthalimido prctces).

(b) (S) -2- (3,4-dioxicarbonylphenyl) -2- (phthalimidooxy) diphenylmethyl acetate

Hydrochloric acid 214 (10 ml) was added to a stirred suspension of the intermediate at 2 (a) (5.0 g) in water (30 ml) in a nitrogen atmosphere at 219 ° C. After 2 minutes, a diphenyldiazomethane solution containing an equivalent in methylene chloride (11 ml) was added. After vigorous stirring for 35 minutes, the organic phase was separated and added dropwise to ethanol with stirring (150 ml). Agotou the mixture at 219C for 10 minutes and then stored at 4 ° C for 1 ² hour. The crystals were collected by filtration, washed with ethanol and dried to obtain the title compound (3.59 g), mp

τ

135 to 135.5 ^S C.

/ W ²¹ ₊ 112.69 (ç 1.18, ethyl acetate).

Intermediate 3 (S) - (3,4-Dihydroxyphenyl) diphenylmethoxycarbonyl) methoxyamine

Was stirred intermediate 2 (b) (5.71 g) in methanol (390 ml) with 1M hydrochloric acid (5.5 ml) at about 40 ² C for 4.5 hours. The solution was concentrated and mixed with methylene chloride. After washing twice with water, the solution was dried with magnesium sulfate and evaporated to a foam. A solution of this foam in methylene chloride (176 ml) was cooled to -50 ² C with

stirring under a nitrogen atmosphere and hydrahydrazine (1.5 ml) was added. The mixture was allowed to warm slowly to 212 ° C and was filtered. After 5.75 hours, the mixture was filtered and the filter cake was washed with methylene chloride. The combined filtrates were diluted with ethyl acetate and washed with citric acid and saline.

, evaporation prog) in the form of a foam After drying over magnesium sulfate gave the title compound (4.35 ^ma * 21 $ 5.02 catechol)

7.1 to 7.4 (m, aromatic protons) + 17.89 (c 1.03 methanol), (s, OGHCO), 6.68 and 6.81 (m, thiazole H, OCH and protons

9.04 (s, 0H)

Intermediate 4

(Z, S) —2— (2-sminothiazol-4-yl) -2 - / (3,4-dihydroxyphenyl) (diphenylmethoxycarbonyl) methoxyimino / acetic

2- (2-Aminothiazol-4-yl) glyoxylic acid (1.91 g) was added over 3 minutes to a solution of intermediate 3 (4.20 g) in N, N-dimethylformamide (22 ml) at 32c with agitation. After an additional 30 minutes cooling with ice, the solution was allowed to warm to 21 ² C for 1.5 hours and then added dropwise to a mixture of ice and water (110 g) with stirring over 20 minutes. The precipitate was collected by filtration, washed with water and

it was. It was resuspended in methylene chloride (45 ml) and stirred for 15 minutes before filtration. The filter cake was washed with methylene chloride and dried to obtain the title compound (3.76 g).

+ 25.42 (c 1.02, methanol) ^ 5.59 (s, 0CHCC), 6.6 to 6.9 (m, thiazole H, OCH, and catechol protons, 7.0 to 7.5 ( m, NH ^ and phenyl proteins) and 9.06 and 9.13 (2s, OH)

Intermediate 5

(Z, S) -2- (2-formamidothiazol-4-yl) -2 - / (3,4-dihydroxyphenyl) (diphenylmethoxycarbonyl) methoxyimino / acetic

2- (2-formamidatiazol-4-yl) glyoxylic acid (6.96 g) was added to a stirred solution of / (3,4-dihydroxyphenyl) diphenylmethoxycarbonyl) / - methoxyamine (12.73g) in N, N-dimethylformamide (100 ml) at room temperature. After 1.5 hours, more N, N-dimethylformamide (40 ml) was added, and then for 2.5 hours the resulting solution in water (700 ml) was added. The products were extracted in ethyl acetate (3 X 250 ml). The combined extracts were washed with water (2 x 250 ml), dried over magnesium sulfate and then evaporated to obtain a solid. This solid was treated with ethyl acetate (20 ml) and then with dichloromethane (200 ml) to obtain a suspension. After cooling, the solid was collected by filtration, washed with dichloromethane, and dried to obtain the title compound (11.38 g) mp 1251272c, · / <// _D + 22.22 (ç 0 , 99, methanol).

