DE2125664A1 - 7-aminoacylamidocephalosporanic acids prepn - from 7-aca and n-(carbamoylalkenyl)amino acids - Google Patents

Abstract

Cpds of formula (I): (where R is alkylene or CR5R6; R5 is H, Me or MeS; R6 is alkyl, alkylthio, aryl, arylthio, aralkyl, aryloxy or a heterocyclic gp or R5+R6 forms an opt. substd ring e.g. cycloalkyl or a heterocyclic gp; X is H, acetoxy 1-3C alkoxy or SY, where Y is alkyl alkenyl or a nucleophilic gp) or their non-toxic salts, are prepd by acylating the corresp. 4-ACA with a cpd (II): (where R1 and R2 are 1-3C alkyl or NR1R2 is piperidino or morpholino, R3 is 1-3C alkyl and R4 is H or 1-3C alkyl or R3 + R4 forms a cyclopentyl or cyclohexyl ring) or a functional acid deriv (pref. mixed anhydride) to give a cpd (III): and hydrolysing this. Cpds (I) have antibacterial activity.

Description

"Acylation of 7-Aminocephalosporanic Acids" This invention relates to a process for the preparation of cephalosporins, in particular of 7-aminoacylamido cephalosporanic acids.

In particular, this invention relates to a process for the preparation of 7-aminoacylamidocephalosporanic acids of the general formula (IV) where H2N-R-CO- is an amino acid residue, (where R is an alkylene group or a residue group of the formula is, (wherein R5 is a hydrogen atom or a methyl or a methylthio group and R6 is an alkyl, alkylthio, aryl, arylthio, arylalkyl, aryloxy or heterocyclic group, including the case that R5 and R6 together are substituted or unsubstituted ring-shaped group, such as a cycloalkyl or heterocyclic group,)), or a non-toxic salt thereof and X is a hydrogen atom, an acetoxy group, a lower alkoxy group having 1 to 3 carbon atoms or a -SY group (where Y is an alkyl, Alkenyl or a nucleophilic group) or a non-toxic salt thereof, including a 7-aminocephalosporanic acid (hereinafter referred to as 7-ACS), which of the general formula (I) corresponds, in which X has the meaning given above or a derivative of this with an N-protected amino acid of the following general formula (II) wherein NR-COOH is an amino acid residue (wherein R has the same meaning as above), each of the residues R1 and R2 is a C1-C3 lower alkyl group, including the case that the residues R1 and R2 together form a piperidine or a morpholine ring and R3 is a C 3 lower alkyl group, R4 is a hydrogen atom or a C1 - C3 lower alkyl group, including the case that R3 and R4 together form a cyclopentyl or a cyclohexyl ring or are acylated with a functional acid derivative of the given, protected amino acid to form the corresponding N- protected 7-aminoacylamidocephalosporanic acid of the general formula (III) wherein the radicals R, R1, R2, R3, R4 and X have the same meaning as above and then the N-protected 7-aminoacylamidocephalosporanic acid or a salt thereof is hydrolyzed.

The term "functional acid derivative" is used here as that it includes such derivatives in which a part of the carboxyl group is replaced by other atoms or functional groups.

The salts as mentioned above include those with inorganic salts Acids; with organic acids such as alkyl sulfonic acids, benzenesulfonic acid, toluenesulfonic acid or naphthylsulfonic acid; with metals like sodium, potassium, calcium, or magnesium Aluminum; with ammonium unc with substituted ammonium such as triethylamine, N, N-dimethylbenzylamine, N-alkyl morpholines, N-alkyl piperidines, procaine, or the like.

The aminocephalosporins produced by the process of the present invention are valuable antibacterial substances as therapeutic agents in humans and animals for treatment in particular of gram-positive and gram-negative Bacteria caused infectious diseases.

