DE2429166A1 - PROCESS FOR THE SELECTIVE SPLITTER OF THE AMIDIC ACID FUNCTION OF A 7- (AMIDIC ACID) CEPHALOSPORINE - Google Patents

Description

PATENT LAWYERS

DR. T. MAAS

DR. Q. SPOTT

8000 MUNICH 40

SCHLEISSHEIMERSTR. 299

TEL. 3592201/205

X-3996

Eli Lilly and Company, Indianapolis, Indiana, V.St.A.

Process for the selective cleavage of the amic acid function of a 7- (amic acid) cephalosporins

The invention relates to a method for selective cleavage of a 7- (amic acid) cephalosporin by converting it to the corresponding mixed anhydride and cleaving the mixed Anhydrides into the corresponding 7-aminocephalosporin or into a corresponding 7-acylamidocephalosporin.

With the development of cephalosporin antibiotics it has been since For some time it was common to have an imide substituent in position 7 use if this part of the molecule is not at the heart of the relevant research. Through the present such a protective group, especially the phthalimido group, position 7 becomes quite chemically inert, which means that other parts of the molecule treat each other with little concern and at the same time you can be relatively sure that the position 7 remains intact.

It has long been known, however, that an imide function in position 7 of a cephalosporin makes the structure antibiotic

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only makes minimal activity. Unfortunately, a 7-imido group can be found so far do not successfully cleave from a cephalosporin to liberate the protected amino group. Research must therefore resign themselves to a stable substituent in position 7, and thus a group that corresponds to a cephalosporin gives only minimal antibiotic effect. The use of such a substituent is therefore only economical interesting when it can be readily removed at any desired point in a synthetic process.

However, the foregoing is not intended to generally mean that successful cleavage of an imide group is impossible. There are already several procedures for such a split. So be in Japanese Publication by Minoru Shindo, "Cleavage Reactions of the Phthaliraido Group," Yuki Gosei Kagaku Kyokai Shi, Jan. (5), (1971) pages 496-509, discussed a number of cleavage techniques. Each of these ways of working caused a split the imide function of a cephalosporin, if that would be the only essential consideration. However, it is at least as important to work under conditions through which a cleavage can be achieved without affecting the structure of the cephalosporin molecule, or is destroyed. The latter, however, has not yet been achieved.

Partial cleavage of the imide side chain of a cephalosporin structure with the formation of the corresponding amic acid side chain was already possible (see, for example, Sheehan et al., Journal of the American Chemical Society, 73, (1951) pp. 4367-4372; Sheehan et al., Journal of the American Chemical Society, 78, (1956) pp. 3680-3683; Perron et al., Journal of Organic Chemistry, 7 (1964) pp. 483-487). the Phthalimide was made through alkaline hydrolysis like them

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for example, described in Sheehan's first publication is converted into the corresponding phthalamic acid. However, as can be seen from Sheehan's second publication, all attempts at a more extensive one were successful Cleavage unsuccessful because the ß-lactam ring of penicillin opens preferentially with destruction of penicillin will.

US Pat. No. 3,487,074 discloses the cleavage of 6-phthalimido-3-penamylcarboxylic acid described by treatment with hydrazine hydrate in dioxane at room temperature for 12 hours. This method however, does not work on penicillins and cephalosporins. A certain success was achieved with the

ο
Achieve cleavage of a 7-phthalimido-delta-cephalosporin / see Spry, D. Ο., Journal of the American Chemical Society, 92, (1970), p. 5007 /.

A method has now been found by which the Amic acid function of a cephalosporin without opening the can split ß-lactam rings. This method is the subject of the invention. The amic acid function is normally obtained by partial cleavage of an imide function, but what is by no means essential.

The invention relates to a method for cleaving the amic acid function of a 7- (amic acid) cephalosporin formula

O Il R -C-ONH _n

R-C

COOH ^υ

COORi

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where R and R are hydrogen or where R and R together with the carbon atoms to which they are attached form an ortho-phenylene ring,

R. stands for a carboxy protecting group, and

R- hydrogen, acetoxy, methoxy, methylthio, (5-methyl-1,3,4-thiadiazol-2-yl) thio or (1-methyl-IH-tetrazol-5-yl) thio is,

which is characterized in that one

(1) this 7- (amic acid) cephalosporin with an alkyl chloroformate in the presence of a tertiary amine and so to the corresponding mixed anhydride of the formula

0 I!

R -CC-NH _x ⁸ II RC I

O = C I

O = C

-CHaRz *

COORi.

arrives, where Rj _{3 is} alkyl with 1 to 4 carbon atoms,

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(2) that obtained from the above chloroformate treatment Product mixture with a hydrazine of the formula

R ₃ HNNHR ₄

where R- and R. are independently hydrogen or methyl, implements, and

(3) (a) The reaction mixture obtained from the above hydrazine treatment treated with an acid halide and thus leads to the corresponding 7-acylamidocephalosporin, or

(b) the corresponding 7-aminocephalosporin is obtained from the reaction mixture of the abovementioned hydrazine treatment if at least one of the substituents R ₃ or R _{4 is} methyl, or

(c) the reaction mixture obtained from the above hydrazine heated to a temperature of about 50 to about 100 ⁰ C and thus arrives to the corresponding 7-amino cephalosporin, if R and R. are hydrogen, or

(d) the reaction mixture obtained from the above hydrazine treatment is treated with acid and thus arrives at the corresponding 7-aminocephalosporin in the form of the respective acid addition salts if the substituents R ₃ and R ₄ are hydrogen.

