GB2053893A - Process for The Manufacture of 7-(oximinoacetamido)-Cephem Compounds - Google Patents

Abstract

Cephem compounds of the formula I <IMAGE> wherein A denotes hydrogen, a cation or the radical of an ester group, R1 denotes hydrogen, an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, acyl, aryl, arylsulfonyl, alkylsulfonyl or heterocyclic group, R2 denotes furyl, thiazolyl or phenyl optionally substituted by alkyl, aryl or by optionally protected amino and B denotes C1-4 alkoxy, methyl, acetoxymethyl, carbamoylmethyl, halogen or-CH2S-Het wherein Het is a 5-to 6-membered ring containing 1 to 4 hetero atoms and n denotes 0, 1 or 2 and the R1O group is in the syn-position, are prepared by reacting carboxylic acids of the formula II <IMAGE> or salts thereof, in the presence of at least 0.1 mol of a compound of the formula R3R4NCOR5 wherein R3, R4 and R5 are C1-6 alkyl groups, or R3 and R4 or R3 and R5 complete a ring optionally interrupted by a hetero atom, R5 denoting optionally dialkylamino, the alkyl groups of which each may contain 1 to 6 carbon atoms and may form a ring optionally interrupted by a hetero atom, with acid-halide-forming agents, and reacting the resulting complexes with cephem carboxylic acids of formula III <IMAGE> in the form of amine salts, esters optionally cleavable by acid hydrolysis or hydrogenolysis or silyl esters and, if desired, converting any substituent A into any other substituent A.

Description

SPECIFICATION Process for The Manufacture of Cephem Compounds The present invention relates to a process for the manufacture of cephem compounds.

It is known that in compounds of the following formula I the oximinoether grouping of the formula

wherein R1 is defined as specified below, may be present in a syn- or anti-form and that the biological activities of these two forms differ from one another.

It is further known that the syn-oximinoethers may readily be converted into the anti-compounds under various reaction conditions, and hence very special processes must be employed to avoid this isomerization and to obtain uniform syn-products.

For example, it is known from DOS 27,02,501 that compounds of the formula I wherein the R10 group is in the syn-position, can be obtained when carrying out acylation with a symmetrical anhydride of 2-alkoximinoacetic acid. This reaction has the disadvantage that the 2-alkoximinoacetic acid must be used in twice the quantity, calculated on the amino component to be acylated.

It is further known from DOS 22,23,375 and 22,65,234 that acid chlorides of the compounds of the following formula II may be prepared in admixture with their anti-compounds, by reacting the sodium salts of the corresponding carboxylic acids with cxalyl chloride with the use of catalytic amounts of dimethylformamide or by reacting the free acids with phosphorus pentachloride. As regards aminothiazolyl compounds, it is further disclosed in DOS 25,56,736 that when using oxalyl chloride as a reagent to form the acid chloride, the sodium salt gives a compound whose NMR spectrum reveals that this compound is present as the anti-form.

syn H 6.75 (D20) DOS 27,02,501 anti H 7.58 (D20) DOS 25,56,736 Finally, as described in the iiterature, when using dimethylformamide and phosphorus oxychloride, thionyl chloride or phosgene, the acylation of 7-amino-cephem compounds with 2-(2amino-4-thiazolyl)-alkoxyiminoacetic acid is said to proceed in particularly advantageous manner.

Tests of applicant have shown that the product obtained in this manner is formed in moderate yields and in insufficient purity, only. As described in the literature, this product must be submitted to chromatographic purification to be present in a pure form.

It is further known from the literature that dimethylformamide reacts with thionyl chloride to form a compound that is not very stable and that may be subject to vigorous decomposition when contacted with traces of Fe3+.

It has now been found, surprisingly, that when using compounds of the following formula IV products of high stability than those specified hereinbefore are obtained, upon adding an acid halide forming agent such as phosgene, oxalyl chloride, phosphorus pentachioride or phosphorus oxychloride.

When reacted with a carboxylic acid of the formula II, this reaction product forms an active complex, which is turn reacts surprisingly with a 7-aminocephem compound of the formula III to give a derivative of the formula I in a surprisingly excellent yield and high purity. It is moreover surprising that the acylation takes place without rearrangement of the 2-oximinoether grouping from the syn- to the anti-form.

The process according to the invention for the manufacture of a cephem compound of the formula I

wherein A denotes hydrogen, a cation, especially an equivalent of an alkali metal or alkaline earth metal or of an organic nitrogen base, or denotes the radical of an ester group, R1 denotes hydrogen, an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, acyl, aryl, arylsulfonyl, alkylsulfonyl or heterocyclic group, R2 denotes furyl, thiazolyl or phenyl optionally substituted by alkyl having 1 to 4 carbon atoms, aryl or by optionally protected amino and B denotes lower alkoxy with 1 to 4 carbon atoms, methyl, acetoxymethyl, carbamoylmethyl, halogen or-CH2S-Het wherein Het is a 5-to 6-membered ring containing 1 to 4 hetero atoms and n denotes 0, 1 or 2 and the RaO groups is in the syn-position, comprises reacting a carboxylic acid of the formula II

or a salt thereof, in which formula R1 and R2 are defined as above, in the presence of at least 0.1, and preferably from about 0.1 to about 3.0 mols of a compound of the formula IV

wherein R3, R4 and Rs may be identical or different alkyl groups having 1 to 6 carbon atoms, R3 and R4 or R3 and R5 forming optionally, when taken together, a ring optionally interrupted by a hetero atom, and R5 denoting optionally dialkylamino, the alkyl groups of which each may contain 1 to 6 carbon atoms and may form a ring optionally interrupted by a hetero atom, with an acid halide forming agent, and reacting the resulting complex with a cephem carboxylic acid of formula III

wherein B and n are defined above, in the form of an amine salt or of an ester optionally cleavable by acid hydrolysis or hydrogenolysis or in the form of a silyl ester and, if desired, converting any substituent A into any other substituent A, for example, converting a carboxyl group optionally obtained in the cephem carboxylic acid of the formula I in known manner into one of the other groups specified sub A.

In this specification, "optionally substituted" means substituted or unsubstituted.

In the cephem compounds of the formula I A may denote hydrogen, or a cation, especially one forming a physiologically tolerable salt, e.g. an alkali metal, in particular sodium, an equivalent of an alkaline earth metal, in particular calcium, an equivalent of an organic nitrogen base, in particular of diethylamine, diethanolamine or procaine; the radial of an ester group such as a low-molecular weight alkyl ester, for example the tert.butylester, an optionally substituted benzylhydryl ester, for example the bis-p-methoxybenzhydryl ester, a p-alkoxy-benzyl ester having a low-molecular weight alkoxy group, with 1 to 4 carbon atoms, for example the p-methoxy-benzyl ester, the phthalide ester, an acetoxymethyl ester or a pivaloyloxymethyl ester.