The various known processes for producing 7-aminoacylamidocephalosporanic acids (IV) include an industrially important process in which a β-diketone or an ester of a β-diketo acid is used to protect the amino group in the α-amino acids. Such a method has already been described in the Journal of Lledicinal Chemistry, Volume 9, page 746 (1-966), in Belgian patent specification 675 298 and so on. As a result of extensive research, both for more universal and more advantageous protecting groups, it was unexpectedly found by the present inventors that the intended product can be obtained in far higher yields and purity than conventional processes when the amino group of an amino acid is replaced by an N, N- disubstituted ß-keto acid amide of the general formula (V) wherein the radicals R1, R2, R3 and R4 have the same meaning as above, the acid amide being an N, N-disubstituted acid amide which has a structure which is quite different from any known protective group mentioned above. The present invention is based on these findings.

In addition, while N-monoaryl-subst. Acetoacetamide already a protective agent known to the person skilled in the art is the specific N, N-disubstituted acid amide of formula (V), in which the radicals R1 and R2 tick the meaning given above the conventional protective agent has the following advantages that an alkali metal salt of the N-protected amino acid (formula (II) produced in high yield and very much easier to handle because of a lack of hygroscopicity and easier crystallization can be and that a higher yield of the condensation product of (formula (III)) of 7-ACS or its salts with a functional acid derivative of this N-protected Amino acid (formula (II)) and a higher yield of 7-aminoacylamidocephalosporanic acid (Formula (IV)) after hydrolysis of this condensation product in comparison to known methods can be obtained, the comparison being based on 7-ACS and is carried out under the same reaction conditions.

The N-protected amino acid (II) used in the present invention can be prepared by the condensation of an amino acid of the formula (VI) or its salt with an N, N-disubstituted β-keto acid amide (formula (v)). The 'amino acid (VI) may be in an optically active form or in a racemic form.

Because the N-protected amino acid (II) is believed to be in the tautomeric forms (IIa) and (IIb) it is assumed that the N-protected 7-aminoacylamidocephalosporanic acid (III) derived therefrom is also present in similar tautomeric forms. For reasons of simplicity, the structural formulas (II) and (I1I) given above are therefore to be regarded here as tautomeric forms of the amino acid, 7-aminoacylamidocephalosporanic acid, and their nomenclatures correspond to the structural formulas given. The dotted line in formulas (II), (IIa), (IIb) and (III) denotes a hydrogen bond.

In the formula (VI) of an amino acid, the group> N-R-COOH an amino acid residue with one or more amino groups in any position represents, and the entire amino groups are to be protected by the process of the invention will.

As the amino acid of formula (VI), can also suitably a variety of amino acids ranging from aliphatic, arylaliphatic, aromatic, cycloaliphatic or heterocyclic compounds can be used.

A particularly suitable amino acid has an amino group in the α-position to the carboxyl group, where it has the formula (VII) corresponds, in which the radical R5 is a hydrogen atom, a methyl group, methylthiomethyl group, etc., R6 is a methylthioethyl, phenyl, nitrophenyl, aminophenyl, alkoxyphenyl, alkylphenyl, halophenyl, thienyl, methylthienyi-, pyridyl, imidazole , Thiazole, pyrazole, pyrazolone, isooxazole, isothiazole, yyrrole, furan, tetrahydropyrrole, tetrahydrothienyl, sydnone, cyclopentyi or cyclohexyl radical, including the case that the radicals R5 and R6 together form a ring such as tetrahydrothienyl, cyclopentyl, cyclohexyl or the like.

Typical examples of N, N-disubstituted B-iseto acid amide of formula (V) which is an amino group protecting agent of this invention N, -Dimetllylacetoacetamide, N, N-diethylacetoacetamide, N-morpholinoacetoacetamide, N-piperidinoacetoacetamide, 2-N, N-dimethylcarbamoylcyclopentanone, 2-N-morpholinocarbonylcyclopentanone, 2-N, N-dimethylcarbamoylcyclohexanone, etc. The particularly preferred protectants are N, N-dimethylacetoacetamide, N, N-diethylacetoacetamide and N-morpholinoacetoacetamide.

According to the invention, 7-ACS or its derivative is protected with a Amino acid of the formula (II) or its functional! Acid derivative protected. as Derivatives of 7-ACS are salts with alkali, alkaline earth and other metals, suost.