Unless specifically stated otherwise, the expression means splitting, splitting and the like the removal of a substituent in the 7-position of a cephalosporin to form a free 7-aminocephalosporin, of a free 7-aminocephalosporin in the form of its acid addition salt or one by splitting off the 7-amic acid function

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and subsequent reacylation with the introduction of another acyl substituent in the 7-position of the 7-aminocephalosporin obtained.

The first step of the process according to the invention consists in a conversion of an amic acid function with the formation of a corresponding mixed anhydride. If the substituents R and R _& together with the carbon atoms to which they are bonded represent an ortho-phenylene ring in this amic acid structure, the preparation of the amic acid generally starts from a phthalimido compound which is partially cleaved by known processes. The resulting phthalamic acid has the following structure:

COOH

-CHaRa!

COORi

The preparation of a compound with the above structure from the corresponding phthalimido compound is known, and it can be all known conditions apply for this. A typical process that results in partial cleavage is one alkaline hydrolysis, as described, for example, in Sheehan at al .. Journal of the American Chemical Society, 73, (1951), pp 4367-4372.

For an alkaline hydrolysis, which can be used for partial cleavage into the amic acid, alkali hydroxides or Alkali sulfides used, such as sodium hydroxide, potassium hydroxide,

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Lithium hydroxide, sodium sulfide, potassium sulfide or lithium sulfide. Generally from about 1 to about 2 equivalents of alkali hydroxide or sulfide is used. However, this is true not in the case of using the free acid of cephalosporin, since here the free carboxyl group itself 1 equivalent of alkali reactant consumed, so that one more equivalent thereof is required.

The pH of the reaction medium is generally between about 9 and about 11. The hydrolysis is generally carried out using an aqueous medium comprising a contains inert, water-miscible organic solvent, such as tetrahydrofuran, N, N-dimethylformamide, acetone, dimethyl sulfoxide or dioxane.

The partial cleavage is generally fairly rapid and is normally complete within about 3 to 30 minutes, and especially within about 5 to 10 minutes. The reaction temperature is usually about -10 C to about room temperature, and it is preferably about 0 ⁰ C.

The amic acid can also have the formula

HOOC

-CHaRa

COORi

to have. This amic acid and the above-mentioned phthalamic acid can also be prepared from other compounds than from their corresponding imide precursors. For example

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wise the free amino compound with the appropriate anhydride, for example maleic anhydride, to react, whereby the corresponding amic acid compound is obtained, in this case the 3-carboxacrylamido compound.

One step in the process of the present invention is the conversion of the amic acid to a mixed anhydride. The mixed anhydride is made according to the method according to the invention although not isolated, it has the following formula

wherein R 1 is alkyl, preferably lower alkyl with 1 to 4 carbon atoms.

The conversion of the amic acid to the mixed anhydride is accomplished by reacting the amic acid with an alkyl chloroformate such as Ethyl chloroformate, propyl chloroformate, t-butyl chloroformate or isobutyl chloroformate. A lower alkyl chloroformate is preferably used, and especially one where the

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Alkyl group has about 1 to 4 carbon atoms. The implementation is carried out in the presence of a tertiary amine, for example pyridine, quinoline, triethylamine, N-methylmorpholine or Ν, Ν-dimethylaniline. The response will also be particular carried out in the presence of an aprotic organic solvent, i.e. a solvent that does not contain protons is still a proton acceptor. A number of suitable such solvents are known to those skilled in the art, and these are these can be used for the method according to the invention. Such solvents are, for example, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, dioxane, aliphatic nitriles such as acetonitrile or propionitrile, aromatic hydrocarbons and their halogen derivatives, such as benzene, toluene or dichlorobenzene, as well as aliphatic halogenated hydrocarbons, such as methylene chloride, chloroform, bromoform, carbon tetrachloride, Carbon tetrabromide, ethylene dichloride or ethylene dibromide. Used based on the amic acid one does not use more than one equivalent of the amine, and in particular one uses a slight deficit of amine. Any excess at tertiary amine favors a conversion of the amic acid to an imide, regardless of the starting material is originally used for the process according to the invention. You can start with a slight excess Chloroformate work. However, this is not preferred because any excess thereof is mixed with that in the following Hydrazine used in the process according to the invention reacts.

The reaction is for a period of about 5 to about 40 minutes, preferably from about 20 to about 30 minutes, at a temperature of about -20 ⁰ C to about +5 ⁰ C, and preferably from about -20 ⁰ C to about - 5 ⁰ C carried out. The mixed anhydride is kept intact by maintaining the reaction mixture at about the temperature at which the reaction was carried out.

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The mixed anhydride cephalosporin mentioned above can then be selectively obtained by treating it in stages with hydrazine, expediently an unsubstituted hydrazine, methylhydrazine or Ν, Ν'-dimethylhydrazine, split, whereupon the obtained Product wins and / or further treated depending on the particular product desired and the particular hydrazine used.