R1 may denote, for example, hydrogen, alkyl having from 1 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, preferably methyl, or cycloalkyl having from 3 to 8, preferably 3 to 6, carbon atoms, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, it also being possible for alkyl or cycloalkyl to be further monosubstituted or polysubstituted, for example by alkyl having from 1 to 4 carbon atoms, preferably methyl, by cycloalkyl having from 3 to 8, in particular 3 to 6, carbon atoms, such as, for example, cyclopentyl or cyclohexyl, by alkoxycarbonyl having from 1 to 4 alkyl carbon atoms, preferably methoxycarbonyl or ethoxycarbonyl, by carboxy, by cyano, by carbamoyl, which can be mono- or disubstituted by optionally substituted, for example hydroxyl-substituted, alkyl with 1 to 4 carbon atoms, it also being possible for 2 substituents to be closed to form a 5- or 6-membered ring optionally interrupted by O or N, such as, for example, morpholino, piperazino, N-methylpiperazino or pyrrolidino, by alkylcarbonyl having from 1 to 4 carbon atoms, in particular acetyl, by sulfo or sulfamoyl, by alkoxysulfonyl having from 1 to 4 carbon atoms, in particular methoxy- or ethoxysulfonyl; by a phosphono group, by hydroxyl, by halogen, preferably chlorine or bromine;; by alkoxy having from 1 to 4 carbon atoms, in particular methoxy or ethoxy, by alkylthio having from 1 to 4 carbon atoms, in particular methylthio or ethylthio, by acyloxy, in particular aliphatic acyloxy having from 1 to 4 carbon atoms, such as, for example, acetoxy or benzoyloxy, by carboxyalkoxy having from 1 to 4 carbon atoms, in particular carboxymethoxy or by aryl, preferably phenyl, optionally carrying further substituents, for example a heterocycle as defined for "Het" in the group -CH2S-Het sub B; alkyl having from 1 to 4 carbon atoms, preferably methyl; alkenyl having from 1 to 4 carbon atoms, preferably allyl; alkyloxy having from 1 to 4 carbon atoms, preferably methoxy; alkylthio having from 1 to 4 carbon atoms, preferably methylthio; halogen, preferably chlorine or bromine; sulfamoyl; carbamoyl; carboxy; trifluoromethyl; alkoxycarbonyl having from 1 to 4 carbon atoms, for example methoxycarbonyl; cyano; nitro; amino; alkylamino having from 1 to 4 carbon atoms, such as, for example, methylamino or ethylamino; dialkylamino having from 1 to 4 carbon atoms, such as for example dimethyl- or diethylamino; or amidino or P1 may further denote alkenyl having from 2 to 6, preferably 3 to 5, carbon atoms, such as, for example allyl or crotonyl optionally further substituted, for example by alkyl having from 1 to 4 carbon atoms, preferably methyl; by halogen, in particular chlorine or bromine; by carboxyl or carbamoyl, optionally substituted as specified sub alkyl(R,); by alkyioxycarbonyl having from 1 to 4 alkyl carbon atoms, in particular methoxycarbonyl or ethoxycarbonyl; or R1 may denote alkynyl having from 3 to 5 carbon atoms, preferably propargyl optionally further substituted, for example by aryl, preferably phenyl; aliphatic, saturated or unsaturated acyl having from 1 to 7, preferably 1 to 4, carbon atoms, such as, for example, formyl, acetyl, propionyl, butyryl, hexanoyl, acryloyl, crotonyl, propionoyl, optionally further substituted, for example by halogen, such as for example, chlorine, bromine or fluorine, in which latter case a chloroacetyl, dichloroacetyl or bromoacetyl radical would be formed; amino; alkylamino having from 1 to 4 carbon atoms, preferably methyl or ethylamino; dialkylamino having from 1 to 4 carbon atoms, in particular dimethylamino or diethylamino, optionally forming a ring which may be interrupted by hetero atoms such as oxygen, nitrogen or sulfur, for example, morpholino, piperazino or perhydrothiazine;; aromatic acyl, such as, for example benzoyl or naphthoyl optionally substituted, for example, by alkyl having from 1 to 4 carbon atorns, in particular methyl; halogen, preferably chlorine or bromine; alkyloxy having from 1 to 4 carbon atoms, in particular methoxy; dialkylamino having from 1 to 4 carbon atoms, in particular dimethyl- or diethylamino, optionally forming a ring as specified above, which may be interrupted by hetero atoms, for example, oxygen or nitrogen; trifluoromethyl;; heterocyclic acyl derived from heterocyclic 5- or 6-membered ring having from 1 to 4 hetero atoms, such as, for example sulfur, oxygen and nitrogen, such as, for example thenoyl, furoyl, nicotinoyl, isonicotinoyl or picolinoyl optionally further substituted, for example by substituents as specified hereinbefore for aromatic acyl(R,), optionally substituted arylsulfonyl, in particular phenylsulfonyl, p-tolylsulfonyl and p-aminophenylsulfonyl; optionally substituted alkylsulfonyl having from 1 to 7; preferably 1 to 4, carbon atoms, in particular methyl- or ethylsulfonyl;; aryl, preferably phenyl, or, for example, 1 - or 2-naphthyl optionally substituted, for example by substituents as specified for aromatic acyl(R,), a heterocyclic group derived from a heterocyclic 5- or 6-membered ring having from 1 to 4 hetero atoms, such as, for example, sulfur, oxygen and nitrogen, such as for example, thienyl, furyl, pyridyl or picolinyl and being optionally further substituted, for example by substituents as specified hereinbefore for aromatic acyl(R).

In the case that R2 denotes any of the aforesaid heterocyclic rings, these may be in particular 2furyl and 4-thiazolyl. These radicals may carry substituents, preferably in the 2-position, such as, for example alkyl having in particular from 1 to 4 carbon atoms, preferably methyl, aryl, preferably phenyl amino or protected amino. Suitable amino protective groups include in particular those that are cleavable by acid hydrolysis or hydrogenolysis, for example halogenacetyl, preferably chloro or bromoacetyl, carbobenzoxy, tert.butyloxycarbonyl or in particular trityl which latter may be further substituted, for example by halogen or alkyl.

B may denote methyl, acetoxymethyl, carbamoyloxymethyl, halogen, preferably chlorine, low molecular weight alkoxy with 1 to 4 carbon atoms, preferably methoxy or a group CH2S-Het with Het being a 5- or 6-membered ring having from 1 to 4 hetero atoms, preferably nitrogen or sulfur, for example thiadiazolyl, preferably 1,3,4-thiadiazolyl or tetrazolyl.

n may denote 0, 1 or 2.

The synthesis of carboxylic acids of the formula II has been described in the patent literature, for example in DOS 27,02,501. The carboxylic acids of the formula II wherein R, denotes phenyl or benzyl, are novel.

The synthesis of the starting compounds of the formula Ill is known in the literature, as well.

When n denotes 1 or 2, the compounds must generally be prepared by previous oxidation, according to processes as described, for example, in E. H. Flynn, Cephalosporins and Penicillins, Academic Press, New York and London (1972).

The active complex of the carboxylic acids of the formula II required for carrying out the process of the invention are preferably submitted to reaction with the 7-aminocephem compounds immediately after having been formed.

The carboxylic acids of the formula II are used preferably as the free acids. However, it is likewise possible to use for the reactions their salts, for example alkali metal salts, in particular the sodium salt, or amine salts, for example, the triethylamine salt.

Suitable acid halide forming agents include thionyl halides, for example thionyl chloride or thionyl bromide, in particular phosphorus pentachloride, phosphorus oxychloride and oxalyl chloride, in particular phosgene.

When in the compounds of the formula IV R3, R4 and R5 each denotes alkyl having from 1 to 6 carbon atoms, these alkyl groups may be methyl, ethyl, propyl, butyl, hexyl, in particular, however, these alkyl groups should have from 1 to 4 carbon atoms, methyl being particularly preferred. When R3 and R4 or R3 and P5 are closed to form a ring optionally interrupted by a hetero atom, these hetero atoms may be in particular oxygen and nitrogen. Suitable rings include in particular those having from 4 to 8, in particular from 5 to 6, ring members, such as, for example a piperidine, morpholine, pyrrolidone, pyrrolidine, azetidinone-2- or piperazine ring.Among compounds of the formula IV preference is given to N-disubstituted carboxylic acid amides, such as, for example dialkylacetamides both alkyl groups of which, preferably of low-molecular weight type with 1 to 4 carbon atoms, being optionally closed to form a ring, preferably a 4-to 8-membered ring which may be interrupted by hetero atoms, such as, for example, nitrogen or oxygen. Examples of these rings are N-methyl-pyrrolidone, N-methylazetidinone, N,N-diethylbutyramide, dialkylpropionamide and di-alkylacetamides, in which the alkyl substituents are preferably of low-molecular weight type, such as, for example dimethylacetamide, diethylacetamide, N-acetyl-piperidine, N-acetyl-morpholine, N-propionyl-piperidine, N-butyryl-pyrrolidine, N-butyrylpiperidine, N,N-dimethyl-N,N'-pentamethylene urea, tetramethyl urea, tetraethyl urea.Particularly preferred are compounds of the formula IV such as diethylacetamide, N,N-dimethylpropionamide, N,Ndiethylpropionamide, N-acetylpiperidine and tetramethyl urea, in particular dimethylacetamide.