Example 1 (6R, 7R, ^L 2 Z, S) 7- / 2- (2-aminothiazol-4-yl) -2 - / (3,4-dihydroxyphenyl) diphenylmethoxycarbonyl) methoxyimino / acetamido / ceph-3-em -diphenylmethylcarboxylate

The (6R, 7R) -7- tosylate salt was converted

diphenylmethyl-aminocef-3-in-4-carboxylate (1.24 g) in the free amine, partitioned between methylene chloride and aqueous sodium bicarbonate solution. The organic phase was washed with water and dried with magnesium sulfate. Evaporation produced a foam which was mixed with intermediate 4 (1.0 g) in THF (25 ml) with stirring and Ν, Ν-dicyclohexylcarbodiimide (830 mg) and benzotriazole hydrate (290 mg) were added. After stirring at 212 ° C for 16 hours, the mixture was filtered and the filter cake was washed with ethyl acetate. The combined organic solutions were evaporated until a foam was obtained which was redissolved in ethyl acetate and filtered through a Sorbsil U30 column (100 g) in ethyl acetate. Evaporation of the appropriate eluate produced the crude product which was redissolved in chloroform and loaded onto a Sorbsil U30 column (100g) placed in chloroform. The column was eluted with chloroform and then with 1% 2% and 3% methanol in chloroform Evaporation of the appropriate eluate yielded the title compound (800 mg) as a foam.

/> / ²¹ + 36.252 (c, 1.17 DMSO);

Ainfl (EtOH) 230.8 (E- ^ _m 303), 290 (E ^ _m 117) and 300.4nm C ^M > ·

Example 2

Salt of trifluoroacetic acid (6R, 7R, 2 * Z, S) -7 / 2- (2-aminothiazol-4-yl) -2- / carboxy) (3,4-dihydroxyphenyl) (methoxyimino / acetamido / cef -3 ~ to-4-carboxylic

The compound of Example 1 (740 mg with anisole (1.5 ml) was stirred and trifluoroacetic acid (7.5 ml) was added. After 1 minute, diisopropyl ether (50 ml) was added. The precipitate was collected by filtration, it was washed with diisopropyl ether and dried under reduced pressure to obtain the title compound (450 mg).

102.82 ( _c 0.88, DMSO).

Amax (pH6 buffer) 236.8 nm (E ^ _m 257), 277.4 (E ^ _m 173) and 296.0 nm (E ^ _m 139).

Example 3 (6R, 7R, 2 ¹ Z, S) 7- / 2- (2-formamidatiazol-4-yl) -2 - / (3,4-diihi hydroxyphenyl) (diphenylmethoxycarbonyl) methoxyimino / acetamido / ceph-3 ~ in ~ diphenylmethyl 4-carboxylate

Intermediate 5 (1.2 g) was suspended in methylene chloride (20 ml) with stirring in a nitrogen atmosphere and N, N-dimethylacetamide (4 ml) was added. The solution was cooled to -25 C and ^the phosphorus oxychloride was added (0.28 mL). After stirring for 1 hour at -252 ca -20 ² c, a solution of diphenylmethyl (6R, 7R) -7-aminocef-3-in-4-carboxylate (derived from its tosylate salt (1.35 g ) by the action of sodium bicarbonate solution in methylene chloride (20 ml) containing N, N-dimethylaniline (2 ml)