The hydrazine treatment consists in reacting the mixed anhydride in an inert organic solvent, for example any of the aprotic solvents mentioned above, with one equivalent of the hydrazine. An excess of hydrazine must be avoided at all costs. In order to avoid such an excess with certainty, only up to one equivalent of hydrazine is used per equivalent of original amic acid, and in particular a slight deficit of hydrazine is used. The reaction is carried out at relatively cold temperatures from about -10 ° C. to about room temperature, and preferably at about ice temperature (0 ^° C.). The hydrazine is best added to the mixture of the mixed anhydride at relatively cold reaction temperatures. For this purpose, the mixture of the mixed acid anhydride in the organic solvent is kept at the reaction temperature and the hydrazine is added in precooled form. The reaction is fairly rapid, generally complete in about 1 to about 10 minutes, and the reaction is generally allowed to continue for about an additional 5 minutes.

The special treatment that you get with the hydrazine reaction mixture then carried out depends on the structure of the particular hydrazine used and the ultimate product desired away.

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The hydrazines that can be used have the structure

R ₃ HNNHR ₄ ,

wherein R ₃ and R _{4 are} independently hydrogen or methyl. If one or both of the substituents R ₃ and R _{4 are} methyl, then no further treatment is necessary, since this results in the free 7-aminocephalosporin, which can be isolated easily by known methods.

If the substituents R ₃ and R ₄ in the hydrazine used both mean hydrogen, a complex is formed from the free 7-aminocephalosporin and the by-product, namely diketophthalazine, and this complex must be broken down. This can be achieved either by heating the reaction mixture or by treating the mixture with acid, or most simply by a combination of heat and acid treatment.

When applying heat, the complex can best be broken down by heating the reaction mixture to about 50 ^° C. to about 100 ^° C. over a period of about 5 to about 20 minutes and then recovering the free amino compound in a known manner.

The diketophthalazine complex can also be obtained by treating the Reaction mixture can be split with an acid. Practically all organic or inorganic ones can be used for this purpose Use acids. Suitable acids are, for example, hydrochloric acid. Hydrobromic acid, phosphoric acid, p-toluenesulfonic acid, sulfuric acid or methanesulfonic acid. An equivalent or a moderate excess of the acid, for example up to about two equivalents of acid based on the amic acids are used. Preferably the use of acid is carried out in conjunction with simultaneous heating, and the reaction mixture obtained is therefore to temperatures between about 50 and about 100 ° C

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heated while decomposing the complex. Depending on the temperature used in each case, the reaction is complete within about 5 to 10 minutes, for example. If you work in the presence of an acid, you get the free 7-aminocephalosporin in the form of its acid addition salt, which is then obtained in a manner known per se.

A 7-acylamidocephalosporin can also be prepared by the hydrazine reaction mixture is treated with an acyl halide which has an acyl function from which in Combination with the 7-aminocephalosporin, the desired acylamido function arises. The use of an acyl halide eliminates the need for heating or acid treatment to decompose the dikatophthalazine complex, if such a complex has formed, as the acyl halide itself is sufficiently acidic for the required decomposition. By simply choosing the appropriate acyl halide, preferably of the corresponding acyl chloride, any desired acyl function can be introduced into position 7 of the cephalosporin molecule. The 7-acylamidocephalosporin obtained can then easily can be obtained in a known manner.

Typical acyl halides, each of which are used in manufacture the 7-acylamido product desired in each case can be used, are those of the formula

wherein Y is halogen, for example chlorine, bromine or iodine, and R is alkanoyl having 1 to 8 carbon atoms, chlorine or Bromoalkanoyl with 2 to 8 carbon atoms, azidoacetyl, cyanoacetyl, a

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, N- (CH ₂ ) - _m C (O) -, where m is O, 1 or 2,

N = N-Q

Ar-C-C (O) -, where Q is in each case hydrogen or methyl,

and Ar is 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, phenyl or by chlorine, bromine, iodine, fluorine, trifluoromethyl, Hydroxy, alkyl with 1 to 3 carbon atoms, alkyloxy with 1 to 3 carbon atoms, cyano or nitro substituted phenyl,

Ar-X-CH ₂ -C (O) -, in which X is oxygen or sulfur and Ar has the above meaning or in which Ar is 4-pyridyl and X is sulfur or

Ar-CH-C (O) - means, in which Ar has the above meaning and B for B

-NH ₂ , one with benzyloxycarbonyl, alkoxycarbonyl with 1 to 4 carbon atoms, cyclopentyloxycarbony1, Cclohexyloxycarbonyl, benzhydryloxycarbonyl, triphenylmethyl, 2,2,2-trichloroethoxycarbonyl, -C (O) NH-C-NH, or the enamine from methyl acetoacetate

NH

or acetylacetone protected amino group, a hydroxyl group, a hydroxyl group protected by esterification with a _{C -C alkanoic acid, a carboxyl group or a carboxyl group protected by esterification with a C -C alkanol, -N 3} , -CN or -C (O) NH ₂ stands.

