HU201946B - Process for producing cefemcarboxylic acid derivatives and pharmaceutical compositions comprising same - 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 novel cephalosporin compounds and their derivatives and to pharmaceutical compositions containing them.

The novel cephalosporin compounds and their derivatives are valuable antibiotic compounds. 5

The cephalosporin compounds of the invention are referred to as cepham compounds according to J. Amer. Chem.

Soc., 1962,24,3400, and the term cefem refers to a cefam structure skeleton where there is a double bond. 10

Cephalosporin antibiotics are widely used in the treatment of diseases caused by human and animal pathogenic bacteria and are particularly useful in the treatment of diseases caused by bacteria resistant to other antibiotics and in the treatment of penicillin-resistant patients and penicillin-sensitive patients. In many cases, it is desirable to use cephalosporin antibiotics, which are active against Gram-positive and Gram-negative microorganisms, and have been the subject of considerable research to develop various types of broad-spectrum cephalosporin antibiotics.

For example, your own 1,399,086. U. S. Patent No. 6,198,125 discloses cephalosporin antibiotics containing a 7β- (α-etherified oxy minino) acylamido side chain, wherein the oximino group is of color configuration. This class of antibiotics exhibits a high degree of antibacterial activity against Gram-positive and Gram-negative microorganisms and exhibits a very high degree of stability against β-lactamases produced by various organisms.

The discovery of this group of compounds has led to further research in the same field, the purpose of which was to find compounds with better properties that act against a particular species of organism, particularly against Gramnegative organisms. This research is indicated by a number of patent applications directed to cephalosporin 40 antibiotics on the 7? -Acylamido side chain and the cephalosporin ring

They contain 3 substituents. For example, U.S. Patent No. 1,576,625. U. S. Patent Application No. 6,198,115 discloses cephalosporin antibiotics having a 7β- (α-etherified oximino) acylamido side chain, wherein the etherification group is an aliphatic hydrocarbon group which may contain suitable substituents (many of which include carboxylic acid). or a protected carboxyl group and a phenyl group substituted with up to three hydroxy groups) and this side chain is further substituted at the α-position by a group which may be, inter alia, an aminothiazolyl group. However, none of the exemplified compounds 55 contain a carboxyphenylalkyl etherification group. The 3-position group can also be diverse, but hydrogen is not included.

No. 1,604,971. U. S. Patent No. 60 also describes a number of cephalosporin antibiotics in general, wherein the 7-position side chain may be, inter alia, 2- (2-aminothiazol-4-yl) -2- (etherified oximino) acetamido, wherein the etherification group can be an alkyl group of many different meanings, for example 65 methyl groups substituted by phenyl and carboxy but not exemplified by carboxyphenylalkyl, and the preferred etherification group is unsubstituted methyl. There are also many examples of the 3-position group and the three substituents include hydrogen.

No. 2,017,702. In U. S. Patent Nos. 6,268, the oximino etherification group may include, but is not limited to, α-carboxyphenylmethyl. Among the compounds mentioned by way of example, the carboxyphenylmethyl group is always combined with an acetoxymethyl group at the 3-position.

No. 2,104,888. U. S. Patent No. 6,102,125 discloses cephalosporin antibiotics which are the 2- (2-amino-thiazol-4-yl) -2- (etherified oximino) -acetamido group at the β-position 7. The oximino etherification group may be, among others, a carboxyphenylmethyl group in which the phenyl group may be substituted by a hydroxyl group. The 3-position is an isothiazolylthiomethyl or iminoalkylidene diethane.

In 197,409. European Patent Application EP-A-004123 discloses cephalosporin antibiotics in which the 7β-side chain is 2- (2-aminothiazol-4-yl) -2- (etherified oximino) acetamido. The oximino etherification group may include, but is not limited to, catecholcarboxymethyloxyimino. The 3-position substituent can have many meanings but does not include hydrogen.

It has been found that when (Z) -2- (2-aminothiazol-4-yl) -2- (etherified oximino) acetamido is combined at the 7β-position with a hydrogen atom at the 3-position and when etherified as an oximino group If an α-carboxy-substituted phenylmethoxyimino group is selected, the resulting cephalosporin compounds have a particularly beneficial effect against a broad spectrum of conventional pathogenic organisms and / or may be used as intermediates for the preparation of other active ingredients.

Thus, the present invention provides novel cephalosporin compounds of formula Ia wherein:

R ^4a and R ^5a are hydroxy - the invention further relates to the preparation of non-toxic salts and solvates, in particular hydrates and metabolically labile esters thereof.

Compounds of formula (I) are prepared by reacting a compound of formula (Π) wherein

R is a carboxyl protecting group, r3 is a hydrogen atom or an amino protecting group,

R ⁴ and R are acylated with a hydroxy or protected hydroxy group or together form a cyclic protected diol group or a salt thereof or a suitable acylation derivative of a compound of formula (ΙΠ), preferably an acid halide, a symmetric or mixed anhydride or an activated ester; optionally performing any of the following reactions in any order:

i) optionally esterifying the carboxyl group to a non-toxic metabolically labile ester group, ii) optionally, a non-toxic salt or solvate with a base or acid, iii) removing the carboxyl protecting group optionally present and / or N-protecting groups; ) removing any hydroxyl protecting groups that may be present.

In the compounds of formula (Π) and (ΠΙ), where R ¹ and / or R ^z is a carboxyl protecting group, the protecting group may be, for example, an ester-forming aliphatic or araliphatic alcohol residue or an ester-forming phenol, silanol or stannalol residue (alcohol, phenol, silanol or stannanol (preferably 1-20 carbon atoms) or a symmetric or mixed anhydride protecting group derived from the corresponding acid. R ¹ or R ^{2 are} particularly preferably t-butyl, diphenylmethyl or p-nitrobenzyl.

When R ^{3 in} formula (ΠΙ) is an amino protecting group, the protecting group may be, for example, a C 7-20 aralkyl group such as triphenylmethyl or 4-methoxybenzyl, an acyl group such as optionally substituted C 1-6 alkanoyl such as formyl. or a chloroacetyl group or an optionally substituted C 1 -C 6 alkoxycarbonyl group such as tert-butoxycarbonyl or 2,2,2-trichloroethoxycarbonyl or a C 7 -C 10 aralkoxycarbonyl group; a group such as benzyloxycarbonyl or a silyl group such as trimethylsilyl.