It has proved particularly advantageous for the usefulness of the compounds of the formula IV according to the invention that the corresponding reaction products with the acid halide forming agents are very stable. Contrary thereto it is known from the reaction product of thionyl chloride and dimethylformamide that it may decompose explosion-like when contacted with traces of Fe3+ as mentioned above.

The active complexes are generally prepared with the carboxylic acids of the formula II in a dry, inert solvent, which does not hinder the further reaction. Suitable solvents include halogenated hydrocarbons such as methylene chloride or chloroform, esters such as acetic acid ethyl ester or aromatic hydrocarbons such as toluene or xylene or ethers such as diethyl ethers or diisopropyl ethers.

To carry out the process of the invention in optimum manner the carboxylic acids of the formula II are preferably used in at least stoichiometrical amounts, calculated on the 7-amino-cephem compounds.

Since it has been ascertained that the active complex need not be isolated, the procedure is suitably the following: The compound of the formula IV is placed first in the reaction vessel in an amount of from about 0.1 to about 3 equivalents, preferably 0.1 to 1.5 equivalents, the corresponding quantity of the halogenation reagent is added and the carboxylic acid of the formula II is then submitted to the reaction as described hereinbefore. The sequence of addition is not critical.

The activation of the carboxylic acid of the formula Il by the above-described complex formation may be achieved in a wide temperature range, for example between70 and +300C, a temperature of from -20 to +1 00C having proved particularly advantageous.

The second step of the process of the invention, namely the acylation, is preferably carried out directly upon the formation of the active complex. For this purpose, the carboxylic acid of the formula III may be used, for example in form of an amine salt, in particular a trialkylamine salt, such as, for example, the triethylamine salt, the trimethylbenzylamine salt or the ethyldicyclohexylamine salt or finally the dialkylarylamine salt, such as, for example, the N,NdimeThylaniline salt. It may alternatively be used in form of an ester, and in the case that a subsequent conversion into a free carboxyl group is desirable, these esters are preferably those that are cleavable by acid hydrolysis or hydrogenolysis.As silyl esters in particular trialkyl silyl esters, preferably the trimethylsilyl ester, can be used, which obtained with the use of the corresponding silylation agents in a manner known in the literature.

The hydrogen halide set free during the acylation is generally neutralized by the addition of a base, if required, the trialkylamine, for example triethylamine, trimethylbenzylamine, ethyldicyclohexylamine or dialkyiarylamine, for example N,N-dimethylaniline, being used preferably for this purpose.

Acylation may be carried out at a temperature between80 and +300 C, preferably between -20 and +200C. At this temperature, the reaction is generally complete after about 30 to 60 minutes.

The acylation products obtained may be isolated easily in known manner, for example by splitting off any protective group present. This group may be split off, for example according to processes as described in DOS 27,02,501 or in Houben-Weyl, volume XV/1, pages 272 and following.

Esters obtained according to the invention may be isolated as such and used as such or may be converted into the free acid, for example by acid hydrolysis or hydrogenolysis, or into another ester.

When the compound of the formula I is obtained in form of an amine salt, in accordance with the invention, this salt may alternatively be converted into the free acid or into another salt, for example, an alkali metal salt in known manner, or into an ester.

The following Examples serve to illustrate the invention: Example 1: Diethylam ine salt of the 3-acetoxymethyl-7-[2-(2-trityla mino-4-thiazolyl)-2-(syn)-methoximino- acetamido]-ceph-3-em-4-carboxylic acid 54 g (0.1 mol) of 2-(2-tritylamino-4-thiazolyl)-2-(syn)-methoximino-acetic acid (82%) are suspended in 800 ml of toluene in a four-necked flask. At a bath temperature of about 500C 400 ml of toluene are distilled off in vacuo. Next, the suspension is cooled to -50C and after addition of 9.3 ml (0.1 mol) of N,N-dimethylacetamide at-50C it is supplemented dropwise with a solution of 12.2 g (0.12 mol) of phosgene in 60 ml of toluene.Stirring is continued for 16 hours at --5 OC. A solution of 28.6 g of 7-aminocephalosporanic acid (95%=0.1 mol) and 55.3 ml (0.4 mol) of triethylamine in 500 ml of methylene chloride that has been filtered with the addition of carbon is dropped into the resulting suspension at -50C to -70C. Then the batch is stirred for 30 minutes at -50C and for 60 minutes in a way such that the temperature rises to 10 to 1 50C. Then the pH is adjusted to 2 with 2N hydrochloric acid, the batch is poured into a mixture of 500 ml of methylene chloride and 500 ml of water and the phases are separated. The organic phase is washed once with 500 ml of water, dried over sodium sulfate and concentrated in vacuo (near the end by means of an oil pump).The residue is dissolved in 270 ml of acetone and after addition of 10.3 ml of diethylamine it is refluxed while stirring for 30 minutes. Crystallization occurs after a short period of time. After a several hours' standing at room temperature, the product is cooled with an ice bath, suction-filtered, washed with cold acetone and dried. The diethylamine salt obtained in a very good yield has the syn-configuration. NMR (DMSO, 60 MHz): 6.68 ppm=thiazole ring proton.

Example 2: Diethylamine salt of the 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(syn)-methoximino- acetamido]-ceph-3-em-4-carboxylic acid 54 g (0.1 mol) of 2-(2-tritylamino-4-thiazolyl)-2-(syn)-methoximino-acetic acid (82%) are suspended in a four-necked flask in 600 ml of toluene and the toluene is distilled off in vacuo at a bath temperature of from about 50 to 600C. Then the residue is suspended in 400 ml of toluene, cooled to -100C and after addition of 9.3 ml (0.1 mol) of N,N-di-methylacetamide it is supplemented dropwise for 20 minutes at -100C with 10.2 mol (0.12 mol) of oxalyl chloride, diluted with 40 ml of toluene.

The mixture is stirred for 2.5 hours at --150C and for 2.5 hours at -150C to -50C.

A solution of 28.6 g of 7-aminocephalosporanic acid (95%) (0.1 mol) and 55.3 ml (0.4 mol) of triethylamine in 500 ml of methylene chloride which has been filtered with carbon, is dropped into the resulting suspension at -80C to -50C for 20 minutes. The mixture is stirred for 30 minutes at -50C and for 60 minutes at --5 OC to + 1 00C. Next, the pH of the batch is adjusted to 2 by 2N hydrochloric acid, the batch is poured into a mixture of 500 ml of methylene chloride and 500 ml of water, shaken and the phases are separated. The organic phase is washed with 500 ml of water and concentrated in vacuo (near the end by means of an oil pump).

The light yellow residue is dissolved in 270 ml of acetone and after addition of 10.3 ml of diethylamine refluxed while stirring for 30 minutes. After a two hours' standing at room temperature the mixture is cooled in an ice bath, suction-filtered, washed with acetone and dried. The diethylamine salt obtained in a very good yield has the syn-configuration.