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As a starting material in the process according to the invention Cephalosporin used has the following formula

O Il

R -CC-NH _n

3 u

R-C I

HOOC

The substituent R ₁ in the above formula and in the various products of the process according to the invention stands for a carboxy protective group. The nature of the carboxy protecting group is not essential and all known protecting groups can be used for this purpose. However, this group is preferably the residue of an ester function which can be split off by acid treatment or hydrogenation. Preferred carboxy protective groups are, for example, alkyl with 1 to 4 carbon atoms, 2,2,2-trihaloethyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl, Cj-Cg-alkanoyloxymethyl, phenacyl or p-halophenacyl, where halogen is in each case chlorine, Understand bromine or iodine. Typical examples of the preferred ester radicals of the carboxyl group of the 7-imidocephalosporin compound are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, 2,2,2-trichloroethyl, 2.2, 2-tribromoethyl, p-nitrobenzyl, benzyl, p-methoxybenzyl, benzhydryl, acetoxymethyl, pivaloyloxymethyl, propionoxymethyl, phenacyl, p-chlorophenacyl or p-bromophenacyl.

Preferred ester radicals are t-butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl or 2,2,2-trichloroethyl, and the Ester radical is in particular p-nitrobenzyl.

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In the above formula contains the 7-position of the cephalosporin a 2-carboxybenzamido group (which is best derived from a phthalimido group) or a maleamido group.

The process according to the invention accordingly takes place in stages, starting with a 7- (2-carboxybenzamido) cephalosporin via an unisolated mixed anhydride to a 7-amino- or 7-acylamidocephalosporin.

The method according to the invention can also be started with a maleamidocephalosporin. This series of reaction steps involves a conversion of a 7-maleamidocephalosporin via an unisolated mixed anhydride to a 7-amino- or 7-acylamidocephalosporin.

The type of substituent in position 3 of the 7-imido or 7- (Amic acid) cephalosporin starting material is not critical and all common substituents can be present. Preferably however, the following substituents are in position 3: methyl, acetoxymethyl, methoxymethyl, methylthiomethyl, (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl or (1-methyl-IH-tetrazol-5-yl) thiomethyl. The substituent present in position 3 of the cephalosporin starting material remains during the entire reaction sequence of the method according to the invention intact. Typical product conversions which can be obtained by the process according to the invention are given below. The relationship of products, however, depending on the particular reactants used, the proportions the reactants and the reaction conditions vary.

Methyl 7- (2-carboxybenzamido) -3-methyl-3-cephem-4-carboxylate to methyl 7-amino-3-methyl-3-cephem-4-carboxylate.

, 2,2,2-trichloroethyl-7- (2-carboxybenzamido) -3-acetoxymethyl-3 -cephem-4-carboxy lat to 2,2,2-trichloroethyl-7-amino-3-acetoxymethyl-3-cephem-4-carboxylate.

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p -nitrobenzyl 7- (2-carboxybenzamido) -3-methoxymethyl-3-cephem-4-carboxylate to p-nitrobenzyl ^ -amino-S-methoxymethyl-3-cephem-4-carboxylate.

Benzyl 7- (2-carboxybenzamido) -3-methylthiomethyl 1-3-cephem-4-carboxylate to benzyl-T-amino-S-methylthiomethyl-S-cephem-4-carboxylate.

Benzhydryl 7- (2-carboxybenzamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylate to benzhydryl 7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl 1-3-cephem-4-carboxylate.

t -Butyl 7- (2-carboxybenzamido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate to t-butyl 7-amino-3- (1-methyl-1H-tetrazol-5-y1) thiomethyl 1-3-cephem-4-carboxylate.

p-Nitrobenzyl 7- (2-carboxybenzamido) -3-acetoxymethyl-3-cephem-4-carboxylate to p-nitrobenzyl-7-amino-3-acetoxymethyl-3-cephem-4-carboxylate.

p-nitrobenzyl 7- (2-carboxybenzamido) cephem-4-carboxylate to p-nitrobenzyl-7-amino-3-methy1-3-cephem-4-carboxylate.

4-nitrobenzyl-7- (2-carboxybenzamido) -3-methylthiomethyl-3-cephem-4-carboxylate to p-nitrobenzyl-7-amino-3-methylthiomethyl-3-cephem-4-carboxylate.

p-Nitrobenzyl 7- (2-carboxybenzamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylate to p-nitrobenzyl-7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) thio methyl 3-cephem-4-carboxylate.

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p-Nitrobenzyl 7- (2-carboxybenzamido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate to p-nitrobenzyl-7-amino-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate.

p-Methoxybenzyl 7- (2-carboxybenzamido) -3-acetoxymethyl-3-cephem-4-carboxylate to p-methoxybenzyl-7-amino-3-acetoxymethyl-3-cephem-4-carboxylate.

p-Nitrobenzyl ^ -maleamido-S-methyl-S-cephem ^ - carboxylate to p-nitrobenzyl-7-amino-S-methyl-S-cephem ^ - carboxylate.

2,2 ^ -Trichloroethyl ^ -maleamido-S- (1 -methyl-iH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate to 2,2,2-trichloroethyl-7-amino-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate.

Benzyl 7-maleamido-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylate to benzyl 7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylate.

Pivaloyloxymethyl 7- (2-carboxybenzamido) -3-methylthiomethyl-3-cephem-4-carboxylate to pivaloyloxymethyl-7-amino-S-methylthiomethyl-S-cephem ^ -carboxylate.