When R ⁴ or R ^{5 represents a} substituted hydroxy group, it may be, for example, an acyloxy group such as formyloxy group or OCOR ⁶ - wherein R 0 is a C 1 -C 8 alkyl group such as methyl, -OCO ² R ⁶ - wherein ^R6 is as defined above butyldimethylsilyloxy group such as a trimethylsilyl group or a tert-butyl dimethyl silyloxy group or OB / oR ⁷⁾ 2 or borate opioid) ^(OR7) 2 represented by the formula phosphate, wherein R ^{7 is C} 1 -C 4 alkyl.

If ^R4 and ^R5 form together a cyclic diol groups is protected, it may be an alkylidene dioxy, preferably 1-20 carbon atoms, such as methylenedioxy, ethylenedioxy or isopropylidenedioxy radical, containing one or more substituents such as phenyl, It may have a C 14 alkoxy or oxo substituent, such as methoxymethylenedioxy, diphenylmethyloxy or carbonyl dioxyl, a cyclic borate group such as -OB (OH) O, a cyclic phosphate group such as -OP (O) (OH) O- or O £ (O) (OR ⁷ ) O- wherein R 'is the above or cyclic silyl ether group, for example di (C 1-4 alkyl) silyloxy; for example dimethylsilyldioxy.

In general, such silyloxy, borate or phosphate groups are protected hydroxy groups which are cleaved to give the free compound of formula (I).

In general, R ⁴ and R 0 are preferably acetoxy, especially hydroxy.

Particularly preferred are cef-3-em compounds of the invention.

When the compound is used in medicine, the carboxylic esters are preferably non-toxic, metabolically labile ester derivatives. By way of example, non-toxic metabolically labile ester derivatives include acyloxyalkyl esters, such as lower alanyloxymethyl or ethyl esters, such as acetoxymethyl or ethyl or pivaloyloxymethyl or alkoxycarbonyl. ethyl esters such as lower alkoxycarbonyloxyethyl esters such as ethoxycarbonyloxyethyl.

In addition to the above ester derivatives, the process of the invention encompasses other physiologically acceptable equivalents, such as physiologically acceptable compounds, which are converted in vivo to the antibiotics of the invention, such as metabolically labile esters.

Non-toxic salts of carboxyl groups in the compounds of formula (Ia) include inorganic basic salts such as alkali metal salts such as sodium and potassium salts and alkaline earth metal salts such as calcium salts, amino acid salts such as lysine and arginine salts, organic base salts, e.g. ethylbenzylamine, dibenzylethylenediamine, ethanolamine, diethanolamine and N-methylglucosamine salts. Non-toxic salt derivatives also include acid addition salts such as those with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid and trifluoroacetic acids. Salts may also be in the form of resins formed with, for example, polystyrene resins or cross-linked polystyrene divinylbenzene copolymer resins containing amino or quaternary amino groups or sulfonic acid groups, or resins containing carboxyl groups such as polyacrylic acid resins. Soluble basic salts, such as alkali metal salts, such as sodium salts, are readily used in pharmaceutical applications because such salts are rapidly distributed throughout the body after administration. However, when insoluble salts of the compounds of formula (Ia) are required for certain applications, such as delayed-release formulations, such salts may be formed by conventional methods, for example, with the appropriate organic amines.

The compounds of the present invention are color isomers. The color isomeric form is characterized by the configuration of formula (I) relative to the carboxamido group. In this specification, the color configuration is structurally represented by formula (2). Since the compounds of the present invention are geometric isomers, certain mixtures occur with the corresponding anti-isomer.

Since the carbon atom adjacent to the oxy group in the oxime etherification group is asymmetric, it may occur in the R or S configuration. The invention also relates to the preparation of R and S forms, including diastereomeric mixtures. In general, compounds of formula (Ia) are those having the S configuration and the S isomeric configuration which dominates the R / S mixtures.

The compounds of the present invention exist in tautomeric forms, such as, for example, with respect to the 2-aminothiazolyl group, and it is naturally within the scope of the invention to prepare tautomeric forms, such as the 2-iminothiazolyl form.

As mentioned above, the compounds of the present invention are active against a broad spectrum of pathogenic organisms and / or are useful as intermediates in the preparation of other agents. usually

-3HU 201946Β when the compounds are used as intermediates / (the compound B /, R ^r and R ^z carboxyl represents a protecting group of formula, R ³ is often an amino protecting group and R ⁴ and R ⁵ are protected hydroxy, such as silyloxy, borate or phosphate group or together form a cyclic protected diol group Non-toxic derivatives of R ⁴ and / or R ⁵ containing acyloxy groups such as acetoxy may be used as intermediates.

Particularly preferred is (6R, 7R, 2'Z, S) -7- [2- (2-aminothiazol-4-yl) -2 - [(carboxyl) - (3,4-dihydroxy) phenylmethoxyimino] -acetamido] -aceph-3-em-4-carboxylic acid and non-toxic salts, solvates, hydrates and metabolically labile esters of this compound.

It has been found that (6R, 7R, 2'Z, S) -7- [2- (2-aminothiazol-4-yl) -2 - [(carboxy) - (3,4-dihydroxyphenyl) -methoxyimino] -acetamido] -ephr-3-em-4-carboxylic acid is preferably prepared and isolated in a highly pure crystalline form, especially the crystalline hydrate form of the above compound. This new material is not only advantageous in terms of crystallinity and enhanced purity, but can be produced with good production and exhibits enhanced stability during long term storage at high temperatures. These properties of the crystalline material make the compound particularly suitable for medical use.

The above hydrate crystalline material is characterized by infrared spectrum and / or X-ray powder diffraction:

IR (Nujol) v _H x 3700-2100 (br), 1760, 1720, 1660, 1555, 1520, 1350, 1300, 1290 1240, 1215, 1170, 1155, 1120, 1030, 1000, 920, 865 and 755 cm ' ¹ .

X-ray diffraction pattern (d intervals in Angstrom units and% intensity in I: 12.5 (21); 9.97 (37); 9.51 (22); 6.79 (11);

6.3 (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 (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).

The compounds of the present invention exhibit a broad spectrum antibiotic activity against Gram-positive and Gram-negative organisms, including many β-lactamase producing strains. The compounds also exhibit a high degree of stability against β-lactamases produced by Gram-negative and Gram-positive organisms. The compounds of the present invention have been found to be active against the following Gram-positive strains, including penicillinase producing strains, such as Staphylococcus aureus, Staphylococcus epidermidis and Sterptococcus species. This is coupled with excellent activity and high activity against Pseudomonas species against various members of the Enterobactericeae, for example (Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus myrabilis strains and indole-positive Proteus v. and Haemophilus influenzae and Acinetobacter calcoaceticus strains .This high level of activity against Gram-positive organisms and Gram-negative organisms in particular against Pseudomonas is extremely and particularly beneficial.

