NO792231L - PROCEDURE FOR MANUFACTURING CEPHEM RELATIONS - Google Patents

Abstract

Process for the preparation of cephem compounds.

Description

It is known that in compounds of the general formula I the oximinoether group of formula

in which FL has the stated meaning, exist in a syn- and an anti-form and that their biological effect is different.

It is also known that syn-oximino ethers under different reaction conditions can very easily be converted into anti-compounds so that very special methods must

is used to prevent this isomerization to achieve

unified vision products.

This is known, for example, from DOS 27 02 501

that one obtains compounds according to formula I, in which the R-^O group is in the syn position by carrying out

the acylation with the symmetrical anhydride 2-alkoxyimino-

acetic acid. This turnover has the downside that it has to

2-Alkoxyimino-acetic acid is used in double the amount depending on the amino component to be acylated.

It is further known from DOS 22 23 375 and

22 65 234 that one can produce acid chlorides from compounds

tendons of formula II in admixture with their anti-compounds by reacting sodium salts of the corresponding carboxylic acid with oxalyl chloride using catalytic amounts of dimethylformamide or reacting the free acids with phosphorus pentachloride. Furthermore, for aminothiazolyl compounds i

■ DOS 25 56 736 described that when oxalyl chloride is used as an acid chloride forming agent, the sodium salt forms a ■compound whose NMR spectrum shows that it relates to the anti-compound.

sight H 6.75 (D20) DOS 27 02 501

anti H 7.58 (D20) ..DOS 25 56 736

It is finally described in the literature that by using dimethylformamide and phosphorus oxychloride, thionyl chloride or phosgene, the acylation of 7-amino-cephem compounds with 2-(2-amino-4-thiazolyl)-alkoxyimino-acetic acid should be successful. Similar investigations show that this method produces products with a poor yield and insufficient purity. As already indicated in the literature, a chromatographic purification must be associated to obtain a pure product.

Furthermore, it is known from the literature that dimethylformamide with thionyl chloride forms a compound which is not very stable and which decomposes quickly in the presence of traces of Fe.

Surprisingly, it was now found that when using compounds of the general formula IV after addition of acid

halogen generators such as phosgene, oxalyl chloride, phosphorus pentachloride or phosphorus oxychloride, reaction products are formed which are characterized by a higher • stability. Of these reaction products, active complexes are formed with the carboxylic acids of formula II which, surprisingly, with 7-aminocephem compounds of formula III do not form expected derivatives of formula I with surprisingly excellent yield and high purity. It must also be considered surprising that the acylation takes place without conversion of the 2-oximinoether group from syn to anti form. ■

The method according to the invention thus relates to the production of cephem compounds of the general formula I

where A stands for hydrogen, an equivalent of an alkali or alkaline earth metal or an organic nitrogen base or for the remainder of an ester group, FL stands for hydrogen, an optionally substituted alkyl-, alkenyl-, alkynyl-, cycloalkyl-, aralkyl-, acyl- ,' aryl-, arylsulfonyl-, alkylsulfonyl- or a heterocyclic group, R^ stands for an optionally with alkyl with 1-4 C atoms, aryl or an optionally protected amino group substituted furyl-, thiazolyl- or phenyl residue and B stands for lower alkoxy , methyl, acetoxymethyl, carbamoylmethyl, halogen or -CH^S-Het, in which Het can stand for a 5- to 6-membered ring with 1-4 heteroatoms and in which the R-^O group is in the syn position and n stands for the number 0, 1 or 2, characterized by reacting a carboxylic acid with the general formula II or its salts, in which B.^ and R^ have the meaning indicated above, in the presence of approx. 0.1 to approx. 3.0 mol of a compound of the general formula IV

in which the residues R^, R^ and R^ may be the same or different and may stand for alkyl with 1-6 carbon atoms, whereby the residues R-j and R[j respectively R^ and R^ 'optionally together with a

heteroatom can form a ring and R^ can also stand for a dialkyl-amino group, in which the alkyl groups can each contain 1-6 C atoms and optionally together with a heteroatom can form a ring, with an acid chloride generator and the resulting complex

is marketed with a cephem acid of the general formula

III ■

in which B and n have the meaning indicated above, in the form of an amine salt or an optionally by acid hydrolysis or hydrogeno-. light detachable. ester or a silyl ester - and if necessary - transfers in the cephem carboxylic acid with formula I a possibly formed carboxyl group in a manner known per se to another group mentioned under A.

In the cephem compounds of formula I, A may have the meaning of hydrogen, an alkali metal, especially sodium, an equivalent of an alkaline earth metal, especially calcium, an equivalent of an organic nitrogen base, especially diethylamine, diethanolamine or procaine. It can also stand for the remainder of an ester group, such as a lower alkyl ester, e.g. tert-butyl ester, an optionally substituted benzhydryl ester, for example bis-p-methoxy-benzhydryl ester, a p-alkoxy-benzyl ester. with lower alkoxy groups, e.g. p-methoxybenzyl ester, phthalide ester, an acetoxymethyl or pivaloyloxymethyl ester.

R^ can, for example, mean hydrogen,

alkyl with 1-4 C atoms, such as methyl, ethyl, propyl, butyl, preferably methyl or cycloalkyl with 3-8, preferably 3-6, C atoms, such as e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, whereby alkyl and cycloalkyl can further be substituted one or more times, for example with alkyl with 1-4 C atoms, preferably methyl.,

with cycloalkyl with 3-8, especially 3-6 C atoms, such as cyclopentyl or cyclohexyl, with alkoxycarbonyl with 1-4 alkyl C atoms, preferably methoxycarbonyl or ethoxycarbonyl,

with carboxy; cyan; carbamoyl, which can be substituted once or twice with optionally, - for example hydroxy-substituted alkyl with 1-4 C atoms, whereby 2 substituents can also be connected to a 5" or 6-membered ring which optionally

may contain 0' or N, such as e.g. morpholino, piperazino, N-methylpiperazino, pyrrolidino, with alkylcarbonyl with 1-4 alkyl-C atoms, especially acetyl, with sulfo; sulfamoyl,

with alkoxysulfonyl with 1-4 C atoms, especially methoxy or ethoxysulfonyl,

with a phosphonic group,

with hydroxy, with halogen, preferably chlorine, bromine,

with alkoxy with 1-4 C atoms, especially methoxy or ethoxy, with alkylthio with 1-4 C atoms, especially methylthio or ethylthio,

with acyloxy., especially aliphatic acyloxy with 1-4 C atoms, which. e.g. acetoxy or benzoyloxy,