NMR (DMSO, 60 MHz): 6.68 ppm=thiazole ring proton Example 3: Diethylamine salt of the 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(syn)-methoximino- acetamido]-ceph-3-em-4-carboxylic acid 5.4 g (10 mmols) of 2-(2-tritylamino-4-thiazolyl)-2-(syn)-methoximino-acetic acid (82% strength) are suspended in 80 ml of toluene. At 50 to 600C, half of the solvent is distilled off in vacuo and the suspension is cooled to -250C. After addition of 1.02 ml (11 mmols) of N,N-dimethylacetamide there are added 2.2 g (11 mmols) of phosphorus pentachloride. The batch is stirred for 30 minutes at -200C and for 3 hours at -50C. After addition of 100 ml of absolute diisopropyl ether the solid product is suction-filtered with the exclusion of humidity and kept in a vacuum exsiccator.The complex compound obtained is added to a solution of 2.8 g (10 mmols) of 7-aminocephalosporanic acid (95% strength) and of 5.4 ml (40 mmols) of triethylamine in 50 ml of methylene chloride, at 250 C. After heating to room temperature the batch is stirred for 1 hour at room temperature. It is worked up and transferred to the diethylamine salt in the manner described in Examples 1 and 2. The product obtained has likewise the syn-configuration.

Example 4: Diethylamine salt of the 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(syn)-methoximino acetamido]-ceph-3-em-4-carboxylic acid 4.8 g (24 mmols) of phosphorus pentachloride are suspended in 100 ml of toluene, supplemented while being stirred at room temperature with a solution of 2.2 ml (24 mmols) of N,Ndimethylacetamide in 10 ml of toluene and stirred for 1 hour at room temperature. The complex compound formed separates by crystallization and precipitates.

After having siphoned off the supernatant solution and after repetition of the above procedure with the use of 100 ml of fresh toluene, the residue is a new supplemented with 100 ml of toluene and the suspension is cooled to -50C. 8.8 g (20 mmols) of 2-(2-tritylamino-4-thiazolyl)-2-(syn)methoximino-acetic acid are added and the mixture is stirred for 20 hours at -50C.

After this period of time a solution of 5.4 g (20 mmols) of 7-amino-cephalosporanic acid and 11.5 ml (83 mmols) of triethylamine in 100 ml of methylene chloride is dropped into the resulting suspension at -50C and the suspension is stirred for 1 hour at room temperature. The product is worked up and transferred to the diethylamine salt in the manner described in Examples 1 to 3. The resulting product has the syn-configuration.

Example 5: Diethylamine salt of the acetoxymethyl-7-[2-(2-tritylamino-4thiazolyl)-2-(syn)methoximino acetamido]-ceph-3-em-4-carboxylic acid 46.5 g (0.1 mol) of the sodium salt of the 2-(2-tritylamino-4-thiazolyl)-2-(syn)-methoximinoacetic acid are suspended in 600 ml of toluene and the toluene is then distilled off at a bath temperature of 600C in vacuo.The residue is suspended in 400 ml of toluene, 9.3 ml (0.1 mol) of N,Ndimethylacetamide are added and the suspension is cooled to -1 00C. Next, while stirring, a solution of 12 g (0.12 mol) of phosgene in 1 50 ml of toluene is added dropwise while stirring for 30 minutes at --1 OOC to -5 OC. The mixture is stirred for 1 7 hours at --1 OOC to obtain a suspension, which is added in 10 minutes to a stirred mixture, --100C cold, of 25.8 g of 7-.aminocephalosporanic acid, 55.3 ml of triethylamine and 500 ml of methylene dichloride.Within 90 minutes the batch is heated to +1 50C, then the pH is adjusted to 2 with 2N hydrochloric acid, the batch is poured into a mixture of 500 ml of methylene dichloride and 500 ml of water and the phases are separated. The organic phase is washed once with 500 ml of water and concentrated in vacuo. The light yellow residue is dissolved in 270 ml of acetone and after addition of 10.3 ml of diethylamine heated to the boil while stirring for 30 minutes. After a one hour's standing at room temperature the product is suction-filtered, washed with acetone and dried. The diethylamino salt obtained in a very good yield has the syn-configuration.

NMR (DMSO) 6.68 ppm (thiazole ring proton) When replacing the toluene by benzene during the complex formation, the diethylamine salt is obtained in an equally good yield, when operating in ether as the solvent the yield is somewhat lower.

When replacing phosgene by oxalyl chloride as halogenating agent and when proceeding for the rest in the above manner, the titel compound is obtained in a yield by about 1/3 lower.

Example 6: 3-Acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-(syn)-methoximino-acetamido]-ceph-3-em-4- carboxylic acid 4 g (0.02 moll of 2-(2-amino-4-thiazolyl)-2-(syn)-methoximinoacetic acid are suspended in 200 ml of toluene and the toluene is distilled off at a bath temperature of 600C in vacuo.The residue is suspended in 100 ml of methylene dichloride, 1.86 ml (0.02 mol) of N,N-dimethylacetamide are added and the batch is cooled to -1 00C. While stirring a solution of 3 g (0.03 mol) of phosgene in 10 ml of toluene is added for 10 minutes and stirring is continued for 5 hours at -50C. Next, a solution of 5.4 g of 7-aminocephalosporanic acid (0.02 mol) and of 11 ml of triethylamine in 100 ml of methylene dichloride that has been filtered with carbon is dropped into the clear, light-yellow solution formed at -5 to -80C, for 10 minutes. The mixture is stirred for half an hour at -50C and for 1 hour at a temperature up to +1 50C and subsequently freed from solvent in vacuo (at the end by means of the oil pump). The brown-yellow, amorphous residue is dissolved in 45 ml of 80% formic acid and introduced dropwise within 1 and a half hour into 300 ml of a stirred 35% aqueous ammonium sulfate solution. The separating precipitate is suction-filtered, washed batchwise with 1 50 ml of water and dried in vacuo over NaOH platelets. The crude product is suspended in 100 ml of 98% ethanol and stirred for 30 minutes at 500C. Cooling, suction-filtration, washing with alcohol and drying gives the titel compound, which has the syn-configuration.

NMR (DMS0,60 MHz): 6.68 ppm (thiazole ring proton) Example 7: 3-Acetoxymethyl-7- [2-(2-amino-4-thiazolyl)-2-(syn)-methoximino-acetamidoi-ceph-3-em-4- carboxylic acid 4 g (0.02 mol) of 2-(2-amino-4-thiazolyl)-2-(syn)-methoximinoacetic acid are suspended in 200 ml of toluene and the toluene is subsequently distilled off in vacuo at a temperature of 600C. The residue is suspended in 100 ml of methylene chloride, the resulting suspension is successively supplemented with 2.8 ml (0.03 mol) of N,N-dimethylacetamide, cooled to -1 00C, supplemented dropwise while stirring with a solution of 2.55 ml (0.03 mol) of oxalyl chloride in 10 ml of methylene chloride.The clear, light-yellow solution formed is subsequent,y stirred for 5 hours at -100C and supplemented with a mixture of 5.2 g of 7-aminocephalosporanic acid, 11 ml of triethylamine and 100 ml of methylene chloride. Stirring is continued for 1.5 hours until a temperature of + 1 50C is reached and subsequently the solvent is removed in vacuo, at the end by means of the oil pump. The residue is dissolved in 50 ml of 80% formic acid and subsequently introduced dropwise for 1.5 hours into 350 ml of 35% aqueous ammonium sulfate solution. The precipitate is successively suction-filtered, washed with water, dried, suspended in 1 5 mi of 98% ethanol and stirred for 30 minutes at +500C.Cooling, suction-filtration, washing with ethanol and drying gives a light-grey colored product having the synconfiguration.

(NMR, DMSO, 6.68 ppm thiazole ring proton).

Example 8: 3-Acetoxymethyl-7-[2-(2-amino-~thiazolyl )-2-(syn)-methoximino-acetamido]ceph-3-em-4- carboxylic acid In analogous manner to Example 7 4.5 g of 2-(2-amino-4-thiazolyl)-2-(syn)-methoximino-acetic acid sodium salt are reacted with 1.86 ml of N,N-dimethylacetamide and 3 g of phosgene. Acylation and purification by means of the formate gives a light-yellow colored product having the synconfiguration.