The cephalosporin derivatives of the present invention exhibit a long serum elimination half-life in vivo.

The compounds of the present invention can be used to treat a variety of diseases caused by human and animal pathogenic bacteria, such as respiratory tract infections and urinary tract infections.

The antibiotic compounds of the present invention may be formulated in any suitable form for administration by analogy to other antibiotics and, therefore, the invention also relates to the manufacture of a pharmaceutical composition comprising the antibiotic of the present invention as an active ingredient for human or veterinary use. Conventional pharmaceutical carriers or excipients may be used for this purpose.

The antibiotics of the invention may be formulated in injection and unit dosage forms, in ampoules, or in multidose containers, optionally with the addition of a preservative. The formulations may be formulated as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and / or dispersing agents. The active ingredient may also be formulated as a powder which is then mixed with a suitable vehicle, for example sterile pyrogen-free water, before use.

If desired, such powder formulations may also contain a suitable non-toxic base to improve the water solubility of the active ingredient and / or to ensure that when the powder is dissolved in water, the pH of the resulting aqueous formulation is physiologically acceptable. Alternatively, the base may be present in water, which is then dissolved in the powder. The base may be, for example, an inorganic base such as sodium carbonate, sodium bicarbonate, sodium acetate or an organic base such as lysine or lysine acetate. The composition may be formulated for absorption from the gastrointestinal tract, for example, in the form of tablets, capsules, syrups or suspensions for oral administration and in the form of suppositories.

For example, the veterinary compositions may be formulated in a ready-to-use form in mammals in sustained or rapidly absorbable bases.

The composition may contain at least 0.1%, for example 0.1-99%, of the active ingredient, depending on the route of administration. When the composition is in unit dosage forms, each unit will preferably contain from 100 to 3000 mg, for example from 200 to 2000 mg, of the active ingredient. The daily adult dose for human treatment is preferably 200 to 12000 mg, for example 1000 to 9000 mg per day, depending, inter alia, on the type of infection and the mode and frequency of administration. Generally, intravenous or intramuscular administration of 400 to 4000 mg of the active ingredient is administered to adult patients. In some cases, for example, lower dosage units and daily doses of 4HU 201946Β may be desirable for newborns.

The antibiotics of the invention may be administered in combination with other active ingredients, such as antibiotics such as penicillins, cephalosporins or other β-lactam compounds. According to the invention, the novel compounds can be prepared by a number of processes.

Thus, the compounds of formula (Ia) and their non-toxic salts, solvates or hydrates may be prepared by reacting a compound of formula (Π) wherein R ¹ is a carboxyl protecting group, or an acid addition salt thereof with mineral acid, hydrochloric acid, hydrobromic acid, or a 7-N-silyl derivative thereof with phosphoric acid or an organic acid such as methanesulfonic acid or paratoluenesulfonic acid, wherein the carboxyl protecting group,

R 4 is hydrogen or an amino protecting group,

R ⁴ and R ^{4 are} hydroxylated or protected together or form a cyclic protected diol - or a salt thereof, or an acylating derivative of a compound of formula (ΙΠ), preferably an acid halide, a symmetric or mixed anhydride or an activated ester and or, if desired, carrying out any of the following reactions in any order:

i) optionally esterifying the carboxyl group to a non-toxic metabolically labile ester group, ii) optionally forming a non-toxic salt or solvate with a base or acid, iii) removing the carboxyl protecting group and / or N-protecting groups, if present, and iv) optionally, the hydroxyl protecting groups present are removed.

The reactions i) to ar) may be carried out in a known manner. The acylating agent used in the preparation of the compounds of formula (Ia) is an acid halide, in particular acid chloride or bromide. Such acylating agents may be prepared by reacting an acid or salt of the general formula (ΙΠ) with a halogenating agent such as phosphorus oxychloride, thionyl chloride or oxalyl chloride.

Acylation using acid halides may be carried out in an aqueous or anhydrous medium at a temperature of -50 to +50, preferably -40 to (+30) 'C, optionally in the presence of an acid acceptor. Suitable reaction media are, for example, aqueous ketones such as aqueous acetone, aqueous alcohol such as aqueous ethanol, esters such as ethyl acetate, halogenated hydrocarbons such as methylene chloride, amides such as dimethylacetamide, nitriles such as acetonitrile or a mixture of two or three such solvents. Suitable binders include tertiary amines such as triethylamine or dimethylaniline, inorganic bases such as calcium carbonate or sodium bicarbonate and oxiranes such as lower 1,2-alkylene oxides such as ethylene oxide or propylene oxide. These compounds bind the hydrogen halide liberated during the acylation reaction.

The acids of formula (ΙΠ) may be used as acylating agents in the preparation of compounds of formula (Ia). Acylations employing acids of formula (ΙΠ) are desirable condensing agents such as carbodiimide such as N, N'-dicyclohexycarbodiimide or N-ethyl-N '- N -dimethylaminopropylcarbodiimide, a carbonyl compound such as carbonyldiimidazole or isoxazolium salts, e.g. N-ethyl-5-phenylisoxazolium perldorate or N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline.

The acylation can also be carried out with an amide-forming derivative of the acids of formula (ΙΠ), for example an activated ester, a symmetric anhydride or a mixed anhydride such as pivalic acid or a mixed alkyl anhydride with chloroformic acid. The mixed anhydrides may also be formed with phosphoric acids such as phosphoric or phosphoric acids, sulfuric acid or aliphatic or aromatic sulfonic acids such as paratoluenesulfonic acid. An activated ester may also be formed in situ, for example using 1-hydroxybenzotriazole in the presence of one of the condensing agents listed above. Alternatively, the activated ester may be preformed.

The acylation reactions using the free acids or the amide-forming derivatives listed above may be carried out, if desired, in anhydrous media such as methylene chloride, tetrahydrofuran, dimethylformamide, acetonitrile, dimethylacetamide or dimethylsulfoxide.