with carboxyalkyloxy with 1-4 alkyl C atoms, especially carboxymethoxy,

with aryl, - preferably phenyl as. can also carry other substituents such as for example '

a heterocycle defined under B in the sense of -CH2S-Het for "Het",

alkyl of 1-4 C atoms, preferably methyl; alkenyl with 1-4 C atoms, preferably allyl; alkyloxy with 1-4 Cratoms, preferably methoxy; alkylthio with 1-4 C atoms, preferably methylthio; halogen, preferably chlorine, bromine; sulfamoyl, carbamoyl, carboxy, trifluoromethyl; alkyloxycarbonyl with 1-4 alkyl C atoms, such as e.g. methoxycarbonyl; cyano,

nitro; amirio; alkylamino with 1-4 C atoms, such as e.g. methyl-amino or -ethylamino; dialkylamino with 1-4 C atoms, such as e.g. dimethyl- or diethylamino, or amidine p

alkenyl with 2-6, preferably 3-5 C atoms, such as e.g. allyl or crotonyl which can also be further substituted, for example

with alkyl with 1-4 C atoms, preferably methyl,

with halogen, especially chlorine, bromine, with carboxyl or carbamoyl, which may be substituted as indicated above lower alkyl (R^),

with alkyloxycarbonyl with 1-4 alkyl C atoms, especially methoxycarbonyl and ethoxycarbonyl,

alkynyl with 3~5 C atoms, preferably propargyl which can also be further substituted, for example

with aryl, preferably phenyl,

aliphatic, saturated or unsaturated acyl with 1-7, preferably 1-4 C atoms, such as e.g. formyl, acetyl, propionyl, butyryl, hexanoyl, acryloyl, crotonoyl, propioloyl which can also be further substituted, for example

with halogen, such as chlorine, bromine, fluorine which, for example, leads to a chloroacetyl, dichloroacetyl or bromoacetyl residue,

with amino,

with alkylamino with 1-4 C atoms, preferably methyl or ethylamino, with dialkylamino with 1-4 C atoms, especially dimethyl or diethylamino which can also possibly be connected to a ring through heteroatoms such as oxygen, nitrogen or sulfur , like for example. morpholine or'piperazine, perhydro-thiazine,

aromatic acyl, such as benzpyl or naphthoyl which can also be substituted, for example

with alkyl of 1-4 C atoms, especially methyl,

with halogen, preferably chlorine, bromine,

with alkyloxy with 1-4 C atoms, especially methoxy,-.

with dialkylamino with 1-4 C atoms, especially dimethyl- or diethylamino, which also optionally over heteroatoms such as e.g. oxygen or nitrogen, may be connected to the above-mentioned ring,

with triflubromethyl,

heterocyclic acyl which is derived from heterocyclic 5- or 6-rings with 1-4 heteroatoms such as e.g. sulphur, oxygen and nitrogen, such as thenoyl, furoyl, nicoinoyl, isonicotinoyl or picolinoyl which can also be further substituted, for example with substituents as indicated above for ■aromatic acyl (R1),

optionally substituted arylsulfonyl, especially phenylsulfonyl, p-tolylsulfonyl and p-amino-phenylsulfonyl,

optionally substituted alkylsulfonyl with 1-7, preferably

1-4 C atoms, especially ■methyl- or ethylsulfonyl, .

aryl, preferably phenyl, or, for example, 1- or 2-naphthyl, which can also be further substituted, for example with sub-

substituents as indicated above for aromatic acyl (R-^),

a heterocyclic group derived from heterocyclic 5- or 6-rings with 1-4 heteroatoms such as e.g. sulphur, oxygen and nitrogen, such as thienyl, . furyl, pyridyl or picolinyl which can also be further substituted, for example with substituents as indicated above for aromatic acyl (R^).

If R 2 stands for one of the above-mentioned heterocyclic rings, the 2-furyl and 4-thiazolyl residues in particular come into consideration. These residues can also carry substituents, preferably in the 2-position, such as, for example, an alkyl group, especially with 1-4 C atoms, preferably methyl, an aryl group, preferably a phenyl residue, an amino group or

■a protected amino group. Amino protecting groups in particular come into consideration which can be split off by acid hydrolysis or hydrogenolysis, such as e.g. a halogen, preferably a chlorine or bromoacetyl group, a carbobenzoxy group, a tert.butyloxycarbonyl group or, in particular, a trityl group which can optionally be further substituted, for example with halogen or alkyl.

B can mean methyl, acetoxymethyl, carbamoyloxymethyl, halogen, preferably chlorine, lower alkoxy, preferably methoxy or a group -CH^S-Het, in which Het stands for a 5- or 6-chained ring with 1-4 heteroatoms, preferably nitrogen or sulphur, such as a thiadiazolyl, preferably 1,3,4-thiadiazolyl radical or a tetrazolyl radical.

n can have the meaning of 0, 1 or 2.

The synthesis of carboxylic acids with the general formula II is described in the patent literature, for example in DOS

27 02 501. The carboxylic acids of the general formula II i'

in which R^ stands for phenyl or benzyl, are new.

The synthesis of the starting compounds of the general formula III is known from the literature. When n means 1 or 2, then the compounds must have been prepared by prior oxidation according to methods which are, for example, described in E.H. Flynn, Cephalosporins and P.enicillins, Academic Press, New York and London (1972).

Those for carrying out the method according to the invention are active complexes of carboxylic acids with formula

II is preferably reacted directly after formation with 7-amino-cephem compounds. .The carboxylic acids of formula II are preferably used as free glacial acids. However, it is possible for the turnover to use their salts, such as alkali salts, spe particularly the sodium salt or also amine salts, such as for example the triethylamine salt.

Examples of acid halide generators include thionyl halides such as thionyl chloride or thionyl bromide, especially phosphorus pentachloride, phosphorus oxychloride and oxalyl chloride, phosgene being particularly preferred.

If R^, R^ and R,- in the formula of the compounds stand for alkyl with 1-6 C atoms, then for example methyl, ethyl, propyl, butyl, hexyl come into consideration, preferably, however alkyl residues with 1-4 C- atoms, especially methyl. If R^ and •. Rjj, respectively R and R,-, are joined via a heteroatom-, then oxygen and nitrogen in particular must be mentioned as heteroatoms. As rings, those with 4-8, especially with 5-6, ring members come into consideration, such as, for example, a piperidine, morpholine, pyrrolidone, pyrrolidine, azetidinone-2 or piperazine ring.