Acetoxymethyl 7- (2-carboxybenzamido) -3-methoxymethyl-3-cephem-4-carboxylate to acetoxymethyl-7-amino-3-methoxymethyl-3-cephem-4-carboxylate.

Phenacyl 7- (2-carboxybenzamido) -3-methyl-3-cephem-4-carboxylate to phenacyl ^ -amino-S-methyl-S-cephem ^ -carboxylate.

p-Chlorophenacyl 7- (2-carboxybenzamido) -3-acetoxymethyl-3-cephem-4-carboxylate to p-chlorophenacyl-7-amino-3-acetoxymethyl-3-cephem-4-carboxylate.

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t -Butyl 7- (2-carboxybenzamido) -S-4-carboxylate to t-butyl ^ -amino-S-methyl-S-cephem ^ -carboxylate.

Benzyl 7- (2-carboxybenzamido) -S-cephem-4-carboxylate to benzyl ^ -amino-S-acetoxymethyl-S-cephem-4-carboxylate.

p-Methoxybenzyl 7- (2-carboxybenzamido) -3-methoxymethyl-3-cephem-4-carboxylate to p-methoxybenzyl-7-amino-3-methoxymethyl-3-cephem-4-carboxylate.

2,2,2-trichloroethyl-7- (2-carboxybenzamido) -3-methylthiomethyl-3-cephem-4-carboxylate to 2,2,2-trichloroethyl-7-amino-3-methylthiomethyl-3-cephem-4-carboxylate.

t -Butyl 7- (2-carboxybenzamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylate to t-butyl 7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylate.

Benzyl 7- (2-carboxybenzamido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephera-4-carboxylate to benzyl 7-amino-3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylate.

The end product in the above list is obtained in the form of the free 7-amino compound. If you use the invention However, in the process of acid treatment, a corresponding acid addition salt is initially obtained as the end product. This salt can of course easily be converted into the free 7-amino compound by known methods .

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Furthermore, the process conversions given above do not represent any other aspect of the invention, namely the Possibility to use a corresponding 7-acylamido compound instead of the free 7-amino compound or its acid addition salt to obtain. This product can be obtained by adding an acyl halide, for example the acyl chloride 7-acylamido function desired in the end product is used. The acyl halide is used in place of the acid used in the final stage of the cleavage process. It turned out that In this procedure, the acyl halide itself is sufficiently acidic to avoid any intermediate product Complex that may be present in the reaction mixture from the hydrazine treatment. Simultaneously with it the free 7-amino group becomes the corresponding 7-acylamido compound acylated.

Appropriate selection of the respective acyl halide allows introduce any known acyl group in position 7. Suitable acyl groups are, for example, phenylacetyl, phenoxyacety1, Phenylglycyl, 2-thienylacety1 or mandelyl.

Virtually any acyl halide can be used. Typical such acyl halides are, for example, acetyl chloride, Hexanoyl bromide, chloroacetyl chloride, gamma-bromooctanoyl chloride, Azidoacetyl bromide, cyanoacetyl chloride, sydnonacetyl chloride, Tetrazole acetyl chloride, 2-thienylacetyl chloride, 3-thienylacety1-bromide, 2-furylacetyl iodide, 3-furylacetyl chloride, 2-pyrrolyl acetyl bromide, 3-pyrrolyl acetyl chloride, phenyl acetyl chloride, alpha, alpha-dimethylphenylacetyl chloride, p-chlorophenylacety1-chloride, m-bromophenylacetyl bromide, p-iodophenylacetyl chloride, p-fluorophenylacetyl chloride, m-trifluoromethylphenylacetyl bromide, p-hydroxyphenylacetyl chloride, p-tolylacetyl bromide, m-methoxyphenylacetyl chloride, p-cyanophenylacetyl chloride, p-nitrophenylacetyl bromide, Phenoxyacetyl chloride, phenylthioacetyl chloride, p-hydroxyphenoxyacetyl bromide, 4-pyridylthioacetyl chloride, m-chlorophenoxyacetyl chloride, alpha-aminophenylacetyl chloride, N- (Benzyloxycarbonyl) -alpha-aminophenylacetyl bromide, N- (methoxycarbonyl) -alpha-aminophenylacetyl chloride, N- (cyclopentyloxy-

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carbonyl) -alpha-aminophenylacetyl chloride, N- (Cyclohexyloxycarbonyl) -alpha-aminophenylacetyl chloride, N- (Benzhydryloxycarbonyl) -alpha-aminophenylacetyl bromide, N- (triphenylmethyl) -alpha-aminophenylacetyl chloride, N- (2,2,2-trichloroethoxycarbonyl) -alpha-aminophenylacetyl chloride, alpha-hydroxyphenylacetyl chloride, alpha-formyloxyphenylacetyl chloride, alpha-acetoxyphenylacetyl chloride, alpha-carboxyphenylacetyl chloride, alpha-methoxycarbonylphenylacetyl chloride, alpha- (t-butoxycarbonyl) phenylacetyl chloride , alpha-azidophenylacetyl chloride, alpha-cyanophenylacety1-chloride or alpha-carbamoylphenylacetyl chloride.

The products obtained by the process according to the invention can be isolated in a customary manner, for example on chromatographic route, by filtration or by recrystallization.