Another method of activation is, for example, by reacting an acid of formula (ΙΠ) with a pre-formed solution or suspension by adding a carbonyl halide, especially oxalyl chloride, or phosgene, or a phosphoryl halide, such as phosphorus oxychloride, to a solvent such as halogenated hydrocarbon, e.g. chloride containing a lower acyl tertiary amide such as N, N-dimethylformamide. The activated form of the acid of formula (Π) is then reacted with the 7-amino compound of formula (Π) in a suitable solvent or solvent mixture such as a halogenated hydrocarbon such as dichloromethane, alcohols such as alkanol such as ethanol or industrial methylated alcohol, esters e.g. in ethyl acetate, ethers such as tetrahydrofuran or dioxane, ketones such as acetone, amides such as dimethylacetamide, acetonitrile, water and mixtures thereof. The acylation reaction can be carried out at -50 to +50, preferably -40 to + 30 'C, if desired in the presence of an acid acceptor such as those described above, for example dimethylaniline, triethylamine or sodium bicarbonate.

If desired, the above acylation reaction may also be carried out in the presence of a catalyst, for example 4-dimethylaminopyridine. The acids of general formula (ΙΠ) and the corresponding acylating agents may also be prepared and used, if desired, in the source of their acid addition salts. For example, acid chlorides, hydrochloride salts and acid bromides in the form of hydrobromic salts may be used. The starting material for the preparation of the compounds of formula (Ia) is the compound of formula (I) and its amide-forming derivatives, such as acid halides and anhydrides, preferably in the form of their color isomers or their color isomers.

-5HU201946Β in the form of a mixture of ders and the corresponding anti-isomers containing at least 90% of the color isomer.

The acids and derivatives of formula (hat) can be prepared by etherification of compounds of formula (IV) (wherein R ³ is as defined above and R ⁸ is hydrogen or carboxyl protecting group) or a salt thereof is selectively reacted with a compound of formula V is a chlorine, bromine or iodine atom, or a sulfate group, or a sulfonate group such as tosylate, followed by removal of the R 0 carboxyl protecting groups.

The etherification reaction is carried out in the presence of a base such as potassium carbonate or sodium hydride, preferably in an organic solvent such as dimethyl sulfoxide, a cyclic ether such as tetrahydrofuran or dioxane or an N, N-disubstituted amide such as dimethylformamide.

Separation of the isomers may be carried out before or after etherification, under the conditions described above, the configuration of the oximino group does not substantially change during the etherification reaction.

When the compound (TV) is used in the form of the free acid or its base salt, the etherification reaction is usually carried out in the presence of a strong base, such as potassium tert-butoxide, and sufficient base is added to form the dianion. The re10 action must be carried out in the presence of a base, so that when the acid addition salt of the compound of formula (TV) is used, the base must be sufficient to rapidly neutralize the acid in question.

The acid of formula (ΙΠ) may also be prepared by reacting a compound of formula (VI), wherein R ³ and R are as defined above, with a compound of formula (VB) wherein R ² , R 4 and R ⁵ are as defined above, and then removing the R ⁸ carboxyl protecting groups and, if necessary, separating the color and anti isomers. The reaction is usually carried out in a solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran or methanol, optionally in the presence of water at a temperature of -20 to + 50 ° C, preferably 0 to 30 ° C.

The acids of formula (ΙΠ) can be converted into the corresponding acid halides and anhydrides and acid addition salts by conventional means.

The intermediates of formula (VII) may be prepared by reacting a compound of formula (VHI) wherein Y is an imido group such as phthalimido, succinimido or maleimido, with a hydrazine such as hydrazine hydrate or an alkyl hydrazine such as methyl hydrazine. The reaction is usually carried out in an inert solvent such as a halogenated hydrocarbon such as methylene chloride at a low end temperature such as -70 to + 30'C.

The intermediates of formula (VHI) may be prepared by alkylation of a suitable N-hydroxyimide, such as N-hydroxyphthalimide, N-hydroxysuccinimide or Nhydroxy-maleimide, wherein Hal is a halogen atom such as a chlorine or bromine base. in the presence of, for example, triethylamine in a solvent such as acetonitrile, for example at -10 to + 30 ° C.

The intermediates of formula (IX) are known compounds or may be prepared by analogy to the preparation of known compounds.

Starting materials of the formula (H) are known, for example, from U.S. Patent No. 2,159,817. British Patent Application Ser.

The metabolically labile ester derivatives of formula (Ia) may be prepared from the compounds of formula (Ia) or their salts or protected derivatives with a suitable esterifying agent such as acyloxyalkyl halide or alkoxycarbonyloxyalkyl halide, e.g. formamide or acetone, followed by deprotection if desired.

The basic salts of the compounds of formula (Ia) are prepared from the acid of formula (Ia) and the corresponding base. For example, the sodium or potassium salt may be prepared using the appropriate acetate, 2-ethylhexanoate or bicarbonate salt. The acid addition salts are prepared by reacting a compound of formula (Ia) or a metabolically labile ester derivative with the corresponding acid.

When the compound of formula (Ia) is obtained at the source of a mixture of isomers, the color isomer is separated, for example, by a known method such as crystallization or chromatography. In the above transformations, it may be necessary to protect sensitive groups to avoid unwanted side reactions. Protective groups can be found, for example, in Theodora W. Greene (John Wiley and Sons, 1981) in Protective Groups in Organic Synthesis. In the above reaction, it may be necessary to protect the NH 2 group in the aminothiazolyl group, for example by tritylation, acylation (e.g., chloroacetylation or formylation), protonation or other known methods. The protecting group may then be removed in a manner known per se so that the desired compound is not degraded. For example, in the case of trityl, a halogenated carboxylic acid such as acetic acid, formic acid, chloroacetic acid or trifluoroacetic acid or a mineral acid such as hydrochloric acid or a mixture of such acids is used, preferably in the presence of a protic solvent such as water.

Similarly, the hydroxyl groups of the catechin group need to be protected in the above reaction sequence. Usually, acetyl or silyl is used as the hydroxy protecting group which can be removed under mild conditions. The introduction of such groups may be effected in a known manner, optionally removed so as not to decompose the product. For example, in the case of the acetyl group, the removal can be effected by solvolysis in 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 carbamate. For example, a trimethylsilyl group may be cleaved by treatment with dilute aqueous acid.

The carboxyl protecting groups used in the preparation of the compounds of formula (Ia) or in the preparation of the starting material are easily cleavable groups at the appropriate step, usually the last

-6EN201946Β step. However, in some cases, it may be necessary to use a non-toxic metabolically labile carboxy protecting group, such as an acyloxymethyl or ethyl group, such as an acyloxymethyl or ethyl or pivaloyloxymethyl group, to retain the ester derivative of formula (Ia).