Particularly suitable as compounds with the general formula IV are N-disubstituted carboxylic acid amides, such as for example dialkylacetamide, whereby both alkyl groups, preferably lower alkyl groups, which can also be linked to a 4- to 8-sided ring, which can also include ■: a heteroatom e.g. nitrogen or oxygen. Examples include N-methyl-pyrrolidone. N-methyl-axetidinone, N,N-diethylbutyramide, dialkylpropionamide and dialkylacetamide which preferably contain lower alkyl substituents, such as e.g. diethylacetamide, diethylacetamide, N-acetyl-piperidine, N-acetyl-morpholine, N-^propiony 1-piperidine, N-butyryl-pyrrolidine, N-butyryl-piperidine, N,N-dimethyl-N',N'-pentamethyleneurea,

.tetramethylurea, tetraethylurea. Particularly preferred compounds of formula IV should be mentioned diethylacetamide, N,N-dimethylpropionamide, N,N-diethylpropionamide, N-acetylpiperidine and tetramethylurea, which are particularly preferred

dimethylacetamide.

Particularly important for the applicability of the compounds of formula IV according to the invention has been shown to be the stability of corresponding reaction products with acid halides. In contrast, it is known that the reaction products of thionyl chloride and dimethylformamide already

traces of Fe^<+>explosively split as already

. mentioned above. The production of active complexes with the carboxylic acids of formula II is carried out in a dry, inert solvent which does not prevent further reactions. Solvents include: halogenated hydrocarbons such as methylene chloride or chloroform, esters such as ethyl acetic acid or aromatic hydrocarbons such as toluene or xylol, but also ethers such as diethyl ether or diisopropyl ether.

For optimal implementation of the method according to the invention, the carboxylic acids of formula II are used in at least stoichiometric quantities calculated by the 7-amino-cephem compound to be reacted. Since it has been shown that an isolation of the active complex is not necessary,

the method can advantageously be carried out so that a quantity of approx. 0.1 to approx. 3 equivalents of, preferably 0.1 to 1.5 equivalents, of the compound of formula IV are filled into the reaction vessel, after which a corresponding amount is added

of the halogenation reagent and then the carbonic acid is reacted with formula II. The order of the additions is not critical.

The activation of the carboxylic acids of formula II

according to the invention with the described complex formation can be carried out in a wide temperature range, e.g. between -70°C and +30°C, whereby the range between -20°C and +10°C has proven particularly advantageous. The second step of the method according to the invention, the acylation, is linked directly, after the formation of the active complex. For this, the carboxylic acids of formula III can be used, for example in the form of their amine salts, especially trialkylamine salts such as, for example, the triethylamine salt, the trimethylbenzylamine or ethyldicyclohexylamine salt, but also a dialkylarylamine salt such as the N,N-dimethylaniline salt can also be used. These can also be used in form.

of their esters, whereby in the event that later conversion to a free carboxyl group is desired, such must be chosen as

by acid hydrolysis or hydrogenolysis is separable. As silyl esters, in particular trialkylsilyl esters, preferably trimethylsilyl esters, come into consideration, which can be obtained with corresponding silylating agents by methods known from the literature.

Freed hydrogen halides during the acylation are - if necessary - neutralized by the addition of a

base whereby trialkylamines, such as e.g. triethylamine, tr.i-methylbenzylamine, ethyldicyclohexylamine- have been found to be particularly useful. But dialkylarylamines such as N,N-dimethylaniline are also usable.

The acylation reaction can be carried out at temperatures between, for example, -80°C and +30°C, preferably between -20°C and +20°C. At these temperatures, the reaction is generally complete after approximately 30-60 minutes.

The acylation products thus obtained allow

itself in a known manner, possibly after cleavage of a possibly occurring protective group, easily isolated. Such cleavage of the amino protecting group can, for example, be carried out according to methods described in DOS 27 02 -501 or in Houben-Weyl, volume -XV/1, page 272 f.

Esters produced according to the invention can be isolated and used as such or transferred into free acids according to known methods such as e.g. hydrolysis or hydrogenolysis. If one obtains the compounds of formula I according to the invention in the form of their amine salts, then

allow these to be transferred in a manner known per se into free acids by the alkali salts.

The following examples shall illustrate the method according to the invention without, however, limiting it

■.. this .

Example 1

Diethylamine salt of 3~ acetoxymethyl- 7-[ 2-( 2- tritylamino- 4-thiazolyl)- 2-( syn)- methoxyimino- acetamidoj- cef- 3- em- 4- carbon-

acid

54 g (0.1 mol) of 2-(2-tritylamino-4-thiazolyl)-2-(syn)-methoxyiminoacetic acid (82 percent) is suspended

in a 4-necked flask in 800 ml toluene. At a bath temperature of approx. At 50°C, 400 ml of toluene is distilled off in a vacuum. There-

then the suspension is cooled to -5°C and after the addition of 9.3 ml (0.1 mol) of N,N-dimethylacetamide at -5°C added dropwise with a solution of 12.2 g (0.12 mol) of phosgene in 60 ml of toluene. The mixture is then stirred for 16 hours at -5°C. To

the thus obtained suspension is added drop by drop

-5°C to -7°C a carbon addition filtered 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. Stir for 30 minutes at -5°C and then 60 minutes so that the temperature rises to 10-15°C. The pH is then adjusted to 2

with 2N hydrochloric acid, pour the batch into a mixture of 500 ml of methylene chloride and 500 ml of water and separate the phases. The organic phase is washed once with 500 ml of water, dried over sodium sulphate and evaporated in vacuo (finally with an oil pump). The residue is dissolved in 270 ml of acetone and, after the addition of 10.3 ml of diethylamine, heated to reflux for 30 minutes with stirring. Already after a short time, crystallization occurs. After standing for several hours at room temperature, cool with an ice bath, vacuum, wash with cold acetone and dry. The diethylamine salt obtained in this way with very good yield has syn configuration.

NMR (DMSO, 60 MHz): 6.68 ppm = thiazole ring proton

Example 2

Diethylamine salt of 3~ acetoxymethyl- 7- 12-( 2- tritylamino- 4-thiazolyl)- 2-( syn)- methoxyimino- acetamido] - cef- 3~ em- 4- carboxylic acid

.54 g (0.1 mol) of 2-(2-tritylamino.-4-thiazolyl)-2-(syn)-methoxyimino-acetic acid (82% vol) is suspended in a 4-necked flask in 600 ml of toluene and the toluene is distilled off

at a bath temperature of approx. 50-60°C in vacuum. The residue is then suspended in 400 ml of toluene, cooled to -10°C and after the addition of 9.3 ml (0.1 mol) of N,N-dimethylacetamide added over 20 minutes at -10°C dropwise with 10.2 ml (0.12 mol) oxalyl chloride, and diluted with 40 ml toluene.