Amines or silyl derivatives are used. To typical examples of the functional acid derivative of the protected amino acid of formula (II) mixed acid anhydrides obtained by reacting the protected amino acid with, for example Dimethylacetyl halides, trimethylacetyl halides (pivalyl halides), diphenylacetyl halides, Diethylacetyl halides, ethyl chloroformate, isobutyl chloroformate or isopropyl chloroformate be formed; one of the intermediates produced by reacting the N-protected Amino acid with carbodiimides such as N, N'-dicyclohexylcarbodiimide, N, N'-carbonylditriazole, N, N'-carbodiimidazole are formed and reactive esters of the protected amino acid such as p-methoxyphenyl ester, p-nitrophenyl ester, propargyl ester, carboxymethyl thioester, N-hydroxysuccinimide ester or cyanomethyl ester.

Acylation of 7-ACS with such a functional acid derivative the N-protected i £ amino acid of formula (II) is preferably at a temperature under OOC in an aqueous solution containing an alkali metal salt of 7-AUS or a tertiary amine salt such as triethylamine salt of 7-AUS or in a mixed solvent, the water contains or carried out in an anhydrous solvent. As an organic solvent can be any inert solvent such as acetone, acetonitrile, isobutyl methyl ketone, Methylene chloride, chloroform, ethylene dichloride, dimethylformamide, dioxane, tetrahydrofuran ethylene glycol dimethyl ether, toluene or dimethyl sulfoxide can be used.

The N-protected 7-4minoacylamidocephalosporanic acids thus obtained (III) are novel connections. These connections can be the following Hydrolysis can be subjected to or without their isolation. About these bonds to obtain in crystalline norm, the above-mentioned reaction solution is filtered, the solvent was removed from the filtrate by distillation under reduced pressure and ether, isopropyl ether, chloroform, etc. are added to the residue, whereby a salt of the N-protected compound of the formula (III) is obtained in high yield.

The N-protected compounds of formula (III) are common Solvents fairly soluble, are relatively stable in almost neutral Solutions and their infrared and ultraviolet absorption spectra are quite different of the compounds of formula (IV) obtained by removing the protective group removed by hydrolysis.

In carrying out the hydrolysis of the present invention can the N-protected 7-aminocephalosporanic acid (III) or a salt the same, either after isolation or isolation, can be hydrolyzed. The hydrolysis is preferably carried out in an aqueous solution or in a solvent, the water contains, at a temperature below room temperature and at a pH; iert, which is preferably below 5, carried out, the hydrolysis by adding a small amount of a dilute mineral acid or an aqueous solution of a strong organic acid such as organic sulfonic acid, organophosphoric acid, formic acid, an aliphatic chlorine-containing acid or the like. To Completion of the hydrolysis can result in 7-aminoacylamidocephalosporanic acid (IV) or their salt can be purified in a conventional manner, such as, for example, by removal of the protective agent released by extracting it from the hydrolyzed mixture with a solvent that can dissolve the released protective agent, such as for example Isobutyl methyl ketone, acetic acid ester, chloroform, carbon tetrachloride or methylene chloride.

Optionally, this cleaning can be done by crystallizing from the hydrolyzed mixture is carried out by adjusting the pH of the mixture will.

The method of the present invention has been found to be particularly useful proven when it is used to produce 7-α-aminophenylacetamidocephalosporanic acid, 7-α-aminophenylacetamido-3-desacetoxycephalosporanic acid and the like are used will.

The 7-aminoacylamidocephalosporanic acids produced by the present process may exist in epimeric forms, which are also within the scope of the present invention Invention fall.

According to the present process, the desired product can be obtained in high Overall yield can be obtained because 1. the N-protected amino acid of formula (II) is stable and easy to crystallize and 2. after the N-acylation of 7-ACS the Protective group at the N-position of 7-aminoacylamidocephalosporanic acid (IV) easily can be removed under such mild conditions that the rupture of the β-lactam ring the 7-ACS is not effected.

The following examples serve to explain the invention, without limiting the scope of the invention.