Carboxyl protecting groups are known in the literature, and a list of protected carboxyl groups can be found in 1,399,086. U. S. Patent No. 4,466,198. Preferred protected carboxyl groups include aryl, lower alkoxycarbonyl groups such as parmethoxy, benzyloxycarbonyl, para-nitrobenzyloxycarbonyl and diphenylmethoxycarbonyl, and lower alkoxycarbonyl groups. such as t-butoxycarbonyl, lower haloalkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl. The carboxyl protecting group may be subsequently removed by any of the methods described in the literature, such as acid catalyzed hydrolysis or reduction such as enzyme catalyzed hydrolysis.

When a particular enantiomer of formula (Ia) is desired, the starting material of the desired stereochemically configuration is used in the above procedures. These intermediates may be prepared by known resolution techniques. For example, the enantiomeric intermediates of formula (VIII) wherein R ² is hydrogen and wherein the asymmetric carbon is in the R or S configuration are obtained by reaction of the enantiomeric mixtures with a resolving agent such as an asymmetric organic base such as R (+) - a-methyl. benzylamine is used in a solvent such as acetone or acetonitrile to give the corresponding diastereomeric salts. The salts are then isolated in a known manner and the desired asymmetric intermediate (VEI) is obtained by treatment with aqueous acid such as aqueous hydrochloric acid, for example at room temperature.

Crystalline (6R, 7R, 2'Z, S) -7- [2- (2-Aminothiazol-4-yl) -2 - [(carboxy) - (3,4-dihydroxyphenyl) methoxy] -imino] -acetamido] -ceph-3-em-4-carboxylic acid and its hydrate may be prepared from an aqueous solution or solvate of the above cephalosporin salt.

According to another embodiment of the process of the present invention, crystalline hydrated (6R, 7R, 2'Z, S) -7- [2- (2-aminothiazol-4-yl) -2 - [(carboxyl) - ( , 4-Dihydroxy-phenyl) -methoxyimino] -acetamido] -ceph-3-em-4-carboxylic acid by crystallizing the acid from an aqueous solution, preferably from the aqueous solution of the acid addition or basic salt or solvate thereof, to obtain the desired crystalline hydrates. product. After crystallization, the product is isolated and dried.

Base salts include, for example, inorganic basic salts, such as alkali metal salts and alkaline earth metal salts and organic basic salts, the list of which is given above.

A particularly suitable basic salt is the sodium salt.

The starting acid addition salts may be formed with organic or inorganic acids. Organic acids include carboxylic and sulfonic acids such as formic acid, trifluoroacetic acid and methanesulfonic acid. Inorganic acids include mineral salts such as hydrochloric acid, hydrobromic acid or sulfuric acid.

In another embodiment, the desired material is (6R, 7R, 2'Z, S) -7- [2- (2-aminothiazol-4-yl) 2 - [(carboxy) - (3,4-dihydroxy) phenylmethoxy-amino] -azetamido] -ceph-3-em-4-carboxylic acid may also be prepared by crystallization of its acid or base salt or solvate in an aqueous medium by adjusting the pH to 1-4. For example, the hydrate may be crystallized from an aqueous solution of a basic salt by the addition of an organic or inorganic acid so as to adjust the pH to the above limits. Suitable acids for the crystallization are, for example, hydrochloric acid or sulfuric acid. Alternatively, the desired hydrate is crystallized from an aqueous solution of the acid addition salt by adding an organic or inorganic base to obtain the desired pH. The base may be, for example, an alkali metal or alkaline earth metal hydroxide, carbonate, bicarbonate or acetate, such as sodium hydroxide, sodium carbonate, sodium bicarbonate or sodium acetate. The aqueous medium may contain a water-miscible organic solvent such as an alcohol such as ethanol or isopropanol, an ether such as tetrahydrofuran or dioxane, an amide such as Ν, Ν-dimethylformamide or Ν, Ν-dimethylacetamide, a ketone such as acetone or nitrile, for example acetonitrile. The crystallization is carried out, if desired, at room temperature, for example 0-30 ° C. The crystalline product may be recovered by filtration, washed in a conventional manner and dried, for example, air-dried or carefully dried under reduced pressure.

The following examples further illustrate the invention. Temperatures are in 'C,' the Nujol and Sorbs trademarks Sorbsil U30 Joseph Crosfield and Són of Warrington, Cheshire, UK. NMR spectra were measured in DMSO-db X-ray measurements were performed on a Siemens D-500 diffractometer using CuK ^a radiation. X-ray intensities were measured at 0.02 'increments at 20 increments of 5 seconds and a scintillation counter was used between 2' and 90 '. The results were stored on a computer for processing.

Intermediate 1

2- (3,4-Dioxocarbonylphenyl) -2- (phthalimidoyloxy) -acetic acid

A solution of 14.6 g of N-hydroxyphthalimide and 25 ml of triethylamine in 50 ml of acetonitrile is added.

To a stirred suspension of 20.5 g of 2- (3,4-dioxycarbonylphenyl) -2-chloroacetic acid in acetonitrile at 2 'C for 20 minutes. After 1 hour at 0 'C, a solution of 7.5 ml of concentrated hydrochloric acid in 100 ml of water was added rapidly. Water (100 mL) was added slowly and the initial oil which liberated crystallized after the addition of seed crystals. The mixture was filtered, and the filter cake was washed with water and ethyl acetate / petroleum ether (b.p. 40-60 ° C) 1: 2, dried to give 30 g of the title compound. Mp 183-185 ° C.

δ 5.84 (s, OCH), 7.53 (s, catechin 5-H and 6-H), 7.69 (s, catechin 2-H), and 7.85 (s, phthalimido protons).

-7HU 201946 Β

Intermediate 2 (R) - (+) -? -Methylbenzylamine salt of (a) (S) -2- (3,4-dioxycarbonylphenyl) -2- (phthalimidoyloxy) acetic acid

A solution of R - (+) -? - 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 L) at N2. After 30 minutes, the mixture was filtered and the precipitate was washed well with acetone to give 16.57 g of the title compound.

[α] ²¹ D + 242 '(cl, 07, EtOH);

δ 1.46 (d, J 7Hz, CH 3 CH), 5.48 (s, OCH), 7.3-7.6 (m, aromatic protons) and 7.80 (s, phthalimido protons).