It is stirred for 2.5 hours at -15°C and then 2.5 hours. hours by

-15°C to -5°C. To the suspension thus obtained, a solution of 28.6 g of 7-aminoc.ephalo-

sporanic acid (95 #-ig) (0.1 mole), and 55.3 ml (0.4 mole) of triethylamine in 500 ml of methylene chloride. Stir for 30 minutes

-5°C and stirring for 60 minutes at -5°C to +10°C, set

titrate the batch with 2N hydrochloric acid to pH 2 and pour into a mixture of 500 ml methylene chloride and 500 ml water, shake and separate the phases. The organic phase. is washed with 500 ml of water and evaporated in vacuum (finally with the oil pump). The pale yellow residue is dissolved in 270 ml of acetone and after adding 10.3 ml of diethylamine quickly with stirring for 30 minutes and reflux. After standing for 2 hours at room temperature, it is cooled for 1 hour in an ice bath, suctioned off, washed with acetone and dried. The diethylamine salt obtained in very good yield has syn configuration.

NMR (DMSO, 60 MHz): 6.68 ppm = thiazole ring proton

Example 3

Diethylamine salt of 3- acetoxymethyl- 7~ t2-( 2- tritylamino- 4- thiazolyl)- 2-( syn)- methoxyimino- acetamido- cef- 3- em- 4- carboxylic acid

5.4 g (10 mmol) of 2-(2-tritylamino-4-thiazolyl)-2-(syn)-methoxyiminoacetic acid (82%) are suspended in 80 ml of toluene. Half of the solvent is distilled off at 50-60°C and the suspension is cooled to -25°C. After adding 1.02 ml (11 mmol) of N,N-dimethylacetamide, 2.2 g (11 mmol) of phosphorus pentachloride are added. The mixture is stirred for 30 minutes at -20°C and then for 3 hours at -5°C. After

addition of 100 ml of absolute diisopropyl ether, the solid ■ is sucked off in the absence of moisture and stored in the vacuum desiccator. The complex compound thus obtained becomes

introduced at -25°C in a solution of 2.8 g (10 mmol) 7-amino-cephalosporanic acid (95%-ig) and 5.4 ml (40 mmol) triethylamine in 50 ml methylene chloride. After heating to room temperature, stir for another hour at room temperature. The storage and transfer to the diethylamine salt is carried out in the same way as described in examples 1 and 2. The product obtained also has a syn configuration.

Example 4

Diethylamine salt of 3~ acetoxymethyl- 7- L2-( 2- tritylamino- 4- thiazolyl)- 2-( syn)- methoxyimino- acetamidoj- cef- 3- em- 4- carboxylic acid. 4.8 g (24 mmol) phosphorus penta-

chloride in 100 ml toluene, while stirring at room temperature, add a solution of 2.2 ml (24 mmol) N,N-dimethylacetamide in 10 ml toluene, and then stir for 1 hour at room temperature. The complex crystallizes and settles.

After extraction of excess solution and repetition.

of this with 100 ml of new toluene, the residue is added to 100 ml of toluene and the suspension is cooled to -5°C. 8.8 g (20 mmol) of 2-(2-tritylamino-4-thiazolyl)-2-(syn)- are added methoxy-imino-acetic acid and stir for 20 hours at -5°C After this time, a solution of 534 g (20 mmol) 7-aminocephalosporanic acid and 11.5 ml (83 mmol) triethylamine is added dropwise to the resulting suspension at -5°C in 100 ml methylene chloride bg then stirred for 1 hour at room temperature. The processing and transfer to the diethylamine salt is carried out as described in examples 1-3- The

obtained product has. view configuration.

' Example 5

Diethylamine salt of 3~ acetoxymethyl- 7~ L^~( 2- tritylamino- 4-thiazolyl)- 2-( syn)- methoxyimino- acetamido] - cef- 3~ em- 4- carboxylic acid

46.5 g (0.1 mol) of the sodium salt of 2-(2-tritylamino-4-thiazolyl)-2-(syn)-methoxyiminoacetic acid are suspended in 600 ml of toluene and the toluene is distilled off at a bath temperature of 60 °C in vacuum. The residue is suspended in 400 ml of toluene, 9.3 ml (0.1 mol) of N,N-dimethylacetamide is added and cooled to -10°C. With stirring, a solution of 12 g (0.12 mol) of phosgene in 150 ml of toluene is then added dropwise over 30 minutes at -10°C to -5°C. It is then stirred for 17 hours at -10°C and the suspension thus obtained

tion is transferred during 10 minutes in a stirred and at -10°C

cold mixture of 25.8 g of 7-aminocephalosporanic acid, 5533 ml of triethylamine and 500 ml of methylene dichloride. During the 90 minutes

ter becomes. the temperature is brought to +15°C, the pH is then adjusted to 2 with 2N hydrochloric acid, the batch is then poured over into a mixture of 500 ml methylene dichloride and 500 ml water and the phases are separated. The organic phase is washed once with 500 ml of water and evaporated in vacuo. The pale yellow residue is dissolved in 270 ml of acetone and after the addition of 10.3 ml of diethylamine in

30 minutes under stirring, the solution was brought to boiling temperature. After an hour's recommendation at room temperature, vacuum off. washed with acetone and dried. The diethylamine salt obtained in very good yield has syn configuration.

NMR (DMSO) 6.68 ppm (thiazole ring proton)

If the toluene in the complex formation was replaced with benzene, then the diethylamine salt is obtained with the same good yield, with ether as solvent this is somewhat lower.

If phosgene is replaced with oxalyl chloride as a halogenating agent and the procedure is carried out as above

for specified, then a dividend is obtained which is approximately 1/3 lower.

Example 6 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-(syn)-methoxyimino-acetamido]-cef-3-em-4-carboxylic acid

4 g (0.02 mol) of 2-(2-amino-4-thiazolyl)-2-(syn)-methoxyiminoacetic acid are suspended in 200 ml of toluene and the toluene is distilled off at a bath temperature of 60°C in

vacuum. The residue is suspended in 100 ml of methylene dichloride,

.1.86 ml (0.02 mol) of N,N-dimethylacetamide is added and it is cooled to -10°C. With stirring, a solution of 3 g (0.03 mol) of phosgene in 10 ml of toluene is then added over 10 minutes and then stirred for 5 hours at -5°C. To the clear pale yellow solution is then added dropwise at -5°C

to -8PC a carbon-addition filtered solution of 5.4 g of 7-amino-cephalosporanic acid (0.02 mol) and 11 ml of triethylamine in 100 ml of methylene dichloride during 10 minutes. It is then stirred for an hour at -5°C and an hour up to +15°C and the mixture is then freed from the solvent in a vacuum (finally with the oil pump). The brownish-yellow, colored, amorphous

The residue is dissolved in 45 ml of 80 per cent formic acid and added dropwise over \\ hour to a 300 ml stirred 35 per cent aqueous ammonium sulphate solution. The precipitate that has formed is suctioned off, washed in portions with 150 ml of water and dried

in vacuum over plates of NaOH. The crude product is then suspended in 10 ml of 98 percent ethanol and stirred for 30 minutes at 50°C. After cooling, vacuum, wash with alcohol and dry. The title connection thus obtained has syn-configuration.