Reference Example 1 a) Preparation of the sodium salt of N- (1-N'-morpholinocarbonylpropen-2-yl) -α-aminophenylacetic acid.

5.0 mmol of D-phenylglycine were in an aqueous solution the 5.0 mmol sodium hydroxide contained, dissolved and the solution by evaporation under reduced Pressure concentrated and then brought to dryness. The dried product was dissolved in 50 ml of methanol or ethanol by heating.

5.0 to 5.5 mmol of N-morpholinoacetoacetamide are added to the solution, and the resulting mixture was heated on a water bath for 30 minutes. After cooling was that Filter the reaction mixture by suction, or the solution was evaporated to dryness under reduced pressure. The residue became overnight dried under vacuum over concentrated sulfuric acid or phosphorus pentoxide and then from methanol or ethanol to form the sodium salt of - (l -'- orholinocarbon3rlpropen-2-yl) - -aminophenylessigsaure recrystallized. Melting point 248 ° C (with decomposition), yield 97.

b) The procedure of reference example 1 a) was repeated except that instead of N-morpholinoacetoacetamide N, N-dimethylacetoacetamide was used, whereby the sodium salt of N- (1-N ', N'-dimethylcarbamoylpropen-2-yl) -g aminophenylacetic acid receives. Melting point 258 ° C. (with decomposition), yield 97%.

c) In a manner similar to Reference Example 1 a), the following were made Compounds using d-phenylglycine and potassium hydroxide in equimolar Get relationship.

Potassium salt of N- (1-N'-morpholinocarbonylpropen-2-yl) -α-amino-2-phenylacetic acid, Melting point 214 to 218 ° C (with decomposition), yield 93%.

Potassium salt of N- (1-N ', N'-diethylcarbamoylpropen-2-yl) -α-amino-2-phenylacetic acid, Melting point 263 to 264 ° C (with decomposition), yield 87%.

Potassium salt of N- (1-N ', N'-dimethylcarbamoylpropen-2-yl) -α-amino-2-phenylacetic acid, Melting point 212 to 213 ° C (with disintegration), yield 92%.

Potassium salt of N- (1-N'-piperidinocarbonylpropen-2-yl) -α-amino-2-phenylacetic acid, Melting point 216 to 2170C (with decomposition), yield 93%.

Reference Example 2 Preparation of sodium salt of N- (2-N'-morpholinocarbonylcyclopent-1-yl) -α-aminophenylacetic acid.

2-Ethoxycarbonylcyclopentanone and morpholine were allowed to stand with heating react in ethanol, with formation of 2-N-morpholinocarbonylcyclopentanone with a Boiling point of 190 to 194 O / 4 Torr, this with the sodium salt of d-phenylglycine, was unset by the method described in Reference Example 1 a), with formation of the condensation product identified in the heading with a melting point from 233 to 236 ° C (with decomposition) and a yield of 83C%.

Reference Example 3 Preparation of sodium salt of N- (1'-N'-morpholinocarbonylpropen-2'-yl) -αamino-2-thienylacetic acid.

The sodium salt of dl-α-amino-2-thienylacetic acid (chemical Abstracts, Volume 51, Page 4944 (1957)) was with Morpholinoacetoacetamid after Process of Reference Example 1 a), with formation of those designated in the heading Connection implemented; Melting point 154 to 16,000 (with disintegration) and a yield from 959t.

Reference Example 4 Preparation of sodium salt of N- (1-N'-morpholinocarbonylpropen-2-yl) -α-amino-γ-methylthiobutyric acid.

dl-methionine sodium salt was made with N-morpholinoacetoacetamide, according to implemented the method described in reference example 1 a); Melting point 98 to 102 ° C; Yield 76%.

Reference Example 5 Preparation of sodium salt of N- (1-N ', N'-dimethylcarbanoylpropen-2-yl) -1-aminocyclollexylcar Don’s aure.

The sodium salt of 1-aminocyclohexylcarboxylic acid (Chemical reports, Volume 19, pages 1722 (1906)) was reacted with N, N-dimethylacetoacetamide; Melting point 242 to 24500 (with decay); Yield 94%.