Since the end product of the process according to the invention is an ester is, this product can in addition to the corresponding acylation of the 7-amino function by cleavage known per se convert the ester function into an active antibiotic. Deesterification can be done by removing the ester with an acid, for example trifluoroacetic acid or hydrochloric acid, or with zinc and acid, for example formic acid, Acetic acid or hydrochloric acid. The esterification can in a similar manner also by hydrogenation of the ester in the presence of palladium, rhodium or a corresponding compound thereof in suspension or on a carrier, such as barium sulfate, carbon or aluminum oxide, be made.

The invention is illustrated in more detail by means of the following examples.

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Manufacture A. Methyl ^ -phthalamido-S-methyl-S-cephem ^ -

carboxylate

A solution of 17.3 g (0.05 mol) of 7-phthalimido-3-methyl-3-cephem-4-carboxylic acid in 50 ml of acetone and 20 ml of water is slowly mixed with 5 g (0.05 mol) of KHCO ₃ . The resulting solution is evaporated to dryness, and 38 ml of dimethylformamide and 5 ml of methyl iodide are added to the residue. The mixture is stirred for 3 hours at room temperature. 100 g of ice are then added to the mixture obtained in this way, and the solid product formed is filtered off. The product obtained is crystallized from a mixture of 100 ml of 2-propanol and 100 ml of acetone. Yield: 7.91 g of crystals with a melting point of 187-188 °; IR (CHCl ₃ ) 1790 and 1735 cm " ¹ , NMR (CDCl ₃ ) delta 2.31 (s, 3, CH ₃ ), 3.0 and 3.75 (ABq, 2, J = 15 Hz), 3, 85 (s, 3, CH ₃ ), 5.15 (d, 1, J = 4.4 Hz), 5.74 (d, 1, J = 4.4 Hz) and 7.73 (m, 4, ArH).

Analysis for C ₁₇ H ₁₄ N ₃ O ₅ S:

Calculated: C, 56.98; H 3.94; N 7.82; S 8.95; found: C, 56.75; H 3.66; N 7.53; S 8.89%.

Manufacture B. t-Butyl-7-phthalimido-3-methyl-3-cephem-4-

carboxylate

A mixture of 13.76 g (40 mmol) of 7-phthalimido-3-methyl-3-cephem-4-carboxylic acid, 10 ml of concentrated sulfuric acid, 100 ml of dry dioxane and 50 ml of liquid isobutylene will stirred at room temperature in a sealed pressure vessel

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and then added to excess ice cold aqueous sodium bicarbonate (44 g). Extraction of the mixture obtained with ethyl acetate and evaporation of the solvent gives a crude ester which is crystallized from chloroform. The first harvest yields 3.34 g of crystals that melt at 189 to 191 C, and the second harvest yields 1.72 g of crystals with a melting point of 181 - 183 ° C, / alpha / = 77.7 ° ( MeCN); IR (CHCl ₃ ) 1800, 1785 and 1735 cm "¹; NMR (CDCl ₃ ) delta 1.55 (s, 9, t-Bu); 2.23 (s, 3, CH ₃ ), 3.05 and 3 , 6 (ABq, 2, J = 16 Hz), 5.1 (d, 1, J = 4.5 Hz), 5.72 (d, 1, J = 4.5 Hz) and 7.8 (m , 4, ArH).

Analysis for C ₂₀ H ₃₀ N ₂ O ₅ S:

calculated: C 59.99; H 5.03; N 7.00; 0 19.98; S 8.01; Found: C, 60.27; H 4.91; N 7.04; 0 20.06; S 7.74%.

Manufacture. C. t-butyl-7-phthalimido-3-acetoxvmethyl-3-cephem-

4-carboxylate and t-butyl 7- (2-carboxybenzamido) -3-acetoxy-3-cephem-4-carboxylate

A mixture of 3.28 g (10 mmol) of t-butyl 7-aminocephalosporanate (7-ACA), 1.5 g (10 mmol) of phthalic anhydride and 25 ml of benzene is refluxed for 2 hours using a Dean-Stark water sampler heated. The resulting solution is cooled, washed with sodium bicarbonate (1.68 g in 20 ml of water), water and brine and finally dried. Evaporation of the solvent gives 1.22 g of a neutral product. The product is chromatographed over silica gel using a gradient mixture of benzene and ethyl acetate. Fractions 54 to 87 give 330 mg of the phthalimido compound, which is crystallized from dichloromethane / ether. The prisms thus obtained melt at 176-178 ⁰ C, / alphaA- + 43.4 ° (MeCN); IR (CHCl ₃ ) 1800, 1785 and 1735 cm " ¹ , lamdaätOH 260 mu

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(epsilon = 10,000); NMR (CDCl ₃ ) delta 1.55 (s, 9, t-Bu); 2.1 (s, 3, CH ₃ ), 3.5 (s, 2, CH ₂ ); 4.9 and 5.3 (ABq, 2, J - 14 Hz); 5.1 (d, 1, J = 4.5 Hz); 5.82 (d, 1, J = 4.5 Hz) and 7.82 (m, 4, ArH).

Analysis for C ₂ 2 ^H 22 ^N 2 ^O 7 ^S:

calculated: C, 57.63; H 4.84; N 6.11; 0 24.43; S 6.99; Found: C, 57.56; H 4.60; N 6.31; 0 24.60; S 6.90%.