NMR (DMSO, 60 MHz): 6.68 ppm (thiazole ring proton)

Example' 7

3- acetoxymethyl- 7- f-' 2- ( 2- amino- 4- thiazolyl)- 2-( syn)- methoxy- imino- acetamido] - cef- 3~ em- 4- carboxylic acid 4 g (0.02 mol ) 2-(2-amino-4-thiazolyl)-2-(syn)-methoxyimino-acetic acid is suspended in 200 ml of toluene and the toluene is distilled off at a bath temperature of 60°C in vacuum. The residue is suspended in 100 ml of methylene chloride, 2.8 ml (0.03 mol) of N,N-dimethylacetamide is added and, after cooling to -10°C under stirring, added dropwise over 10 minutes in a solution of .2.55 ml (0. 03 mol) of oxalyl chloride in 10 ml of methylene chloride. The clear pale yellow colored solution formed is stirred for 5 hours at -10°C and then added,

a mixture of 53 2' g of 7-aminocephalosporanic acid, 11 ml of triethylamine and 100 ml of methylene chloride. It is then stirred for 1.5 hours to a temperature of +15°C and then the solvent is removed in vacuum, finally with the oil pump. The residue was dissolved in 50 ml of 80 per cent formic acid and 350 ml of 35 per cent aqueous ammonium sulphate solution was added dropwise over 1.5 hours. The precipitate is suctioned off, washed with water and dried, then suspended in 15 ml of 98% ethanol and stirred for 30 minutes at +50°C. After cooling, suction, wash with ethanol and dry. The light yellow colored product has a visual configuration.

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

Example 8 3-acetoxymethyl-7-[2-(2-amino-4-thiazblyl)-2-(syn)-metbximino-acetamido]-cef-3-em-4-carbonic acid •

Analogous to. example 7, 4.5 g of 2-(2-amino-4-thiazolyl)-2-(syn)-methoxyimino-acetic acid sodium salt becomes

set with 1.86 ml of N,N-dimethylacetamide and 3 g of phosgene. After acylation and purification over the formate, a pale yellow colored product was obtained which has the syn configuration.

Example 9

7-[2-(2-amino-thiazol-4-yl)-2-syn-benzyloximino-acetamido-cephalosporanic acid

A solution of 18.2 g of 2-(2-tritylamino-thiazol-4-yl)-2-syn-benzyloximino-acetic acid in 160 ml of absolute toluene is added to 3.05 g of N-N-dimethylacetamide and cooled to -8°C and 13.5 ml of a toluene solution containing 38 per cent phosgene is added dropwise, whereby a product is secreted which after a short time is converted into an almost colourless, crystalline product.

After 5 hours, the suspension is introduced into a solution of 9.6 g of 7-aminocephalosporanic acid and 19.6 ml of triethylamine in 160 ml of absolute methylene chloride at -5°C, stirred for 45 minutes at -1°C, then allowed to stand overnight at 5 °C

and finally, after adding a further 125 ml of methylene chloride, 150 ml of ice water is added.

The reaction mixture is brought to pH 1 with 2N HCl, the organic phase is separated, washed three times with ice water and, after drying over Na 2 SO 3 , evaporated to dryness.

The formed 7-[.2-(2-tritylamino-thiazol-4-yl)-2-syn-benzyloximino-acetamido]-cephalosporanic acid appears as a light beige colored product. 20 g of the tritylated compound obtained is introduced into 110 ml of a 50 percent formic acid and heated to 50°C. The substance dissolves after a short time, then triphenylcarbinol precipitates as colorless crystals. After one hour, it is filtered, the filtrate is evaporated in vacuo and then the residue is introduced into 250 ml of water, where

in doing so, a colorless crystalline product is secreted. The product is filtered off, washed with isopropanol and finally with ether. 7-[2-(2-aminothiazol-4-yl)-2-syn-benzyloximino- is isolated. acetamido]-cephalosporanic acid as colorless crystals. Thin layer chromatogram: Rf 0.35 (n-Bu-OH-: H 2 O : EtOH : AcOH = 20 : 4 : 3 3)

Example 10

7- f. 2- ( 2- amihothiazol- 4- y 1) - 2- syn- benzyloximino- acetamidoj - 3-( l- methyI- tetrazol- 2- yI)- thiomethyl- A 3- cephem- 4- carboxylic acid En resolution of 11.4. g of 2-(2-tritylaminothiazol-4-y1)-2-syn-benzyloximinoacetic acid in 120 ml of absolute toluene, add 2.0 g of N,N-dimethylacetamide and react dropwise at

-8°C with 8.5 ml of a 38 percent phosgene containing toluene solution. After 5 hours, a solution of 7.35 g of 3~(1-methyltetrazol-2-yl-thiomethyl-A 3-cephem-4-carboxylic acid in a mixture of 9.6 g of triethylamine and 160

ml of methylene chloride over 10 minutes. The reaction mixture is then stirred for one hour at -5°C, then allowed to stand for 16

hours at + 2°C and add 70 ml of water and adjust with IN HC1 to pH 1. After brief stirring, filter, the organic phase is washed twice with water and evaporated to dryness. •One obtains 7~(2-(2-tritylamino-thiazol-4-yl)-2-syn-benzyloximino-acet.amido]-3-(1-methyl-tetrazol-2-yl-thiomethyl) - A 3-cephem-4-carboxylic acid as a cream-colored solid.

15 g of the obtained solid was introduced into

65 ml of 50 percent formic acid and heated to 50°C-. After 1.5 hours, the formed triphenylcarbinol is filtered off.

The filtrate is added with 2 g of active charcoal, filtered and evaporated to dryness. The residue - 250 ml of cold water is added, the cream-coloured powder formed is filtered off, washed with water and dried. The crystals obtained are stirred with 100 ml of ether for 2 hours and dried.