(b) (S) -2- (3,4-Dioxocarbonylphenyl) -2- (phthalimidoyloxy) diphenylmethylacetate 2 ml hydrochloric acid (5 g) Intermediate 2 (a) (5 g) in 30 ml slurry in water under nitrogen at 21 ° C. After 2 minutes, a solution of 1 equivalent of diphenyl diazomethane in 11 ml of methylene chloride was added. After stirring vigorously for 35 minutes, the organic phase was separated and added dropwise to 150 ml of mixed ethanol. The mixture is stirred at 21 'C for 10 minutes and then stored at 4' C for 1 hour. The crystals were filtered off, washed with ethanol and dried to give 3.59 g of the title compound. M.p. 135135,5'C.

[a] ² d + 112.6 ° (C 1.18, ethyl acetate).

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

Intermediate 2 (b) (5.71 g) was stirred in methanol (390 ml) with 1 mol of hydrochloric acid (5.5 ml) for ca. At 40 'C for 4.5 hours. The solution was evaporated and mixed with methylene chloride. Wash twice with water, dry over magnesium sulfate and evaporate to a foam. This foam was dissolved in methylene chloride (176 mL) and the resulting solution was cooled to -50 ° C with stirring under a stream of nitrogen and 1.5 mL of hydrazine hydrate was added. The mixture was allowed to slowly warm to 21 ° C and stirred. After 5.75 hours, the mixture is filtered and the cake is leached with methylene chloride. The combined filtrates were diluted with ethyl acetate and washed with citric acid and brine. After drying over magnesium sulfate, evaporation to give 4.53 g of the title compound as a foam.

[?] d 17,8 '(c 1.03, methanol); δ 5.02 (s, OCHCO), 6.68 and 6.81 (m, thiazole H,

OCH and catechin protons), 7.1-7.4 (m, aromatic protons), 9.04 (s, OH).

Intermediate 4 (Z, S) -2- (2-Aminothiazol-4-yl) -2 - [(3,4-dihydroxyphenyl) (diphenylmethoxycarbonyl) methoxyimino] -acetic acid

2- (2-Aminothiazol-4-yl) -glyoxylic acid (1.91 g) is added over 3 minutes to a solution of Intermediate 3 (4.2 g) in N, N-dimethylformamide (22 ml) at 3 ° C with stirring. After cooling for a further 30 minutes with ice water, the solution was allowed to warm to 21 ° C for 1.5 hours and then added dropwise to 110 g of ice water with stirring for 20 minutes. The precipitate was filtered off, washed with water and dried. It was resuspended in methylene chloride (45 mL) and stirred for 15 minutes and then filtered. The filter cake was washed with methylene chloride and dried. 3.76 g of the title compound are obtained.

[α] ²¹ D + 25.4 '(c 1.02, methanol); δ 5.59 (s, OCHCO), 6.6-6.9 (m, thiazole H, OCH and catechin protons), 7.0-7.5 (m, NH2 and phenyl protons), and 9.06 and 9 , 13 (2s, OH).

Intermediate 5 (Z, S) -2- (2-formamidothiazol-4-yl) -2 - [(3,4-dihydroxyphenyl) (diphenylmethoxycarbonyl) methoxyminone] ] acetic acid

6.96 g of 2- (2-formamidothiazol-4-yl) glyoxylic acid are added 12.73 g of [(3,4-dihydroxyphenyl) (diphenylmethoxycarbonyl)] methoxyamine in 100 ml of N, N solution of -dime20 in ethyl formamide at room temperature. After 1.5 hours another 40 ml of N, N-dimethylformamide was added and after 2.5 hours the resulting solution was poured into 700 ml of water. The product was extracted with ethyl acetate (3 x 250 mL).

The combined extracts were washed with water (2 x 250 mL), dried over magnesium sulfate and evaporated to a solid. This was treated with ethyl acetate (20 mL) followed by dichloromethane (200 mL) to give a suspension, after cooling the solid was filtered off, washed with dichloromethane and dried. 11.38 g of the title compound are obtained, m.p. 125127C.

[?] D +22.2 '(c 0.99, methanol).

Example 1 (6R, 7R, 2'Z, S) -7- [2- (2-Aminothiazol-4-yl) -2 - [(3,4-dihydroxyphenyl) - (diphenylmethoxy) carbonyl) -methoxyimino] -acetamido] -ceph-3-em-4-diphenylmethylcarboxylate

The tosylate salt of (6R, 7R) -7-aminoceph-3-em-4-diphenylethylcarboxylate (1.24 g) is converted into the free amine by extraction with ethylene chloride and aqueous sodium bicarbonate. The organic layer was washed with water and dried over magnesium sulfate. After evaporation, the foam was mixed with Intermediate 4 in 25 mL of tetrahydrofuran with stirring and 830 mL of N, N'-dicyclohexylcarbodiimide and 290 mg of hydroxybenzyltriazole hydrate were added. After stirring at 21 'C for 16 hours, the mixture was filtered and the filter cake was leached with ethyl acetate. The combined organic solutions were evaporated and the resulting foam was re-seeded in ethyl acetate and filtered through a column containing 100 g of Sorbsil U30 in ethyl acetate. Evaporation of the appropriate eluate gave the crude product which was dissolved in chloroform and applied to a 100 g column of Sorbsil U30 in chloroform. The column was eluted with chloroform and eluted with 1%, 2% and 3% methanol in chloroform. The appropriate eluate was evaporated to give the title product as a foam (800 mg).

[α] ²¹ D +36.25 '(c 1.17, DMSO); , ₉

Xinfl (EtOH) 230.8 (E ^1% _C 303), 290 (E 1 cm.)

117) and 300.4 nm ^(I% i 84 cm).

-8HU 201946Β

Example 2 (6R, 7R, 2'Z, S) -7- [2- (2-Aminothiazol-4-yl) -2 - [(carboxy) - (3,4-dihydroxyphenyl) methoxy] imino] -ac etamido] -cef-3-em-4-carboxylic acid, trifluoroacetic acid salt

740 mg of the compound of Example 1 are mixed with 1.5 ml of anisole and 7.5 ml of trifluoroacetic acid are added. After 1 minute, 50 ml of diisopropyl ether are added, the precipitate is filtered off, washed with diisopropyl ether and dried in vacuo. 450 mg of the title compound are obtained.

[ ^α ] ²⁵ D + 102.8 ° (c 0.88, DMOS):

kinfl (pH6 buffer) 236.8 nm (cm j cm 335), kinfl

250.0 (E1 ^% cm 257), 277.4 (E1 ^% _cm 173) and 296.0 nm (E * _cm @ 139).