The temperature of the reaction solution was now -10 ^to C and was surrounded by ice with water and stirred for 1.75 hours, then the solution was successively washed with sodium bicarbonate solution, diluted hydrochloric acid and water for three times, each time back-stripping the aqueous phases with methylene chloride. The organic phases were dried with magnesium sulfate and concentrated. The crude product in methylene chloride was loaded onto a column of Sorbsil U30 (50 g) with 40% ethyl acetate in petroleum ether (PE 40 to 60 ^and c) containing 2% acetic acid) · Evaporation of the eluate produced the title compound (1.56 <

/ / ²¹

D max λ ίτ-1%

g) + 36.22 (c 1.05, DMSO) · (EtOH 269.2 nm (Ε ^ ζ ° 184) infl 232.0 285), 260, ^{4 (E} lcm ¹⁷⁹ >' ^{and 266} ' ^{8 nm (E} lcm ¹⁸³⁾ *

Example 4 (6R, 7R, 2 ^1, Z, S) 7- / 2- (2-aminothiazol-4-yl) -2 - / (3,4-dihydroxyphenyl) difenilmetoxicarbinil) methoxyimino / acetamido / 3- cephem- diphenylmethyl em-4-carboxylate ·

The compound of Example 3 (1.5 g) was stirred with.

methanol (15 ml) at 2isc and perchloric acid was added to

60% (1 ml). After 2.5 hours, the solution and ethyl acetate were partitioned and an excess sodium bicarbonate solution was carefully added. The aqueous phase was extracted with more ethyl acetate and the combined organic phases were washed with saline twice, dried with magnesium sulfate and evaporated to obtain the title compound (1.34 g );

/ <* / ²¹ ₊ 36, 5 ² (ç 0.96 DMSO);

T / max (Nujol) 3600 to 3100 (Largo), 1785, 1730 and 1680 cm ”^

Example 5

Sodium salt of (6R, 7R, 2 ¹ Z, S) 7- / 2- (2-a.rainotiazol-4-yl) -2- / (carboxy) (3,4-dihydroxyphenyl) methoxyimino / acetamido / ceph -3-in-4-carboxylic

The compound of Example 2 (11 g) was dissolved in ethanol (110 ml) with stirring at 212 ° C and a saturated solution of sodium acetate (4.8 ml) was added. After 1 minute, the mixture was filtered and the filter cake was washed well with ethanol four times, with ether for four times, and dried under reduced pressure to obtain the title compound (5.45 g). More tro ter ter product (2.73 g) was obtained by adding more saturated sodium acetate solution (2 ml) to the mother liquor / £ * / ²¹

D

Amax (pH6 buffer) 234.4 (E ^{276.8 (E} lcm ¹⁸⁴ > ·

Exampleõ + 185.02 (c 0.78 DMSO);

_: .1% lcm

386), z \ infl 250.4 (E ^ ° _m 276), (3,4-dihydroxyphenyl) methoxyirain / acetamido / cef-3-on-4-carbo « _> xylic

The compound of Example 5 (1.0 g) was mixed with water (4 ml) and sodium acetate (41 mg) was added to form a solution. This solution was filtered and seeded to initiate crystallization. The mixture was stored at 21 ² C for 14.5 hours and then the crystals were collected:

by filtration, they were washed with water and dried under reduced pressure at 212 ° C to obtain the title compound (250 mg). The addition of 2N hydrochloric acid (0.9 ml) produced more crystalline product (360 mg).

/ O </ ²¹ + 136.272 (c 0.54, DMSC);

Amax 234.4nm (E ^ ^{/ o} 408), Ainfl 249.6 (E ^ ^{/ o} η y JLCHl η Q / JLCin

7 * 192) and 295.0 nm (ETC * 156).

lcm ^r lcm

295),

277.8 (E

Example 7

(6R, 7R, 2'Z, S) -7- / 2- (2-aminothiazol-4-yl) -2 - / (carboxy) (3,4-dihydroxyphenyl) methoxyimino / acetamido / hydrochloric acid salt cef-3-in-4-carboxylic

Dissolve the compound of Example 4 (27.4 g) in formic acid (110 ml) with stirring at 20 ² C and was added concentrated hydrochloric acid, 3 equivalents (82 ml). The mixture was stirred for an additional 15 minutes and then was added dropwise over 6 minutes to diisopropyl ether (1.11) with stirring at 202 ° C. The precipitate was collected by filtration, washed with diisopropyl ether (500 ml) and dried under reduced pressure to obtain the title compound (18.02 g).