7-(2-(2-aminothiazol-4-yl)-2-syn-benzyloximino-acetamido]-3-(1-methyl-tetrazol-2-ylthiomethyl)-A3-cephem-4-carboxylic acid is obtained as a beige solid Thin layer chromatogram: Rf 0.35 (n-BuOH : H20 : EtOH AcOH = 20 . : 4 : 3 : 3) ..

Example 11

7 - ( 2- ( 2- aminothiazol-4- yl)- 2:- syn- benzyloximino- acetamido') ~ 3~

(2-methyl-1,5,4-thiadiazol-5-yl-thiomethyl)-A3~cephem-4-carboxylic acid In an analogous way, one obtains by using 7~amino-3-(2-methyl-1,354- thiadiazol-5-yl-thiomethyl)- 3-cephem-4- carboxylic acid and 2-(triphenylmethylamino-thiazol-4-yl)-2-syn-benzyloximino-acetic acid 7- 2-(2-tritylaminothiazol-4-yl)- 2-syn-benzyloximino-acetamido -3-(2-methyl-1,3>4-thiadiazol-5-yl-thiomethyl)-3_cephem-4-carboxylic acid which, on treatment with 50 percent formic acid at 60°C, is converted to 7- 2-(2-aminothiazol-4-yl)-2-syn-benzyloximinoacetamido -3-(2-methyl-1,3,4-thiadiazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid (cream colored solid ).-Thin layer chromatogram: Rf 0.38 (n-BuOH : H2O : EtOH : AcOH

■20: 4 : 3 : 3)..

Example 12

7-[ 2-( 2- aminothiazol-4-yl)- 2- syn- phenoxyimino- acetamidoJ- cephalosporanic acid

In an analogous manner, from 2-(triphenylmethylamino-thiazol-4-yl)-2-syn-phenoximino-^acetic acid in toluene by adding N,N-dimethylacetamide with phosgene, the corresponding complex is obtained, which with a solution of 7 -aminocephalosporanic acid in methylene chloride/triethylamine reacts to 7_r2-(2-triphenyl-methyl-amino-thiazol-4-yl)-2-syn-phenoxyimino-cephalosporanic acid.

The tritylated product obtained is stirred in 50 percent formic acid for one hour at approx. 60°C, the split off

triphenylcarbinol is removed} the filtrate evaporated to dryness and taken up in ether. A beige colored 7_ 2-(2-aminothiazol-4-yl)-2-syn-phenoximino)-cephalosporanic acid is obtained as a solid, which according to the thin-layer chromatogram is shown to

be a uniform substance with Rf 0.54. (Bu-OH : H 2 O : EtOH : AcOH = 10 : 4 : 3 : 3).

Example 13

Diethylamine salt of 3-acetoxymethyl-7-(2-(2-tritylamino.-4-thiazolyl)-2-( syn)- methoxyimino-acetamido-cef-3-em-4-carboxylic acid 54 g (0.1 'mol) 2-(2-Tritylamino-4-thiazolyl)-2-(syn)-methoxyiminoacetic acid (82%) is suspended in a 4-necked flask in 800 ml of toluene. At a bath temperature of approx. 50 °C, 300 ml of toluene is distilled off in water. After cooling the suspension to -5 °C, 9.3 ml (0.1 mol) of N,N-dimethylacetamide are added and within 15 minutes 70 ml of a 2 molar phosgene solution in toluene (= 0.14 mol) and stir for 5 hours.

To the suspension thus obtained, add dropwise at -5°C a solution of 27.2 g (0.1 mol) 7-amino-cephalosporanic acid and 48.7 g (0.2 mol) N,0-bis-trimethylsilyl- acetamide in 300 ml of methylene chloride and stir for 30 minutes at

-5°C and 60 minutes at room temperature. After dilution with 500 ml of methylene chloride, the mixture is shaken three times with 500 ml of water each, the organic phase is dried over sodium sulphate

and evaporate in vacuo to dryness. The residue is dissolved in 250 ml of acetone and after the addition of 10.3 ml of diethylamine added with stirring for 30 minutes and heated to reflux. After cooling, vacuum, wash with acetone and dry. The title connection thus obtained with very good profit

has syn configuration.

NMR (DMSO, 60 MHz): 6.68 ppm - thiazole ring proton.

Example 14

3- acetpoxymethyl- 7- L2-( 2- amino- 4- thiazolyl)- 2-( syn)- methoxy- imino- acetamido J- cef- 3- em- carbonic acid

20.1 g (0.1 mol) of 2-(2-amino-4-thiazolyl)-2-(syn)-methoxyiminoacetic acid was suspended in 350 ml of methylene chloride, cooled to -10°C, added 9.3 ml (0.1 mol) N,N-dimethylacetamide and then within 5 minutes with stirring added 75 ml of phosgene solution in toluene (2 molar solution = 0.15

moles). To the light yellow, colored solution is added afterwards

25 minutes drop by drop over 30 minutes a solution of 21.4 g

(0.08 mol) 7-aminocephalosporanic acid and 39 ml (0.16 mol) bis-trimethylsilylacetamide in 500 ml methylene chloride in such a way that the temperature does not exceed -3°C. ■ During this time, the secretion of a resinous product begins. For complete precipitation, add after. 30 minutes 3 ml water. The organic solution is decanted and discarded, the residue is taken up in 200 ml of methylene chloride, the solvent is removed and the residue is freed from remaining solvent in vacuum at room temperature. The light yellow, colored, amorphous residue contains the title compound. ■ It is dissolved in 150 ml of 80 per cent formic acid and the solution is introduced drop by drop into

700 ml of 40 per cent aqueous ammonium sulphate solution.• The formed resinous precipitate is removed and taken up three times with 60 ml of ice water. It is extracted and dried. The product is the formate of the title compound and has syn configuration.

NMR (DMSO, 60 MHz): 6.68 ppm (thiazole ring proton),

8.13PPm (formyl). For deformylation, suspend in 50 ml of absolute ethanol, stir for 30 minutes at 50°C and, after cooling, suction off and wash with ethanol. The light yellow colored title compound thus obtained has syn configuration:

NMR (DMSO, 60 MHz): 6.68 ppm (thiazole ring proton).

Example 15 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-(syn)-methoxyimino-acetamido]-cef-5-em-4-carboxylic acid

10.0 g (0.05 mol) of 2-(2-amino-4-thiazolyl)-2-(syn)-methoxyiminoacetic acid is suspended in 200 ml of absolute methylene chloride. " After cooling to -10°C, 4.65 ml (0.05 mol) of dimethylacetamide and 5.75 ml (0.062 mol) of phosphorus oxychloride are added dropwise and then stirred for 2.5 hours. In this

a solution of 10.8 g (0.04 mol) 7-aminocephalosporanic acid is added dropwise to the suspension at -10°C. and 19.5 ml (0.08 mol) of bistrimethylsilylacetamide in 250 ml of methylene chloride. It is stirred for 2 hours at 0°C and worked up as indicated in example 13. The title compound thus obtained has syn configuration.