Example 3 (6R, 7R, 2'Z, S) -7- [2- (2-Aminothiazol-4-yl) -2 - [(carboxy) - (3,4-dihydroxyphenyl) - (diphenyl) -methoxy-arbonyl) -methoxyimino] -acetamido] -cef-3-em-4-diphenylmethyl carboxylate

Intermediate 5 (1.2 g) was suspended in methylene chloride (20 mL) under a stream of nitrogen with stirring and N, N-dimethylacetamide (4 mL) was added. The solution was cooled to -25 ° C and 0.28 mL of phosphorus oxychloride was added. After stirring for 1 hour at -25 to -20 ° C, a solution of (6R, 7R) -7-aminoceph-3-em-4-diphenylmethylcarboxylate (1.35 g) in methylene chloride (20 ml) was added. Containing Ν-dimethylaniline and the carboxylate is obtained from the tosylate salt and sodium bicarbonate solution. The solution was kept at -10 ° C and cooled with ice water, stirring for 1.75 hours. The mixture was washed with sodium bicarbonate solution, dilute hydrochloric acid and water three times in succession and in each case the aqueous layers were extracted with methylene chloride. The combined organic layers were dried over magnesium sulfate and evaporated. The crude product was taken up in methylene chloride at 40-60 ° C in 40% ethyl acetate in 2% acetic acid. The appropriate eluate was evaporated to give 1.56 g of the title compound.

[?] d +36.2 '(c 1.05, DMSO);

Λmax (EtOH) 269.2 nm ( ^1% _cm 184), λίπΠ 232.0 (E * 1 cm 285), 260.4 ( ^Γ% ι cm 179), and 266.8 nm (Extern 183).

Example 4 (6R, 7R, 2'Z, S) -7- [2- (2-Aminothiazol-4-yl) -2 - [(carboxy) - (3,4-dihydroxyphenyl) - (diphenyl) -methoxy-aronyl) -methoxyimino] -acetamido] -ceph-3-em-4-diphenylmethyl carboxylate

1.5 g of the compound of Example 3 are mixed with 15 ml of methanol at 21 ° C and 1 ml of 60% perchloric acid is added. After 2.5 hours, the solution was partitioned between water and ethyl acetate and cautiously added with excess sodium bicarbonate as a solution. The aqueous phase was extracted with more ethyl acetate and the combined organic phases were washed twice with saturated brine, dried over magnesium sulfate and evaporated to afford 1.34 g of the title compound [a] ² ~ d + 36.5 ° (c 0.96 , DMSO);

Umax (Nujol) 3600-3100 (wide, 1785, 1730 and 1680 cm ').

Example 5 (6R, 7R, 2'Z, S) -7- [2- (2-Aminothiazol-4-yl) -2 - [(carboxy) - (3,4-dihydroxyphenyl) methoxy] Sodium salt of imino] -ac etamido] -ceph-3-em-4-carboxylic acid Example 2 was dissolved in 110 ml of ethanol with stirring at 21 ° C and 4.8 ml of saturated sodium acetate solution was added after 10 minutes. The mixture was filtered and the cake was washed with four volumes of ethanol and then washed four times with ether and dried in vacuo to give 5.45 g of the title compound. After addition of 2 ml of saturated sodium acetate solution to the mother liquor, an additional 2.73 g of

Xmax (n) H6 buffer) 234.4 (E / i cm 386); Xinfl

250.4 (ε cm 276), 276.8 (ε ^1% cm 184), and 294.4 nm (ε ^% cm 148).

She. Example 6 (6R, 7R, 2'Z, S) -7- [2- (2-Aminothiazol-4-U) -2 - [(carboxy) - (3,4-dihydroxyphenyl) methoxyimino] -ac etamido] -cef-3-em-4-carboxylic acid

1.0 g of the compound of Example 5 is mixed with 4 ml of water and 41 g of sodium acetate to give a solution. The solution was filtered and crystallized by scratching. The mixture was stored at 21 'C

After 14.5 hours, the crystals are filtered off, washed with water and dried in vacuo at 21 'Ck. 250 mg of the title compound are obtained, and addition of 0.9 ml of 2N hydrochloric acid gives 360 mg of crystalline product.

[α] ²¹ D + 136.27 '(c 0.54, DMSO);

Λmax 234.4 nm λ ^{1 S} cm 408), Xinfl 249.6 < ^1% 1 cm 295), 277.8 (Ε i cm 192) and 295.0 nm ¢) 1 1 cm 156).

Example 7 (6R, 7R, 2'Z, S) -7- [2- (2-Amothiazol-4-yl) -2 - [(carboxy) - (3,4-dihydroxyphenyl) methoxy] imino] -acetamido] -cef-3-em-4-carboxylic acid hydrochloride

27.4 g of the compound of Example 4 are dissolved in 110 ml of formic acid and stirred at 20 'C and 3 equivalents of 8.2 ml of concentrated hydrochloric acid are added. The mixture was stirred for an additional 15 minutes and then added dropwise over 6 minutes to 1.1 L of diisopropyl ether with stirring at 20 ° C. The precipitate was filtered off, washed with 500 ml of diisopropyl ether and dried in vacuo. 18.02 g of the title compound are obtained.

vmax (Nujol) 3600-2800 (wide) and 1780 cm ^-1 , δ 3.3-3.7 (m, H-2), 5.05 (d, H-6), 5.4 (s, CHON )

5.8 (m, H-7), 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) methoxy] imino] -ac-ethamido] -cef-3-em-4-carboxylic acid

2.65 g of the compound of Example 7 are added with stirring at 20 DEG C. to 0.6 ml of distilled water and the mixture is stirred for another 30 minutes, during which time crystallization occurs. The stirred suspension was cooled in ice water for 15 minutes, then the crystals were filtered and washed with chilled 10 ml of water at 30 ° C in an air oven and 2.9 g of the title compound

-9GB 201946 ú Púnk. Water content 12% (Kari Fischer).

IR (Nujol) 3700-2100 (br), 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 (in d intervals in Angstrom units and% intensity in 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 (5); 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); 2.10 (10); 2.05 (4); 2.01 (9).