Ύ max (Nujol) 3600-2800 (wide) and 1780 cm

3.3-3.7 (m, H-2), 5.05 (d, H-6), 5.4 (s, CHON), 5.8 (m, H7), 6.46 (m, H-3) and 9.6 (d, NHCO).

Example 8

(6R, 7R, 2 * Z, S) -7- / 2- (2-aminothiazol-4-yl) -2 - / (carboxy) (3,4-dihydroxyphenyl) methoxyimino / acetamido / cef-3-em -4-carboxylic.

The compound of Example 7 (2.65 g) was added, with stirring, to distilled water (10.6 ml) at 202 ° C and the mixture was stirred for 30 minutes during which crystallization occurred. The stirred suspension was cooled in water / ice for 15 minutes and then the crystals were collected by filtration, washed with cold distilled water (10 ml), air dried in an oven at 302 q to obtain the

the title compound (2, O9g). Water content; 12% (Karl Fischer);

Spectrum IV (l \ ujol) Vmax 3700-2100 (wide), 1760, 1720, 1660, 1555, 1520, 1350, 1300, 1290, 1240, 1215, 1170, 1155, 1120, 1030, 1000 920, 860 and 755 cm ” ¹ ;

X-ray Diffraction Pattern (data such as d-spacing in Angstbm units and percentages of intensities I).

12.5 (21); 9.97 (37); 9.51 (22); 6.79 (11); 6.33 (35); 5. 29 (10); 4.76 (30); 4.63 (100); 4.39 (54); 4.32 (5); 4.18 (15); 4.09 (31); 3.91 (24); 3.78 (69); 3.69 (17); 3.61 (9) 3.52 (12); 3.48 (21); 3.42 (6); 3.33 (37); 3.15 (36); 3.07 (22); 3.02 (4); 2.96 (36); 2.85 (9); 2.38 (6); 2.78 (3) 2.75 (3); 2.65 (11); 2.59 (49); 2.50 (6); 2.44 (9); 2.38 (6); 2.31 (3); 2.27 (4); 2.20 (5); 2.16 (9); 2.10 (10); 2.05 (4); 2.01 (9).

Example 9 (6R, 7R, 2 * z, S) -7- / 2- (2-formamidothiazol-4-yl) -2- / 3,4-dihydro xiphenyl) (diphenylmethoxycarbonyl) methoxyimino / acetamido / cef-3 - tert-butyl em-4-carboxylate.

Was dissolved Intermediate 5 (1.53 g) with stirring in methylene chloride (15 ml) and N, N-dimethylacetamide (2.9 ml) and the solution cooled to -35 was added ^2-ce phosphorus oxychloride (0.41 ml). The mixture was stirred at -25 to -20 C ^{O 9} C for 1 hour, and then postponed, Onou a solution of (6R, 7R) -7-aminocephalosporanic-3-carboxylate # 4-tert-butyl ( derived from its tosylate salt (1.0 g) by action of aqueous sodium bicarbonate solution as described in Example 1 for diphenylmethyl ester) in methylene chloride (15 ml) containing N, N-dimethylaniline (2.9 ml ). The reaction mixture was maintained at about G ² C for 16 hours, then washed successively with water, diluted hydrochloric acid (twice) and water, each time the aqueous phase was reextracted with methylene chloride. The combined organic phases were concentrated to obtain a foam, which was redissolved in methylene chloride

(15 ml) and passed through a Sorbsil U3O silica column (5 g) eluting with methylene chloride (30 ml). The eluate was concentrated to a small volume and treated with diisopropyl ether (65 ml) to precipitate the title compound as a white solid (1.2 g).