Example 9: 7-[2-(2-Amino-thiazol-4-yl )-2-syn-benzyloximino-acetamido]-cephalosporanic acid A solution of 1 8.2 g of 2-(2-tritylamino-thiazol-4-yl)-2-syn-benzyloximinoacetic acid in 1 60 ml of absolute toluene is supplemented with 3.05 g of N,N-dimethylacetamide, cooled to -80C and supplemented dropwise with 1 3.5 ml of a 38% phosgene-containing toluene solution. During this procedure a product precipitates that passes over into a nearly colorless crystalline product after a short period of time.

After 5 hours the suspension is introduced into a solution of 9.6 g of 7-aminocephalosporanic acid and of 19.6 ml of triethylamine in 160 ml of absolute methylene chloride at --5 OC, the mixture is stirred for 45 minutes at -1 OC, left subsequently overnight at 50C and finally a further 125 ml of methylene chloride and 1 50 ml of ice water are added subsequently.

The pH of the reaction mixture is brought to 1 by means of 2N HCI, the organic phase is separated, washed three times with ice water, dried over Na2SO4 and finally concentrated to dryness.

This gives the 7-[2-(tritylaminothiazol-4-yl)-2-syn-benzyloximino-acetamino]-cephalosporanic acid as light-beige solid matter.

A 20 g portion of the resulting tritylated compound is introduced into 110 ml of a 50% formic acid and heated to 500 C. The substance passes into solution for a short period of time and the triphenylcarbinol subsequently separates in the form of colorless crystals.

After 1 hour the reaction mixture is filtered, the filtrate is substantially concentrated in vacuo and the residue is mixed while stirring with 250 ml of water, a colorless, crystalline product precipitating thereby. The product is suction-filtered, washed subsequently with isopropanol and ether. The 7-[2-(2 aminothiazol-4-yl)-2-syn-benzyloximino-acetamido]-cephalosporanic acid is isolated in the form of colorless crystals.

Thin layer chromatogram: Rf 0.35 (n-Bu-OH; H2O:EtOH:AcOH=20:4:3:3).

Example 10: 7-[2-(2-Aminothiazol-4-yl)-2-syn-benzyloximino-acetamido]-3-(1 -methyltetrazol-2-yl) thiomethyl-A3-cephem-4-carboxylic acid To a solution of 11.4 g of 2-(2-tritylaminothiazol-4-yl)-2-syn-benzyloximinoacetic acid in 1 20 ml of absolute toluene there are added 2.0 g of N,N-dimethylacetamide and subsequently dropwise at -80C 8.5 ml of a 38% phosgene-containing toluene solution.After 5 hours a solution of 7.35 g of 3 (1 -methyltetrazol-2-yl-thiomethyl-A3-cephem-4-carboxylic acid in a mixture of 9.6 g of triethylamine and 1 60 ml of methylene chloride is added dropwise while stirring within 10 minutes, at -50C. The reaction mixture is stirred for a further one hour at 50C, left at +20C for 1 6 hours, 70 ml of water is added thereto and the pH of the reaction mixture is adjusted to 1 with 1 N HCI. After a brief stirring, the reaction mixture is filtered, the organic phase is washed twice with water and concentrated to dryness.

There is obtained the 7-[2-(tritylam ino-thiazol-4-yl)-2-syn-benzyloximino-acetamido]-3-( 1 - methyltetrazol-2-yl-thiomethyl)-A3-cephem-4-carboxylic acid as cream-colored solid.

1 5 g of the solid obtained are introduced into 65 ml of 50% of formic acid and heated to 500 C. The tri-phenylcarbinol formed is suction-filtered after 1.5 hours.

To the filtrated 2 g of active carbon is added, the filtrate is filtered and subsequently concentrated to dryness. The residue is stirred with 250 ml of cold water, the cream-colored powder formed is suction-filtered, washed with water and dried. The crystals obtained are stirred with 100 ml of ether for 2 hours and dried. This gives the 7-[2-aminothiazol-4-yl)-2-syn-benzyloximino-acetimido]-3-( 1-methyl) tetrazol-2-ylthiomethyl)-A3-cephem-4-carboxylic acid as a beige-colored solid.

Thin layer chromatogram: Rf 0.35 (n-BuOH:H,O:EtOH :AcOH=20:4:3:3) Example 11: 7-[2-(2-Aminothiazol-4yl)-2-syn-benzyloximino-acetamidoj-3-(2-methyli ,3,4thiadiazol-5-yl- thiomethyl)-A3-cephem-4carboxylic acid When using the 7-amino-3-(2-methyl- 1 ,3,4-thiadiazol-5-yl-thiomethyl)-A3-cephem-4-carboxylic acid and the 2-(triphenylmethylaminothiazol-4-yl)-2-syn-benzyloximinoacetic acid there is obtained the 7-[2-(tritylaminothiazol-4-yl)-2-syn-benzyloximino-acetamido]-3-(2-methyl- 1 ,3,4-thiadiazol-5-yl- thiomethyl)-A3-cephem-4-carboxylic acid which is converted into the 7-[2-(2-aminothiazol-4-yl)-2 syn-benzyloximinoacetamido]-3-(2-methyl-1 ,3 ,4-thiadiazol-5- yl-thiomethyl5-A3-cephem-4-carboxylic acid (cream-colored solid) when treating it with 50% formic acid at 600C.

Thin layer chromatogram: Rf 0.38 (n-BuOH:H2O:EtOH:AcOH=20:4:3:3) Example 12: 7-[2-(2-AminothiazolA-yl )-2-syn-phenoximino-acetamido]-cephalosporanic acid When using the 2-(triphenylmethylamino-thiazol-4-yl)-2-syn-phenoximino-acetic acid in toluene with the addition of N,N-dimethylacetamide and phosgene there is obtained the corresponding complex compound which upon reaction with a solution of 7-aminocephalosporanic acid in methylene chioride/triethylamine gives the 7-[2-(2-triphenylmethylaminothiazol-4-yl)-2-syn-phenoximino- cephalosporanic acid.

The tritylated product obtained is stirred for 1 hour in 50% formic acid at 6O0C, the separated triphenylcarbinol is removed, the filtrate is concentrated to dryness and triturated with ether. This gives the beige-colored 7-[2-(2-aminothiazol-4-yl)-2-syn-phenoximinoj-cephalosporanic acid as a solid, which in the thin layer chromatogram reveals as a uniformous substance with Rf 0.54 (BuOH :H2O rEtOH rAcOH= 10:4:3 :3).

Example 13: Diethyl amine salt of the 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(syn)methoximino- acetamido]-ceph-3-em-4-carboxylic acid 54 g (0.1 mol) of 2-(2-tritylamino-4-thiazolyl)-2-syn-methoxyiminoacetic acid (82% strength) are suspended in 800 ml of toluene in a four-necked flask. Next, 300 ml of toluene are distilled off in vacuo at a bath temperature of about 500C. The suspension is allowed to cool to --5 OC, then 9.3 ml (0.1 mol) of N,N-dimethylacetamide are added and subsequently within 1 5 minutes a further 70 ml of a 2 molar phosgene solution in toluene (=0.14 mol) and stirring is continued for 5 hours.

A solution of 27.2 g (0.1 mol) of 7-aminocephalosporanic acid and 48.7 g (0.2 mol) of N,O-bistrimethylsilyl-acetamide in 300 ml of methylene chloride is added while stirring at --5 OC to the resulting suspension and stirring is continued for 30 minutes at -50C and for 60 minutes at room temperature. After dilution with 500 ml of methylene chloride, the reaction mixture is shaken three times with each time 500 mi of water to extract the organic phase, which is subsequently dried over sodium sulfate and concentrated to dryness in vacuo. The residue is dissolved in 250 ml of acetone and after addition of 10.3 ml of diethylamine refluxed while stirring for 30 minutes. Cooling, suctionfiltration, washing with acetone and drying gives the titel compound in a very good yield. It possesses the syn-configuration.