NMR (DMSO, 60 MHz): 6.68 ppm (thiazole ring proton).

Example 16

3- acetoxymethyl- 7- C2-( 2- amino- 4- thiazoly1)- 2-( syn)- methoxyimino-acetamido J- cef- 3~ em- 4- carboxylic acid

Analogously to example 14, 5 g (0.025 mol) of 2-(2-amino-4-thiazolyl)-2-(syn)-methoxyimino-acetic acid are reacted with 3.17 g of N-acetyl-piperidine and 3.8 g of phosgene. The product

.has view configuration.

Example 17

3- acetoxyrnetyl- 7~[ 2 -( 2- amino- thiazolyl)- 2-( syn)- methoxyimino-acetamidoj- cef- 3~ em- 4- carboxylic acid

Analogous to example 14, 5 g (0.025 mol) of 2-(2-amino-4-thiazolyl)-2-(syn)-methoxyiminoacetic acid are reacted with 2.5 g of N-methyl-pyrrolidone and 3.8 g of phosgene. The product has syn configuration.

Example 1' 8

3- acetoxymethyl- 7-[ 2 - ( 2- amino- 4- thiazolyl)- 2- ( syn)- methoxyimino^-acetamidoj- cef- 3~ em- 4- carboxylic acid

Analogous to example 14, 5 g (0.025 mol) of 2-(2-amino-4-thiazolyl)-2-(syn)-methoxyiminoacetic acid are reacted with 2.5 g of N,N-dimethylpropionamide and 3.8 g of phosgene. The product has syn configuration.

Example 19

3- acetoxymet yl- 7~ £ 2-( 2- amino- 4- thiazolyl)- 2-( syn)- methoxyimino-acetamidoj- cef- 3- em- 4- carboxylic acid

Analogously to example 14, 5 g of 2-(2-amino-4-thiazolyl)-2-(syn)-methoxyimino-acetic acid are reacted with 3.15 ml of N,N-diethylacetamide and 3.8 g of phosgene. The product has syn -conf iguras j on .

Preparation of the output compound of example 9

a) 2-syn-benzyloximinoacetate ethyl ester

To a. solution of 23.5 g of 2-syn-oximino-acetic acid diester in 120 ml of acetone was introduced with stirring at 15°C 30.5 g of potassium carbonate and then 25.6 g of benzyl bromide was added dropwise to the reaction mixture, after which the mixture was stirred for 4 hours at room temperature and then set aside for 16 hours without stirring.

The solids were filtered off and the solution

was evaporated to dryness. The remaining oil was heated to 80°C in vacuo (0.05 mm) to remove benzyl bromide, then the residue after cooling was added to 5% sodium bicarbonate solution and extracted with ether. The ether phase was washed twice with water, dried with Na2SO4 and then evaporated. The remaining residue was a pale yellow oil of 2-syn-benzyloximinoacetate diester. (Ty.nnsj ikt chromatogram in CHCl.3/acetic ester 20 : 1 : Rf 0.7*0 .

b) 2-syn-benzyloxyimino-4-bromoacetate ethyl ester

To a solution of 12.5 g of 2-syn-benzyloximino-acetacetic acid ester in 80 ml of absolute methylene chloride is added 150 mg of toluenesulfonic acid and then approx. 2 g required 8 g of bromine at room temperature. Upon stirring, the first deep brown color of the solution disappears. The rest of the bromine is then added dropwise. After the completion

of the addition is stirred 1| hour at room temperature and the reaction mixture is cooled to 0°C and washed with 10 per cent. sodium bicarbonate solution.

The organic phase is separated, dried over Na 2 SO 4 , evaporated and the remaining oil recrystallized from cyclohexane. 2-syn-benzyloximino-.4-bromoacetic acid ethyl ester is obtained as colorless crystals with a melting point of 66-68°C.

c) 2-(2-amino-thiazol-4-yl)-2-syn-benzyloximino-acetic acid urea ethyl ester

To a solution of 2.66 g of thiourea i

50 ml of 40 percent ethanol is added dropwise to a solution of 11.8 g of 2-syn-benzyloximino-4-bromoacetic acid ethyl ester in 60 ml of ethanol (98%) and 40 ml of acetone over the course of 20 minutes at room temperature. The reaction mixture is stirred for 2 hours at 25°C, then evaporated to crystallization of the final product and the crystals obtained are isolated. The product is dissolved in 50% ethanol under heating and then added the pH is adjusted to 7 using aqueous ammonia. The precipitated cream-colored crystals are isolated, washed with 40% ethanol and diisopropyl ether and dried. 2-(2-Aminothiazol-4-yl)-2-syn-benzyloximino-acetic acid ethyl ester with melting point 135-138°C is obtained as almost colorless crystals. d) 2-(2-triphenylmethylamino-thiazol-4-yl}-2-syn-benzyloxy-iminoacetic acid ethyl ester. To a solution of 18.3 g of 2-(2-aminothiazol-4-yl)-2-syn-benzyloximine p- acetic acid ethyl ester in. 125 ml of absolute CH2C12 and 25 ml of dimethylformamide are added at -15°C. 6.7 g of triethylamine, then cooled to -35°C, 17.5 g of triphenylchloromethane are introduced in portions, then stirred for one hour at -30°C and then 3 hours at room temperature.