£ (CDC1 ₃ ) 1.57 (s, (CH ₃ ) ₃ ), 5.74 (s, OCHCO), 6.15 (m, H-7), 6.49 (d, H-3), 8.4-8.7 (m, NHCO e - CH).

Example 10 (6R, 7R, 2 * Z, S) -7- / 2- (2-aminothiazol-4-yl) -2- / 3,4-dihydroxyphenyl) (diphenylmethoxycarbonyl) methoxyimino / acetamide / cef-3em-4 tert-butyl carboxylate.

The compound of Example 9 (6.29 g) was stirred in methanol (64 ml) and 1,4-dioxane (16 ml) was added at 202 ° C and 60% perchloric acid (5.63 ml). After 3.5 hours, the solution was added to a well stirred sodium bicarbonate solution (240 ml). The mixture was stirred for an additional hour and then cooled. The product was collected by filtration, washed with water and dried. It was then dissolved in a mixture of ethyl acetate and methylene chloride (1: 1) and the solution was loaded onto a Sorbsil ”U3C silica column (65 g) which was eluted with more solvent Evaporation of the appropriate eluate fraction produced the title compound (4.0 g);

§1.5 (s, (CH ₃ ) ₃ ), 5.06 (d, H-6), 5.61 (s, CHON), 5.8 (m, H7), 6.41 (m, H-3), 9.0 (wide, -OH ), 9.5 (d, NHCO).

Example 11

(6R, 7R, 2 * Z, S) -7- / 2- (2-aminothiazol-4-yl) -2 - / (carboxy) (3,4-dihydroxyphenyl) methoxyimi no / acetamide hydrochloric acid salt / cef-3-in-4-carboxylic

It was dissolved the compound of Example 10 (1.5 g) in formic acid (6 ml) with stirring under stirring at 20 ² C, and concentrated hydrochloric acid (0.35 ml, 2.1 equivalents). The mixture was stirred for 2 hours and then clarified by filtration and then evaporated.

reduced pressure. Ethyl acetate (6 ml) was added to the residue and the mixture was re-evaporated to obtain a foam which was triturated with ethyl acetate (6 ml). The resulting suspension was stirred for 30 minutes at room temperature. The solid was collected by filtration, washed twice with ethyl acetate and the reduced pressure was dried to obtain the title compound (1.33 g) identical to the product of Example 7.

Pharmaceutical Example

Dry Powder for Injections

Per Vial Acid (6R, 7R, 2'Z, S) -7- 2- / 2-aminothiazol-4-yl / -2 - / (carboxy) (3,4-dihydroxyphenyl) me- 5GC mg toxiimino / acetamido cef -3-in-4-carboxylic.

Sodium carbonate (anhydrous) 99 mg

Sterile components are aseptically mixed and filled into sterile bottles. Purge the upper space of the flask with sterile nitrogen and close the flasks with rubber plugs and metal sealing (applied by stapling). The product can be constituted by dissolving it in Water for Injections or another properly sterilized vehicle shortly before administration.

Claims (2)