NMR (DMSO, 60 MHz): 6.68 ppm=thiazole ring proton Example 14: 3-Acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-(syn)-methoximino-aceta mido]-ceph-3-em- carboxylic acid 20.1 g (0.1 mol) of 2-(2-amino-4-thiazolyl)-2-syn-methoximinoacetic acid are suspended in 350 ml of methylene chloride, cooled to --1 OOC, supplemented with 9.3 ml (0.1 mol) of N,Ndimethylacetamide and subsequently, while stirring, in 5 minutes, with 75 ml of a phosgene solution in toluene (2-molar solution=0.1 5 mol).A light yellow solution is formed to which after 25 minutes a solution of 21.4 g (0.08 mol) of 7-aminocephalosporanic acid and 39 ml (0.16 mol) of bistrimethylsilylacetamide in 500 ml of methylene chloride is added dropwise in a manner such that the temperature does not exceed --3 OC. During the addition a resinous product begins to precipitate.

To reach a complete precipitation, 3 ml of water are added after 30 minutes. The organic solution is decanted and discarded. The residue is digested with 200 ml of methylene chloride, the solvent is removed and the residue is freed from residual solvent in vacuo at room temperature. The light yellow amorphous residue contains the titel compound. It is dissolved in 1 50 ml of 80% formic acid and the resulting solution is introduced dropwise into 700 ml of a 40% aqueous ammonium sulfate solution.

The resinous precipitate formed is removed and triturated three times with a 60 ml portion of ice water. The resulting product is suction-filtered and dried. This gives the formate of the titel compound which possesses the syn-configuration.

NM (DMSO; 60 MHz): 6.68 ppm (thiazole ring proton), 8.13 ppm (formyl) For the purpose of deformylating, the product is suspended in 50 ml of absolute ethanol, stirred for 30 minutes at 5O0C, cooled, suction-filtered and washed with ethanol, thus giving the light-grey titel compound which possesses the syn-configuration.

NMR (DMSO; 60 MHz): 6.68 ppm (thiazole ring proton) Example 15: 3-Acetoxymethyl-7-[2-(2-a m ino-4-thiazolyl) -2-(syn)-methoximino-acetamido]-ceph-3-em-4- carboxylic acid 10.0 g (0.05 mol) of 2-(2-amino-4-thiazolyl)-2-(syn)-methoximinoacetic acid are suspended in 200 ml of absolute methylene chloride. After cooling to -1 00C, 4.65 ml (0.05 mol) of dimethylacetamide are added and 5.75 ml (0.062 mol) of phosporus oxychloride, which is added dropwise and the batch is stirred for 2.5 hours.

A solution of 10.8 g (0.04 mol) of 7-aminocephalosporanic acid and 19.5 ml (0.08 mol) of bistrimethylsilylacetamide in 250 ml of methylene chloride is dropped into the suspension formed at -1 OOC. Stirring is continued for 2 hours at OOC and the product is worked up in the manner described in Example 13. The resulting product possesses the syn-configuration.

NMR (DMSO; 60 MHz): 6.68 ppm (thiazole ring proton) Example 16: 3-Acetoxymethyl-7-[2-(2-a mino-4-thiazolyl)-2-(syn)-methoximino-aceta mido]-ceph-3-em-4carboxylic acid In analogous manner as in Example 14, there are reacted 5 g (0.025 mol) of 2-(2-amino-4thiazolyl)-2-syn-methoximinoacetic acid, 3.17 g of N-acetylpiperidine and 3.8 g of phosgene. The resulting product possesses the syn-configuration.

Example 17: 3-Acetoxymethyl-7-[2-(2-a m ino-thiazolyl)-2-(syn)-methoxymino-acetamido]-ceph-3-em-4- carboxylic acid In analogous manner to Example 14 there are reacted 5 g (0.025 mol) of 2-(2-amino-4-thiazolyl)- 2-syn-methoximino-acetic acid, 2.5 g of N-methylpyrrolidone and 3.8 g of phosgene. The resulting product possesses the syn-configuration.

Example 18: 3-Acetoxymethyl-7-[2-(2-a mino-4-thiazolyl)-2-(syn)-methoxi mino-aceta mido]-ceph-3-em-4carboxylic acid In analogous manner to Example 14 there are reacted 5 g (0.025 mol) of 2-(2-amino-4-thiazolyl)2-syn-methoxyiminoacetic acid, 2.5 g of N,N-dimethylpropionamide and 3.8 g of phosgene. The resulting product possesses the syn-configuration.

Example 19: 3-Acetoxymethyl-7-[2-(2-a mino-4-thiazolyl)-2-(syn)-methoxi mino-acetamido]-ceph-3-em-4carboxylic acid In analogous manner to Example 14 there are reacted 5 g of 2-(2-amino-4-thiazolyl)-2-synmethoximinoacetic acid, 3.15 ml of N,N-diethylacetamide and 3.8 g of phosgene. The resulting product has the syn-configuration.

Preparation of The Starting Compound of Example 9: a) 2-syn-Benzyloximinoacetoacetic acid ethyl ester 30.5 g of potassium carbonate is added while stirring at 1 50C to a solution of 23.5 g of 2-synoximinoacetoacetic acid ester in 120 ml of acetone. Next, 25.6 g of benzylbromide are added dropwise for 4 hours at room temperature and subsequently left at this temperature for 1 6 hours without stirring.

The solids are filtered off and the solution is concentrated to dryness. The remaining oil is heated to 800C in vacuo (0.05 mm) to remove excess benzyl bromide, then after cooling a 5% sodium bicarbonate solution is added to the residue and the mixture is submitted to extraction with ether. The ether phase is washed twice with water, dried subsequently with Na2SO4 and concentrated.

A light yellow oil of the 2-syn-benzyloximinoacetoacetic acid ester results. (Thin layer chromatogram in CHCIs/acetic ester reveals the ratio 20:1 :Rf 0.74).

b) 2-syn-Benzyloximino-4-bromcacetoacetic acid ethyl ester A solution of 12.5 g of 2-syn-benzyloximinoacetoacetic acid ester in 80 ml of absolute methylene chloride is supplemented with 1 50 mg of toluene sulfonic acid and subsequently at room temperature with about 2 g of the required quantity of bromine of 8 g. After stirring, the deep-brown colored solution fades. Then the residual bromine is added dropwise. At the end of the addition, stirring is continued for 1.5 hours, the reaction mixture is cooled to OOC and subsequently washed with a 10% sodium bicarbonate solution.

The organic phase is separated, dried over Na2SO4, concentrated and the remaining oil is recrystallized from cyclohexane. 2-syn-Benzylo:imino-4-brnmoacetoacetic acid ethyl ester is obtained as colorless crystals having a melting point of from 66 to 680C.

c) 2-(2-Amino-thiazcl-4-yl)-2-syn-benzyloximinoacetic acid ethyl ester A solution of 11.8 g of 2-syn-benzyloximino-4-bromoacetoacetic acid ethyl ester in 60 ml of ethanol of 98% strength is added to a solution of 2.66 g of thiourea in 50 ml of 40% ethanol and subsequently 40 ml of acetone is added dropwise within 20 minutes at room temperature. The reaction mixture is stirred for another 2 hours at 250C, concentrated until the final product separates by crystallization and the crystals obtained are isolated. The resulting product is dissolved at elevated temperature in 50% ethanol, and its pH is adjusted to 7 with aqueous ammonia.The separating creamcolored crystals are isolated, washed with 40% ethanol and diisopropyl ether and dried, which gives the 2-(2-aminothiazol-4-yl)-2-syn-benzyloximinoacetic acid ethyl ester having a melting point of from 135 to 1 380C in the form of nearly colorless crystals.

d) 2-(2-Triphenylme:hylamino-:hiazol-4l)-2-syn-benzoyIoxi mino-acetic acid ethyl ester A solution of 1 8.3 g of 2-(2-aminothiazol-4-yl)-2-syn-benzyloximino-acetic acid ethyl ester in 125 ml of absolute CH2CI2 and 25 ml of dimethylformamide is supplemented at --1 C with 6.7 g of triethyl amine, then the batch is cooled to -350C, supplemented portionwise with 17.5 g of triphenylchloromethane, and finally stirred subsequently for 1 hour at -300C and for 3 hours at room temperature.