Example 1 Preparation of 7- (1'-N ', N'-Dimethylcarbamoylpropen-2'-yl) -α-aminophenlyacetamidocephalosporanic acid (X = OCOCH3) and hydrolysis thereof to form aminophenylacetamidocephalosporansä ure (X = OCOCH3).

5 mmol of isobutyl chloroformate were dissolved in 20 ml of dry acetone or Acetonitrile dissolved and the solution cooled to a temperature below 1000. To the cooled solution was a drop of N, N-dimethylbenzylamine or N-1 "; 'ethylmorpholine present. Then became the. 5 mmol of the solution obtained at this temperature the aforementioned sodium salt of N- (1-N ', N'-dimethylcarbamoylpropene-2-xl) -α-aminophenylacetic acid admitted and the solution was stirred for 30 minutes.

In another approach, 5 mmoles of 7-ACS were added to 15 ml of acetonitrile-water (1: 1 vol), which contained 5.5 mmol of triethylamine or sodium hydrogen carbonate, dissolved and the solution cooled to a temperature below -8 ° C. Became the cooled solution quickly while stirring vigorously the cooled solution of the above mixed Acid anhydride was added while the temperature was kept below 0 ° C.

After stirring for 30 minutes, the reaction mixture was added 4 g of sodium chloride zuegeuen and stirred for a further 30 minutes at Dei G ° C. Daiin became the organic layer separated and evaporated to dryness under reduced pressure. Of the. obtained syrup was with 30 ml isobutyl methyl ketone water (10: 3 vol), the 1.8 ml 80% formic acid contained, mixed, stirred for 30 minutes and then for 20 hours at one temperature kept below 0 ° C. The crystals were collected by centrifugal precipitation then suspended in 10 ml of acetonitrile, again centrifugally precipitated and then permeable dried under vacuum. The yield of crystals was 60% m and the crystals showed a single spot on the paper chromatogram (butanol: acetic acid: water = 3: 1: 1 vol). The minimum inhibition concentration against Escherichia coli was 10 γ / ml.

Example 2 Preparation of 7- (α-amino-2'-thienylacetamido) -cephalosporanic acid (x = OCOCH3).

5 mmol of pivalyl chloride were dissolved in 20 ml of dry tetrahydrofuran, and the solution was cooled to a temperature below -10 ° C. To the cooled solution 1 drop of N-methylmorpholine was added. Then the Dei became the same temperature held solution 5 mmol sodium salt of N- (1'-N'-morpholinocarbonylpropen-2'-yl) -α-amino-2-thienylacetic acid, obtained according to reference example 3 ,, was added and the mixture was stirred for 30 minutes. In another approach, 5 mmol 7-ACS in 15 ml acetone-water (1: 1 vol), the 5.5 mmol of sodium hydrogen carbonate or triethylamine was dissolved and the solution cooled to a temperature below -8 ° C.

The chilled solution quickly became a chilled with vigorous stirring Solution of the mixture of acid anhydride prepared above is added while the Reaction temperature was kept below oQc. After stirring for 30 minutes at the same Temperature, the mixture was further stirred at OOC for 1 1/2 hours, then the organic Solvent removed by distillation at low temperature. The concentrated, aqueous solution were after cooling 30 ml of isobutyl methyl ketone and then under vigorous stirring at 0 ° O 4 ml cold water; which contained 1.8 ml of 80% formic acid, added in small portions. The mixture was stirred for 30 minutes and then for 20 minutes Held at a temperature below 0 ° O for hours to precipitate crystals. The crystals were collected by centrifugal precipitation according to the conventional method cleaned under formation of the in the heading designated product with a yield of 65%.

This showed a single spot on the paper chromatograph. The minimum inhibition concentration against Escherichia coli was 20 γ / ml.

Example 3 Preparation of 7-tX -amino-2'-thienylacetamido) -desacetoxycephalosporanic acid (X = H).