- 13 Process for the preparation of compounds of formula (I) CONH CCHCOOR ² 1 2 in which R and R, which may be the same or different, each represent 1 hydrogen atom or a carboxyl blocking group, the R represents a hydrogen atom or an amino protecting group; 4 5 R and R each represent a substituted hydroxy group 45 or R or R together represent a protected cyclic diol group; Z is —S— or —SO— (Z- or (^ .-) and the dotted line connecting positions -2, -3 and -4 indicates that the compound is and a compound cef-2-em or cef- 3-em, or its salts or solvates (including hydrates characterized by acylating a compound of formula (II) π ₂ ν Η Ζ \ ¹ : ί Ν -Ί I! COOR (II) in which r \ Ζ and the a-dotted line are as defined above or a salt or derivative thereof 7-N-silyl, with a compound of formula (III) NHR ³ Λ Y N! ---! __ C.COOH II N \ 2 OCHCOOR ^Z I (III) Δ ir> 2 3 4 5 in which R, R, R er are as defined above or a salt thereof, or with a corresponding acylating agent, and then, if necessary and / or desired in each case, any of the following following reactions, in any suitable sequence: i) conversion of a -Zl isomer to a desired -Δ ° isomer ii) reduction of a compound in which Z is -S0- to obtain a compound in which Z is -S-, iii) conversion of a carboxyl group to an ester function non-toxic metabolically iv) formation of a non-toxic salt or solvate # v) removing any c-blocking groups and / or protecting E, and vi) removing any hydroxy blocking groups. Process according to claim 1, characterized in that the compound of formula (I) is a compound of formula (la) Nn THE Y N 1 ___. 1 C KNOWLEDGE H • B / ^s \ * · II 1 i I N \ // N. \ / \ OCHCOOH j 1 COOH \ / \ _R 4a R5 ^a (Ia) in which R4 ^a is a group hydroxy or acetoxy, R5 ^a is a group hydroxy or acetoxy, or your salt, solvate, (including hi non-toxic metabolically labile ester or ester. Process according to claim 1 or 2, characterized in that the esterifying oxime group has the “S · configuration - 4th - Process according to claim 1, characterized in that the compound (I) is the acid (6R, 7R, 2'Z, S) -7 / 2- (2-aminothiazol-4-yl) -2 - / (carboxy) (3,4-dihydroxyphenyl) methoxyimino) acetamido) cef-3-in-4-carboxylic acid or a salt, solvate (including hydrate) or metabolically labile ester Ρ non-toxic. - 5- - Process for the preparation of crystalline hydrate of (6R, 7R, 2'Z, S) -7- / 2- (2-aminothiazol-4-yl) -2 / (carboxy) (3,4-dihydroxyphenyl) methoxyimino) acetamido) cef-3-in-4-carboxylic acid characterized by preparing an aqueous solution of said compound or an acid or base addition salt or a solvate of said salt and crystallizing said hydrate from it . - 63 _ Process for the preparation of crystalline hydrate of (6R, 7R, 2'Z, 3) -7- / 2- (2-aminothiazol-4-yl) -2 - / (carboxy) (3,4-dihydroxyphenyl) methoxyimino / acetamido / cef-3-in-4-carboxylic acid characterized by preparing an aqueous solution of an acid or base addition salt of said compound or its solvate and adjusting the pH of said solution to values between 1, 0 and 4.0. process according to claim 5 or 6, characterized in that the product obtained has an infrared spectrum containing absorption bands at 3700-2100 wide, 1760, 1720, 1660, 1555, 1520, 1350, 1300, 1290,1240, 1215, 1170, 1155, 1120, 1030, 1000, 920, 860 and 755cm “ ¹ - 8th - Process according to claim 5 or 6, characterized in that the product obtained has an X-ray diffraction pattern (expressed as d-spacings in Ansgtrõm units and percentages of intensities) as follows: 12.5 (21; 9.97 (37); 9.51 (22); 6.79 (11); 6.33 (35); 5.29 (10); 4.76 (30); 4.63 (100) ; 4.39 (54); 4.32 (5); 4.18 (15); 4.09 (31); 3.91 (24); 3.78 (69); 3.69 (17); 3, 61 (9) 3.52 (12); 3.48 (21); 3.42 (6); 3.33 (37); 3.15 (36); 3.0 7 (22); 3.02 (4 ); 2.96 (36); 2.85 (9); 2.78 (3); 2.65 (11) 2.59 (49); 2.50 (6); 2.44 (9); 2.38 (6); 2.31 (3); 2.27 (4); 2.20 (5); 2.16 (9); 2.10 (10); 2.05 (4); 2.01 (9). - 9S - Process for the preparation of a pharmaceutical composition characterized in that one or more compounds of formula (la) as defined in claim 2 are incorporated as an active ingredient in association with a pharmaceutically acceptable carrier and / or excipient. - 10- - Process according to claim 9 characterized in that the active ingredient is composed as defined in claim 4.