The reaction solution is then cooled to OOC, washed repeatedly with 2N I HCl and with water, the organic phase is isolated, dried over Na2SO4 and freed from solvent. The resulting product is 2-(2 triphenylmethylamino-thiazol-4-yl)-2-syn-benzylo::iminoacetic acid ethyl ester in the form of a creamcolored solid (DC in CHClacetic ester 1:1 Rf 0.98, cf. starting material Rf 0.63), which may be submitted to further reactions without previous purification.

e) Sodium salt of 2-(2-triohen"l mc:h"lamino-thiaol-4-"l)-2-cyn-benzylcximino-acctic acid The resulting 2-(2-triphenylmethylamino-thiazol-4-yl)-2-syn-benzyloximinoacetic acid ethyl ester is dissolved in a mixture of 230 ml of ethanol and 40 ml of dioxin at 60 C, a solution of 3 g of NaOH in 45 ml of water is added and the batch is refluxed for 2 hours. Then the reaction mixture is substantially concentrated, 350 mi of water is added to the residue and the sodium salt of the 2-(2-triphenylmethylaminothiazol-4-yl)-2-syn-benzyloximinoacetic acid is obtained as a colorless solid having a melting point of from 257 to 2580C (decomp.).

f) 2-(2-Tri,nhenyl methylamino-thiazol-4-yl)-2-syn-benzyloxim inoacetic acid The resulting sodium salt of the 2-(2-triphenylmethylaminothiazol-4-yl)-2 benzyloximinoacetic acid is suspended in 250 ml of methylene chloride and stirred at 50C with 50 ml of 2N hydrochloric acid, during this procedure an acid forms, that is well soluble in CH2CI2.

The organic phase is isolated, dried with sodium sulfate and the solvent is removed. The residue is supplemented with cyclohexane to provide a nearly colorless solid, that is subsequently isolated and washed with diisopropyl ether, thus yielding the 2-(2-triphenyl-methylamino-thiazol-4-yl)-2-synbenzyloximinoacetic acid as amorphous solid having the Rf value of 0.21 as shown in the DC in CHClWCK3OH of 6:1.

Preparation of The Starting Compound of Example 12: a) BromoacetyigEyossylic acid ethyl ester 120 g of acetylglyoxylic acid ethyl ester are dissolved in 700 ml of methylene chloride and the solution is reacted at 50C with a solution of 146 g of bromine in 200 ml of methylene chloride within 1 hour.

After decoloration of the solution, the solvent is withdrawn and the remaining oil is reacted without further purification.

b) 2-Amino-thiazol-4-yl-glyoxylic acid ethyl ester To a solution of 66 g of thiourea in 450 ml of water and 450 ml of ethanol there is added dropwise at 50C 195 g of bromoacetoglyoxylic acid ethyl ester, upon completion of the addition the batch is stirred for 30 minutes at room temperature and for 30 minutes at 50 C and subsequently the resulting reaction mixture is filtered, after active carbon has been added. The pH of the filtrate is brought to 7 by adding sodium bicarbonate solution, the 2-amino-thiazol-4-ylglyoxylic acid ethyl ester crystallizing thereby in the form of crystals having a melting point of 1 470C.

c) 2-Triphenyimethylamino-thiazol-4-yl-glyoxylic acid ethyl ester A solution of 90 g of 2-aminothiazol-4-yl-glyoxylic acid ethyl ester in 225 ml of dimethylformamide and 375 ml of CH2Cl2 is supplemented subsequently with 27 g of triethylamine at -1 5CC and with 75 g of triphenylchloromethane at 300C. After having been left for 1 5 minutes at -300C the batch is stirred for 3 hours without cooling bath, the resulting reaction mixture is supplemented successively with 500 ml of CH2Cl2, with 300 ml of 1N HCI and twice with 200 ml of water. The organic phase is dried over Na2SO4 and the solvent is evaporated.

An oil remains that is used for the further reactions without previous purification.

d) 2-Triphenyl methyla m ino-thiazol-4-yl-glyoxylic acid A solution of 1 56 g of crude 2-triphenylmethylaminothiazol-4-yl-glyoxylic acid ethyl ester in 1 50 ml of methanol is supplemented with a solution of 14.8 g of NaOH in 370 ml of methanol, refluxed for 5 minutes, the sodium salt of the 2-triphenylmethylamino-thiazol-4-yl-glyoxylic acid separating thereby by crystallization.

The resulting sodium salt is suspended in 380 ml of water and supplemented while being stirred vigorously with 76 ml of 2N HCI. After 1 5 minutes the precipitate is suction-filtered, washed with water and dried.

The 2-triphenylmethylamino-thiazol-4-yl-glyoxylic acid is obtained as yellow crystals having a melting point of from 163 to 1 650C (decomp.).

e) 2-(2-Triphenylmethylamino-thiazol-4yl)-2-syn-phenoximinoacetic acid 30 g of triphenylmethylamino-thiazol-4-yl-glyoxylic acid are added to a solution of 450 ml of giacial acetic acid and 90 ml of water and subsequently 8 g of O-phenylhydroxylamine are added thereto. The reaction mixture clarifies and subsequently the oxime starts to crystallize. After 1 5 minutes 200 ml of water are added while stirring at 10 to 1 50C. The separating crystals are suctionfiltered, stirred with acetone and anew filtered to give the 2-(2-triphenylmethylaminothiazol-4-yl)-2syn-phenoximinoacetic acid having a ,melting point of from 141 to 1 430C (decomp.) in the form of a colorless solid.

Claims (44)

Claims

1. A process for the manufacture of a cephem compound of the formula I

wherein A denoted hydrogen or a cation, or denotes the radical of an ester group, R1 denotes hydrogen, an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, acyl, aryl, arylsulfonyl, alkylsulfonyl or heterocyclic group, R2 denotes furyl, thiazolyl or phenyl optionally substituted by alkyl, aryl or by optionally protected amino and B denotes lower alkoxy with 1 to 4 carbon atoms, methyl, acetoxymethyl, carbamoylmethyl, halogen or -CH2S-Het wherein Het is a 5- or 6-membered ring containing 1 to 4 hetero atoms and n denotes 0, 1 or 2 and the R10 group is in the syn-position, which comprises reacting a carboxylic acid of the formula II

or a salt thereof, in which formula R, and R2 are defined as above, in the presence of at least 0.1 mol of a compound of the formula IV

wherein R3, R4and R5 may be identical or different alkyl groups having 1 to 6 carbon atoms, R3 and R4 or R3 and R5 forming optionally, when taken together, a ring optionally interrupted by a hetero atom and R5 denoting optionally dialkylamino, the alkyl groups of which each may contain 1 to 6 carbon atoms and may form a ring optionally interrupted by a hetero atom, with an acid halide forming agent, and reacting the resulting complex with a cephem carboxylic acid of formula III

wherein B and n are defined above, in the form of an amine salt or of an ester optionally cleavable by acid hydrolysis or hydrogenolysis or in the form of a silyl ester and, if desired, converting any substituent A into any other substituent A.

2. A process as claimed in claim 1, wherein a cation A is an equivalent of an alkali metal or alkaline earth metal or of an organic nitrogen base.

3. A process as claimed in claim 1 or claim 2, wherein the carboxylic acid of formula Ills reacted with from 0.1 to 3.0 mols of the compound of formula IV.

4. A process as claimed in claim 3, wherein the carboxylic acid of formula lis reacted with from 0.1 to 3.0 mols of the compound of formula IV.

5. A process as claimed in any one of claims 1 to 4, wherein the acid halide forming agent is a thionyl halide.

6. A process as claimed in any one of claims 1 to 4, wherein the acid halide forming agent is phosphorus pentachloride, phosphorus oxychloride, oxalylchloride or phosgene.