The reaction solution is cooled to 0°C and washed several times with 2N HC1 and finally with water, the organic phase is isolated and dried over Na2SO4 and the solvent is removed. 2-(2-triphenyl-methylamino-thiazol-4-yl)-2-syn-benzyloximino-acetic acid ethyl ester is obtained as a cream-colored solid (DC in CHCl-j/acetic ester 1 : 1 Rf 0.98, cf. starting -material Rf 0.63)" which can be traded on without further purification.

e) Sodium salt of 2-(2-triphenylmethylamino-thiazol-4-yl)-2-syn-benzyloximino-acetic acid

The 2-(2-triphenylmethylamino-thiazol-4-yl)-2-syn-benzyl pximinacetic acid ethyl ester obtained is dissolved in a mixture of 230 ml of ethanol and 40 ml of dioxane at 60°C and a solution of 3 g of NaOH in . 45 ml of water and heated for 2 hours under reflux. The reaction mixture is then strongly evaporated and the residue is added to 350 ml of water and the sodium salt of 2-(2-triphenylmethyl-amino-thiazol-4-yl)-2-syn-benzyloximinoacetic acid is isolated as a colorless solid with a melting point of 257~258°C (decomposes ).

f) .2-(2-triphenylmethylamino-thiazol-4-yl)-2-syn-benzyloxy-iminoacetic acid

The obtained sodium salt of 2-(2-triphenylmethyl-amino-thiazol-4-yl)-2-syn-benzyloximinoacetic acid is suspended in 250 ml of methylene chloride and stirred at 5°C with 50 ml of 2N hydrochloric acid, whereby an acid is formed which is good soluble in C12•

The organic phase is isolated, dried with sodium sulphate and the solvent is removed. The residue is added

cyclohexane, whereby an almost colorless solid is formed which is isolated and washed with diisopropyl ether. 2-(2-Triphenylmethylamino-thiazol-4-yl)-2-syn-benzyloximino-acetic acid is obtained as an amorphous solid which in DC in CHCl^/CH^OH 6:1 shows an Rf value of 0.21.

Preparation of output compounds■for example 12.

a) Bromoacetylglyoxylic acid ethyl ester 120 g of acetylglyoxylic acid ethyl ester are dissolved

in 700 ml of methylene chloride and reacted at 5°C during one hour with a solution of 146 g of bromine in 200 ml of methylene chloride.

After clarification of the solution, the solvent was extracted and the remaining oil was reacted without further purification.

b) 2-amino-thiazol-4-yl-glyoxylic acid ethyl ester

A solution of 66 g of thiourea in 450 ml

water and <4>50 ml of ethanol were added dropwise with 195 g of bromoacetglyoxylic acid ethyl ester and after the addition was completed, the mixture was stirred for 30 minutes at room temperature and 30 minutes at 50°C and then the reaction mixture obtained after addition was filtered with activated charcoal. The filtrate was brought to pH 7 by the addition of sodium bicarbonate solution, whereby 2-amino-thiazol-4-yl-glyoxylic acid ethyl ester crystallized out in crystals with a melting point of 147°C<.>

c) 2-triphenylmethylamino-thiazol-4-yl-glyoxylic acid ethyl ester

One solution of 90 g of 2-aminothiazol-4-yl-glyoxylic acid ethyl ester in 225 ml of dimethylformamide and 375 ml of CH2C12 is added at -15°C. -27 g of triethylamine and then

at 30°C 75 g of triphenylchloromethane. After 15 minutes at

-30°C is stirred for 3 hours without a cold bath, 500 ml of CH2C12 is added to the reaction mixture obtained, washed with 300 ml of 1N HCl and then twice with 200 ml of water, the organic phase is dried over Na2SO4 and the solvent is evaporated. The remaining residue is an oil that was used in further sales without purification.

d) 2-triphenylmethylamino-thiazol-4-yl-glyoxylic acid

A solution of 156 g of crude 2-triphenylmethyl-amino-thiazol-4-yl-glyoxylic acid ethyl ester in 150 ml of methanol is added to a solution of 14.8 g of NaOH in 370 ml of methanol, boiled for 5 minutes under reflux, whereby the sodium salt of 2-triphenylmethylamino -thiazol-4-ylglyoxylic acid crystallized.

The sodium salt obtained is suspended in 380 ml of water and 76 ml of 2N HCl is added with vigorous stirring. After 15 minutes, the precipitate is suctioned off and washed with water and dried. 2-Triphenylmethylamino-thiazc51-4-yl-gly-■ oxylic acid was obtained as yellow crystals with a melting point of 163'-165°C ■

(split).

é) 2-(2-triphenylmethylamino-thiazol-4-yl)-2-syn-phenoxyimino-acetic acid

In a solution of 450 ml of glacial acetic acid and 90 ml of water, 30 g of triphenylmethylamino-thiazol-4-yl-glyoxylic acid are introduced and added at 15° C. with 8 g of 0-phenylhydroxylamine. The reaction mixture first becomes clear, after which crystallization of the oxime occurs. After 15 minutes, 200 ml of water at 10-15°C are added while stirring. The precipitated crystals are suctioned off, stirred with acetone and filtered again. 2-(2-triphenylmethylamino-thiazol-4-yl)-2-syn-phenoxyiminoacetic acid with melting point 141-143°C (decomposed) was isolated in the form of a colorless solid.

Claims (3)

1. Process for the preparation of cephem compounds of the -general formula I where A stands for hydrogen, an equivalent of an alkali or alkaline earth metal or an organic nitrogen base or for the remainder of an ester group, R^ represents hydrogen, an optionally substituted alkyl-, alkenyl-, alkynyl-, cycloalkyl-, aralkyl-, acyl-, aryl-, arylsulfonyl-, alkylsulfonyl- or hetero-. cyclic group, R2 stands for an optionally with alkyl with 1-4 C atoms, aryl or an optionally protected phenyl residue substituted furyl-, thiazolyl- or phenyl ester and B stands for lower alkoxy, methyl, acetoxymethyl, carbamoylmethyl, halogen or -CH2S-Het , where Het can stand for a 5- or 6 <-> .membered ring with 1-4 heteroatoms, in which the R^ O group is in the syn position and n stands for the number 0, 1 or 2, k a r a k- terisers. t by converting a carbonic acid with the general formula II or its salt, in which R 1 and R 2 have the above meaning, in the presence of approx. 0.1 to approx. 3.0 mol of a for- bond with the general formula IV in which the residues R^ , R^ and R^ can be the same or different and stand for alkyl with 1-6 carbon atoms, whereby the residues R^ and R^, respectively R-^ and R^, optionally together with a heteroatom can form a ring and R^ can also stand for a dialkyl, amino group in which the alkyl groups can each contain 1-6 C atoms and optionally together with a heteroatom can form a ring, with an acid halogen generator and the resulting complex is reacted with a cephem acid with the general formula in which B and n have the meaning stated above, i. in the form of an amine salt or an ester or a silyl ester that can optionally be split off by acid hydrolysis or hydrogenolysis - and if necessary - transfer a possibly obtained carboxyl group in a manner known per se to another under A mentioned groups. 2. Process according to claim 1, characterized in that dimethylacetamide, diethylacetamide, dimethylpropionamide, diethylpropionamide, N-acetyl-morpholine, N-acetyl-piperidine, N-methyl-pyrrolidone or tetramethylurea are used as the tertiary amide. 3. Method according to claims 1 and 2, characterized in that phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride or phosgene are used as acid halide generators.