After removing the neutral product, the aqueous product is acidified Part to pH 3.6, and the acidic mixture is then washed with ethyl acetate extracted. Obtained by evaporation of the ethyl acetate 2.9 g of t-butyl 7- (2-carboxybenzamido) cephalosporanate. This material is dissolved in 50 ml of benzene, and the solution is mixed 15 mg iraidazole and heat the mixture using for 30 minutes a Dean-Stark water collector to reflux. To appropriate work-up and chromatographic purification gives 430 mg of t-butyl-7-phthalimidocephalosporanate.

The ratio of the condensation of phthalic anhydride and the t-butyl ester of 7-ACA depends on products obtained on the respective implementation time. If you only heated the mixture for 15 minutes, you would have about 160 mg of the Phthalimido compound and about 4.34 g of the phthalamic acid compound obtain·

Production D. p-Methoxybenzyl ^ -phthalimido-S-Tnethyl-S-

cephem-4-carboxylate

A suspension of 13.4 g (38 mmol) of 7-phthaliraido-3-methyl-3-cephem-4-carboxylic acid in 20 ml of dioxane and 10 ml of water, 3.8 g of potassium hydrogen carbonate are slowly added. The solution one evaporates to dryness one, and the potassium salt residue

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100 ml of dimethylformamide and 8.8 g of p-methoxybenzyl bromide are added. The mixture is stirred for 2 hours and then poured onto 200 g of ice. The mixture obtained is extracted twice with ethyl acetate. The extract is washed with water and brine and then dried, followed by evaporation of the solvent. The residue is crystallized from ethyl acetate. Yield: 4.1 g of large crystals of melting point 118-121 ⁰ C, obtained in the second crop, 1.8 g product / alpha / + 41.2 (MeCN), IR (CHCl ₃₎ 1800, 1785, 1745 and 1735 cm " ¹ , NMR (CDCl ₃ ) delta 2.15 (s, 3, CH ₃ ); 3.0 and 3.7 (ABq, 2, J = 15 Hz), 3.8 (s, 3, CH ₃ ), 5.11 (d, 1, J = 4.5 Hz), 5.28 (s, 2, CH ₃ ), 5.75 (d, 1, J = 4.5 Hz), 6.8 up to 7.8 (m, 8).

Analysis for ^C ₂ 4 ^H 2O ^N 2 ^O 6 ^S:

calculated: C, 62.06; H 4.34; N 6.03; 0 20.67; S 6.90; Found: C, 62.15; H 4.31; N 6.32; 0 20.88; S 6.82%.

Example 1 Methyl 7- (2-carboxybenzamido) -3-methyl-3-cephem-4-carboxylate

A solution of 2.86 g (8 mmol) of methyl 7-phthalimido-3-methyl-3-cephem-4-carboxylate in 80 ml of tetrahydrofuran maintained at 0 ⁰ C and treated with 2.4 g (10 mmol) of Na ₂ S.9H ₂ O and 32 ml of ice water are added. The whole thing is kept at 0 ^° C. for 7 minutes, whereupon 10 ml of 1 η hydrochloric acid are added to the mixture. The whole is then evaporated in vacuo to a volume of about 40 ml and the aqueous solution obtained is washed with ethyl acetate. The aqueous layer is adjusted to pH 4.5 with 1 η hydrochloric acid and then extracted with ethyl acetate (40 ml). The ethyl acetate layer is washed with brine (30 ml), dried over magnesium sulfate and evaporated to give 1.8 g of methyl 7- (2-carboxybenzamido) -3-methyl-3-cephem-4-carboxylate as an amorphous colorless solid receives. Obtained by recrystallization from acetone

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to an analytical sample: Melting point 182-184.5 C (decomposition), IR (KBr) 1768, 1630, 1610 (shoulder) and 1665 cm "¹; NMR (CDCl ₃ ZDMSO _4-6 ) 2.08 (s, 3, CH ₃ ), 3.12 and 3.52 (ABq, 2, J »17 Hz), 3.8 (s, 3, CH ₃ ester), 5.06 (d, 1, J = 4.5 Hz), 5.86 (dd, 1, J = 4.5 and J = 8.0 Hz) and 7.4 to 8.0 delta (m, 4, ArH).

Analysis for C ₁₇ H ₁₆ N ₃ OgS:

calculated: C, 54.25; H 4.28; N 7.44; S 8.52; Found: C, 53.98; H 4.18; N 7.73; S 8.58.

The pH of the above aqueous layer is lowered to 2.5 by adding 1 η hydrochloric acid, and extraction is then carried out with ethyl acetate (twice 30 ml). The ethyl acetate extracts are combined, washed with brine (30 ml) and dried over magnesium sulfate. The ethyl acetate is evaporated in vacuo and a colorless crystalline product crystallizes out during this time. As soon as a volume of about 10 ml has been reached, the solution is filtered, and 190 mg (6.5%) 7- (2-carboxybenzamido) -3-methyl-2-cephem-4-carboxylic acid are obtained. Melting point 196-198 ° C (decomposition), IR (KBr) 1773, 1700 and 1658 cm "¹; NMR (DMSO ₄₆ ) 1.88 (s, 3, CH ₃ ), 4.64 (s, 1, C ₄ -H), 5.15 (d, 1, J = 4.0 Hz), 5.5 (dd, 1, J = 4.0 and 8.0 Hz), 6.15 (s, 1, C ₃ -H) and 7.4 to 8.0 delta (m, 4, ArH).