The sodium salt of N- (1'-N'-Morpholinocarbonylpropen-2'-yl) -α-amino2-thienylacetic acid, obtained according to reference example 3, was with 7-amino-3-deacetooxycephalosporanic acid (X = H) (Journal of Medicinal Chemistry, Volume 7, Page 118 (1964)), according to the in Example 1, reacted, and then the product was hydrolyzed; Yield 70%; minimal inhibition concentration against Escherichia coli, 40 γ / ml.

Example 4 7-N- (α-Aminophenylacetamido) -cephalosporanic acid.

5 mmol dry, fine powder of the potassium salt of N- (1-N ', - N'-Dimethylcarbamoylpropan-2-yl) -d-α-aminophenylacetic acid, obtained according to reference example 1 c) were suspended in 15 ml of dry acetone and the suspension cooled to -45 ° C. To the cooled suspension were 5 mmol Ethyl chlorocarbonate and 2 drops of N-methylmorpholine were added and the mixture was approximately Stirred for 1 hour at the same temperature. Then 15 ml of methylene chloride, the 5 mmoles Triethylamine salt of 7-ACS contained the mixture at -45 ° C added with vigorous stirring. The reaction was left at this temperature for 1 hour expire. Then the temperature was gradually raised and the reaction was allowed to take place Run for 1 hour at 0 ° C and another 3 hours at 2 to 5 ° C.

Then most of the organic solvent became means Removed distillation under reduced pressure. The residue obtained was in Dissolve 15 ml of chloroform, add 10 ml of water and adjust the pH to 2.0 by adding set of 50% formic acid while cooling and stirring in ice. After about 30 minutes of stirring, the organic layer was removed and the pH was adjusted the aqueous layer to 4.5 by adding triethylamine in small portions, set. The resulting solution became overnight. kept in a refrigerator, and the precipitated crystals were collected, with a small volume of cold 50% methanol, then washed with ether and dried.

The yield was 52S and the purity was 92% m with this means biological testing and chemical analysis, using hydroxylamine was determined.

The above procedure was carried out under the same reaction and treating conditions repeated except that 30 ml of 50% acetone was substituted of methylene chloride were used; Yield 53%; Purity 92%.

Example 5 7-N- (α-Aminophenylacetamido) -3-desacetoxycephalosporanic acid.

5 mmol of the potassium salt of N- (1-N ', N'-dimethylcarbamoylpropen-2-yl) -d-α-aminophenylacetic acid, obtained according to reference example 1 c), were with 5 mmol of triethylamine salt of 7-amino-3-deacetoxycephalosporanic acid implemented and then treated according to the method described in Example 4. yield 52%; Purity 92%, determined by means of biological tests and chemical analysis using hydroxylamine.

The present invention therefore encompasses the preparation of 7-aminoacylamidocephalosporanic acids in high yields, wosu one 7-Ainino'cephalosporanäure with an amino acid or their functional equivalent, where their Ämb'ogruppe with N, N-disubst.ß-keto acid amide is protected, then converts the protective group of the protected one obtained 7-Aminoacylamidocephalosporanic acid removed by hydrolysis.

Patent claims:

Claims (11)