Example 9 (6R, 7R, 2'Z, S) -7- [2- (2-Aminothiazol-4-yl) -2 - [(carboxyl) - (3,4-dihydroxyphenyl) - methoxyimino] -acet mido] aceph-3-em-4-tert-butyl carboxylate

Intermediate 5 (1.53 g) was dissolved with stirring in methylene chloride (15 mL) and Ν, Ν-dimethylacetamide (2.9 g), and the solution was cooled to -35 ° C and phosphorus oxychloride (0.41 mL) was added. The mixture was -25

After stirring for one hour at 20 ° C, (6R, 7R) -7-aminoceph-3-em-4-tert. (1 g) from the tosylate salt was treated with an aqueous solution of sodium bicarbonate. butyl carboxylate solution in N, n-dimethylaniline (2.9 ml) in methylene chloride (15 ml) was added. After 16 hours at 0 ° C, the mixture was washed with water and dilute hydrochloric acid twice and again with water, and after each wash, the aqueous phase was extracted with methylene chloride. The combined organic phases were evaporated to give a foam which was dissolved in methylene chloride (15 mL) and passed through a silica column (5 g Sorbsil U30), eluting with methylene chloride (30 mL). The eluate was evaporated and the resulting small volume was treated with 15 ml of diisopropyl ether. The title compound is precipitated as a white solid. Yield 1.2 g.

(CDCl 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 and -OH).

Example 11 (6R, 7R, 2'Z, S) -7- [2- (2-Aminothiazol-4-yl) -2 - [(carboxyl) - (3,4-dihydroxyphenyl) - methoxyimino] -acetamido] -aceph-3-em-4-carboxylic acid hydrochloride hydrochloride salt

1.5 g of the compound of Example 10 are dissolved in 6 ml of formic acid with stirring at 20 ° C, 2.1 equivalents of 0.35 ml of concentrated hydrochloric acid. After stirring for 2 hours, the mixture was clarified by filtration and concentrated under reduced pressure. Ethyl acetate (6 mL) was added to the residue and the mixture was evaporated again to a foam which was triturated with ethyl acetate (6 mL). The resulting slurry was stirred at room temperature for 30 minutes, filtered, washed twice with ethyl acetate and dried under vacuum (1.33 g). which is identical to the product of Example 7.

Medicine example

Dry powder for injection (6R, 7R, 2'Z, S) -7- {2- [2-aminothiazol-4-yl] -2 - [(carboxy) - (3,4-dihydroxyphenyl)] per vial -methoxyimino-acetamido} -ceph-3-em-4-carboxylic acid 500 mg sodium carbonate (anhydrous) 99 mg

The two sterile components are mixed aseptically and filled into sterile vials. The vial head is flushed with sterile nitrogen, sealed with rubber stoppers and metal seal (spray applied). The product is dissolved in water for injections or other suitable sterile medium well before use.

Example 10 (6R, 7R, 2'Z, S) -7- [2- (2-Aminothiazol-4-yl) -2 - [(carboxy) - (3,4-dihydroxyphenyl) methoxy] imino] -ac etamido] -cef-3-em-4-tert-butyl carboxylate

6.29 g of Example 9 are stirred in 64 ml of methanol and 16 ml of 1,4-dioxane at 20 'C and 5.63 ml of 60% perchloric acid is added. After 3.5 hours, the solution was added to 240 mL of rapidly stirred sodium bicarbonate solution. The mixture was stirred for an additional hour and then cooled. The product is filtered off, washed with water and dried. Then, it was dissolved in a 1: 1 mixture of ethyl acetate and methylene chloride, and the solution was applied to a 65 g Sorbsil U30 silica dloxide column and eluted with additional solvent. Concentration of the appropriate fraction afforded 4 g of the title compound.

δ 1.5 (s, (CH 3) 3), 5.06 (d, H-6), 5.61 (s, CHON), 5.8 (m, H-7), 6.41 (m, H-3), 9.0 (broad, -OH), 9.5 (d, NHCO).

Claims (7)

A process for the preparation of compounds of formula (Ia): wherein R ^4a and R ^5a are hydroxy and their salts or solvates, including hydrates, or their metabolically labile esters, for the preparation of a compound of formula (Π) wherein R is a carboxyl protecting group, or a 7-N- silyl derivative (ΠΙ) with a compound of general formula I - wherein R Carboxyl protecting group, R ^{3 is} hydrogen or amino, R ⁴ and R are either acylated with a hydroxyl or protected hydroxyl group or together form a cyclic protected diol group or a salt thereof or a suitable acylation derivative of a compound of formula (IH), preferably an acid halide, a symmetric or mixed anhydride or an activated ester; optionally performing any of the following reactions in any order: i) optionally esterifying the carboxyl group into a non-toxic metabolically labile ester group, ii) optionally forming a non-toxic salt or moiety with a base or acid, iii) optionally containing a carboxyl protecting group -10HU201946Β and / or N-protecting groups are removed and arc) any hydroxyl protecting groups present are removed. (Priority; September 26, 1986) Process for the preparation of a compound of formula (I) having an oxime etherification group in the S configuration according to claim 1, characterized in that the appropriate starting materials are reacted. (Priority: September 26, 1986) The process according to claim 1, wherein (6R, 7R, 2'Z, S) 7- [2- (2-Aminothiazole-4-U) -2 - [(carboxy) - (3,4-dihydroxy) -phenyl) -methoxyimino] -acetamido] -ceph-3-em4-carboxylic acid or its non-toxic salt, solvate, preferably hydrate or metabolically labile esters thereof, by reacting the appropriate starting materials. (Priority: September 26, 1986) The process according to claim 1, which is crystalline (6R, 7R, 2'Z, S) -7- [2- (2-aminothiazol-4-yl) -2 - ((carboxylic) - (3,4) -dihydroxyphenyl) -methoxyimino] -acetamido] -aceph-3-em-4-carboxylic acid hydrate, wherein the compound, an acid addition or base salt thereof, is solvated to form an aqueous solution by spontaneous separation of the hydrate. . (Priority: March 13, 1987) The process according to claim 1, which is crystalline (6R, 7R, 2'Z, S) -7- [2- (2-aminothiazol-4-yl) -2 - [(carboxyl) - (3,4) -dihydroxy-phenyl) -methoxyimino] -acetamido] -aceph-3-em-4-carboxylic acid hydrate, comprising forming an aqueous solution of the acid addition salt, the basic salt or a solvate of the compound and separating the crystals. The pH is adjusted to 1-4. (Priority: March 13, 1987) 6. A process for the preparation of a pharmaceutical composition comprising mixing an active ingredient or compounds of formula (Ia) according to claim 1, wherein the substituents are as defined in claim 1, with pharmaceutically acceptable carriers and formulating them into a pharmaceutical composition. (Priority: September 26, 1986) 7. The process of claim 6 wherein the compound of claim 3 is active ingredient.