7. A process as claimed in any one of claims 1 to 6, wherein the compound of formula Ills reacted with acid halide forming agent in the presence of the compound of formula IV in a dry, inert solvent.

8. A process as claimed in any one of claims 1 to 7, wherein the carboxylic acid of formula Ills used in at least a stoichiometric amount, calculated on the compound of formula Ill.

9. A process as claimed in any one of claims 1 to 8, wherein the resulting complex is reacted with the cephem compound of formula III without isolation of the complex.

10. A process as claimed in any one of claims 1 to 9, wherein, if desired, any one or more of the following steps is or are carried out: (i) a free acid of formula lis converted into a salt or an ester, (ii) a salt of formula I is converted into the free acid, an ester or another salt, (iii) an ester of formula I is converted into a salt, the free acid or another ester.

11. A process as claimed in any one of claims 1 to 10, wherein a salt of formula lis a physiologically tolerable salt.

12. A process as claimed in claim 1, wherein the compound of formula lis reacted with the acid halide forming agent in the presence of the compound of formula at a temperature of from -70 to +300 C.

13. A process as claimed in claim 12, wherein the temperature is from -20 to +1 00C.

14. A process as claimed in any one of claims 1 to 13, wherein the resulting complex is reacted with the compound of formula III at a temperature of from -80 to +300C.

1 5. A process as claimed in claim 14, wherein the temperature is from -20 to +20 C.

16. A process as claimed in any one of claims 1 to 15, wherein R1 denotes alkyl having from 1 to 4 carbon atoms, or cycloalkyl having from 3 to 8 carbon atoms, an alkyl or cycloaikyl group optionally being monosubstituted or polysubstituted.

1 7. A process as claimed in any one of claims 1 to 15, wherein an alkyl or cycloalkyl is monosubstituted or polysubstituted by alkyl having from 1 to 4 carbon atoms, by cycloalkyl having from 3 to 8 carbon atoms, by alkoxy-carbonyl having from 1 to 4 alkyl carbon atoms by carboxy, by cyano, by carbamoyl, which can be mono- or disubstituted by optionally substituted alkyl with 1 to 4 carbon atoms, it also being possible for 2 substituents to be closed to form a 5- or 6-membered ring optionally interrupted by O or N, by alkylcarbonyl having from 1 to 4 carbon atoms, by sulfo or sulfamoyl, by alkoxysulfonyl having from 1 to 4 carbon atoms, by a phosphono group, by hydroxyl, by halogen, by alkoxy having from 1 to 4 carbon atoms, by alkylthio having from 1 to 4 carbon atoms, by acyloxy, by carboxyalkoxy having from 1 to 4 carbon atoms, or by aryl.

1 8. A process as claimed in claim 17, wherein aryl optionally carrys further substituent(s), selected from a heterocycle as defined for "Het" in the group -CH2S-Het in claim 1; alkyl having from 1 to 4 carbon atoms; alkenyl having from 1 to 4 carbon atoms; alkoxy having from 1 to 4 carbon atoms; alkylthio having from 1 to 4 carbon atoms; halogen; sulfamoyl; carbamoyl; carboxy; trifluoromethyl; alkoxycarbonyl having from 1 to 4 carbon atoms; cyano; nitro; amino; alkylamino having from 1 to 4 carbon atoms; dialkylamino having from 1 to 4 carbon atoms.

1 9. A process as claimed in any one of claims 1 to 16, wherein R, denotes alkenyl having from 2 to 6 carbon atoms, and being optionally substituted.

20. A process as claimed in claim 19, wherein an alkenyl group R, is substituted by alkyl having from 1 to 4 carbon atoms; by halogen; by carboxyl or carbamoyl, optionally substituted as specified for alkyl groups R, in claim 17; by alkyloxycarbonyl having from 1 to 4 alkyl carbon atoms.

21. A process as claimed in any one of claims 1 to 15, wherein R, denotes alkynyl having from 3 to 5 carbon atoms, and being optionally substituted.

22. A process as claimed in claim 21, wherein an alkynyl group R, is substituted by aryl.

23. A process as claimed in any one of claims 1 to 1 5, wherein R, denotes aliphatic, saturated or unsaturated acyl having from 1 to 7 carbon atoms and being optionally substituted.

24. A process as claimed in claim 13, wherein an aliphatic acyl group is substituted by halogen; amino; alkylamino having from 1 to 4 carbon atoms; dialkylamino having from 1 to 4 carbon atoms, optionally forming a ring which may be interrupted by hetero atoms.

25. A process as claimed in any one of claims 1 to 15, wherein R denotes aromatic acyl, which is optionally substituted.

26. A process as claimed in claim 25, wherein aromatic acyl is substituted by alkyl having from 1 to 4 carbon atoms; halogen; alkyloxy having from 1 to 4 carbon atoms; dialkylamino having from 1 to 4 carbon atoms, optionally forming a ring which may be interrupted by hetero atoms; trifluoromethyl.

27. A process as claimed in any one of claims 1 to 1 5, wherein R, denotes heterocyclic acyl derived from heterocyclic 5- or 6-membered ring having from 1 to 4 hetero atoms, and being optionally substituted.

28. A process as claimed in claim 27, wherein heterocyclic acyl is substituted by substituent(s) as specified in claim 26 for aromatic acyl groups R,.

29. A process as claimed in any one of claims 1 to 15, wherein R1 denoted phenylsulfonyl, ptolylsulfonyl orpaminophenylsulfonyl.

30. A process as claimed in any one of claims 1 to 15, wherein R1 denotes optionally substituted alkylsulfonyl having from 1 to 7 carbon atoms.

31. A process as claimed in any one of claims 1 to 15, wherein R, denotes aryl, optionally substituted by substituent(s) as specified in claim 26 for aromatic acyl groups R,.

32. A process as claimed in any one of claims 1 to 1 5, wherein R, denotes a heterocyclic group derived from a heterocyclic 5- or 6-membered ring having from 1 to 4 hetero atoms, and being optionally substituted.

33. A process as claimed in claim 32, wherein a heterocyclic group R, is substituted by substituent(s) as specified in claim 26 for aromatic acyl groups R,.

34. A process as claimed in any one of claims 1 to 33, wherein R2 denotes optionally substituted 2-furyl or 4-thiazolyl.

35. A process as claimed in any one of claims 1 to 34, wherein R, is substituted at the 2-position.

36. A process as claimed in any one of claims 1 to 35, wherein a protected amino group substituting R2 is an amino group protected by a protective group that is removable by acid hydrolysis or hydrogenolysis.

37. A process as claimed in any one of claims 1 to 36, wherein B denotes thiadiazolyi or tetrazolyl.

38. A process as claimed in any one of claims 1 to 37, wherein R2, R3, R4 and Rs each denotes an alkyl group having from 1 to 4 carbon atoms.

39. A process as claimed in any one of claims 1 to 38, wherein when R3 and R4, or R3 and R5 are closed to form an optionally heterocyclic ring, this has from 4 to 8 ring members.

40. A process as claimed in any one of claims 1 to 39, wherein the compound of formula IV is an N-disubstituted carboxylic acid amide both alkyl groups of which are optionally closed to form an optionally heterocyclic ring having 4 to 8 ring members.

41. A process as claimed in claim 40, wherein compound IV is dimethylacetamide, diethylacetamide, N,N-dimethylpropionamide, N,N-diethylpropionamide, N-acetylmorpholine, Nacetylpiperidine, N-methylpyrrolidone or tetramethylurea.

42. A process as claimed in claim 1, carried out substantially as described in any one of the Examples herein.

43. A compound of the general formula I as defined in claim 1, whenever produced by a process as claimed in any one of claims 1 to 42.

44. A compound of the general formula II

in which R, represents a phenyl or benzyl group and R2 is as defined in claim 1.