Patent claims: 1. Process for the preparation of 7-aminoacylamidocephalosporanic acids of the general formula where H2N-R-CO- is an amino acid residue (where R is an alkylene group or a residue group of the formula is, (wherein R5 is a hydrogen atom or a methyl or methylthio group and R6 is an alkyl, alkylthio, aryl, arylthio, arylalkyl, aryloxy or heterocyclic group, including the case that the radicals R5 and R6 together, if any substituted ring such as a cycloalkyl or heterocyclic group)) and X is a hydrogen atom, an acetoxy, a C1 u1 to C3 lower alkoxy group or a group of the formula -SY (where Y is an alkyl, alkenyl or a nucleophilic group) or a non-toxic salt thereof, thereby g. This indicates that a 7-aminocephalosporanic acid of the general formula is used wherein X has the same meaning as above or its derivative with an N-protected amino acid of the general formula wherein R has the same meaning as ooen; each of the radicals R1 and R2 is a C1 to C3 lower alkyl group, including the fact that the radicals R1 and R2 together form a piperidine or a morpholine ring, R3 is a C1 to C3 lower alkyl group, R4 is a hydrogen atom or a C1 to C3 -Lower alkyl group, including the case that the radicals R3 and R4 together form a cyclopentyl or a cyclohexyl ring, or acylated with a functional acid derivative of the designated protected amino acid to form an N-protected 7-aminoacylamidocephalosporanic acid. the general formula in which the radicals R, R1, R2, R3, R4 and X have the meaning given above and then the N-protected 7-aminoacylamidocephalosporanic acid or its salt is hydrolyzed. 2. The method according to claim 1 d a d u r c h g e k e n n -z e i c h n e t that 7-aminoacylamidocephalosporanic acid of formula (IV), wherein R5 is a Hydrogen atom and R6 is a phenyl or thienyl group, including the case that R5 and R6 together form a cyclohesyl ring, produces. 3. The method according to claim 1 d a d u r c h g e k e n n -z e i c h n e t that times the 7-aminoacyl amidocephalosporanic acid of the formula (IV), wherein X a hydrogen atom, a C1 to C3 lower alkoxy group or an acetoxy group and Y is a heterocyclic group. 4. Verfanren according to one of claims 2 or 3 d a -d u r c h g e X e n n e i n e i n e t that a mixed acid derivative is a functional acid derivative Acid anhydride is used. 5. The method according to any one of claims 2 or 3 d a -d u r c h g e it is not stated that a functional acid derivative is an intermediate which is achieved by reacting an N-protected amino acid with carbodiimide, carbonyldiimidazole or an activated acid amide or an activated ester is used. 6. The method according to claim 4 d a d u r c h g e k e n n -z e i c h n e t that one uses the N-protected 7-aminoacylamidocephalosporanic acid, wherein the N-protected 7-aminoacylamidocephalosporanic acid is prepared in that one is a 7-aminocephai-ospranic acid or its 3-subst.Derivat or a salt thereof with a mixed acid anhydride obtained by treating a salt of N-protected amino acid with a substituted acetic acid halide or a Reacts alkyl chloroformate in the presence of a small amount of catalyst. 7. The method according to claim 6, characterized in that the catalyst is a tert. Base of the general formula is used, wherein each of the radicals R7 and R8 is a lower alkyl, benzyl group, including the case that the radicals R7 and R8 together form a morpholine or piperidine ring, together with an oxygen or nitrogen atom. 8. The method according to any one of claims 3 to 7 da-durchgeken jj zeic hnet that one is an N-protected amino acid of the general formula - in which the radicals R, R1, R2, R3 and R4 have the same meaning as in claim 1, the N-protected amino acid being prepared by using an α-amino acid of the general formula (wherein R5 is a hydrogen atom or a lower, aliphatic group and R6 is a lower aliphatic or aryl group or an optionally substituted thienyl or heterocyclic group, including the case that the radicals R5 and R6 together form a cyclohexyl or piperidine ring) with a ß-keto acid amide of the general formula (wherein each of R1 and R2 is a lower alkyl or aryl group, including the case that R1 and R2 together form a piperidine or morpholine derivative, together with a nitrogen or oxygen atom). 9. The method according to claim 1 d a d u r c h g e k e n n -z e i c-h n e t that a 7-aminoacephalosporanic acid or its 3-subst.Derivat or a salt thereof with a functional acid derivative of the N-protected amino acid condensed in an anhydrous or water-containing solvent. 10, method according to one of claims 1 Dis 5 and 8 d a -d u r c h e k e d n z e i g n e t that one can use the N-protected 7-aminoacylamidocephalosporanic acid or their 3-subst. Derivative or a salt thereof with a dilute mineral acid or a strong organic acid. 11. The method according to claim 10 d a d u r c h g e k e n n z e i-c n e t, that one uses the N-protected 7-aminoacylamidocephalosporanic acid or a 3-subst. Derivative thereof or a salt thereof is hydrolyzed at the same time.