Analysis for C ₁₆ H ₁₄ N ₂ OgS:

Calculated: C, 53.03; H 3.89; N 7.73; S 8.85; Found: C, 52.76; H 3.85; N 7.68; S 8.77.

Evaporation of the above filtrate gives more 600 mg of methyl 7- (2-carboxybenzamido) -S-methyl-S-cephem ^ -carboxylate. The overall yield is 80%.

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Example 2 Methyl-7-amino-3-methyl-3-cephem-4-carboxylate-hydrochloric !

A suspension of methyl-7- (2-carboxybenzamido) -3-methyl-3-cephem-4-carboxylate (752 mg, 2 mmol) in 35 ml of tetrahydrofuran at 0 ml ⁰ C with triethylamine (0.28, 2 mmol ) offset. After 15 minutes, ethyl chloroformate (0.2 ml, 2 mmol) is added, the whole is then kept at 0 ° C. for 0.5 hours and anhydrous hydrazine (0.07 ml, 2.2 mmol) is then added to the reaction mixture. After 15 minutes the mixture is filtered and the filtrate is evaporated to dryness in vacuo. The crude product obtained is taken up in 20 ml of chloroform, whereupon heated for 90 minutes to reflux and then is stirred overnight at about 35 ⁰ C. By filtration to obtain 180 mg Diketophthalazin (m.p. 340-343 ⁰ C). The filtrate is evaporated to dryness in vacuo. The crude product obtained is taken up in 3 ml of 1N hydrochloric acid plus 2 ml of water and the whole is then washed with ethyl acetate (2 × 7 ml). Evaporation of the aqueous layer in vacuo gives a yellow amorphous solid which, after recrystallization from ethanol / diethyl ether, gives 115 mg of methyl 7-amino-3-methyl-3-cephem-4-carboxylate hydrochloride.

Example 3

t-butyl-7- (2-carboxybenzamido) -S-acetoxymethyl-S-cephem-

4-carboxylate

A solution of 458 mg (ImMoI) t-butyl-7-phthalimido-3-acetoxymethyl-3-cephem-4-carboxylate in 10 ml of tetrahydrofuran is cooled in an ice-water bath, whereupon this solution with 1.1 ml of 1N sodium hydroxide were added. After stirring for 5 minutes, 10 ml of water and 30 ml of ethyl acetate are added. the

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The ethyl acetate layer is separated and 70 mg of starting material is recovered from it. The aqueous layer is acidified to pH 4.0 and the acidified layer is extracted. one then with ethyl acetate. After working up, 330 mg (83%) of the desired phthalamic acid are obtained with the following characteristics: /, alpha / + 26.37 (MeCN); X _ÄtQH 260 m, u ( ί 880) ^D ; IR (CHCl ₃ ) 1785, 1730 and 1685 cm "¹; NMR (CDCl ₃ ) cfi # 55 (s, 9, t-Bu), 2.05 (s, 3, Ac), 3.3 and 3.6 (ABq, 2, J = 17 Hz), 4.72 and 5.2 (ABq, 2, J = 14 Hz), 4.98 (d, 1, J = 4.5 Hz), 5.9 (dd , 1, J = 4.5 and 9 Hz) and 7.5 to 8 (m, 4, ArH).

Example 4 t -Butyl 7-amino-3-acetoxymethyl-3-cephem-4-carboxylate

According to the procedure described in Example 2, one sets t-butyl-7- (2-carboxybenzamido) -S-acetoxymethyl-S-cephem - ^ - carboxylate to t-butyl ^ -amino-S-acetoxymethyl-S-cephem - ^ - carboxylate hydrochloride and this is converted by treating with sodium bicarbonate and extracting with chloroform to the free amine. Melting point, infrared spectrum and NMR spectrum are correct with an authentic sample according to the method of R. J. Stedman, J. Med. Chem., (1966) page 444.

Example 5 t -Butyl 7- (2-carboxybenzamldo) -3-methyl-3-cephem-4-carboxylate

A solution of 800 mg (2 mmol) of t-butyl 7-phthalimido-3-methyl-3-cephem-4-carboxylate in 25 ml of tetrahydrofuran and 8 ml of water is cooled in an ice bath. _{660 mg of Na 2} S.9H ₂ O are added to the solution obtained, and the mixture is stirred and cooled for 10 minutes. At the end of this time, 10 ml of water

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added, whereupon the mixture is extracted with 40 ml of ethyl acetate. The extract is discarded. The aqueous part is acidified with 1N sulfuric acid to pH 4.3 and then extracted with ethyl acetate. The ethyl acetate extract is dried and evaporated to give 700 mg of the title compound. The product is recrystallized from chloroform / cyclohexane, and then it has the following characteristics: (. + DMSO ,, CDCl-) Melting point 178-179 ⁰ C, IR (Nujol) 1770, 1735 and 1680 cm ^"1 NMR

J ClO

cT1.5 (s, 9, t-Bu), 2.1 (s, 3, CH ₃ ), 3.2 and 3.5 (ABq, 2, J = 18 Hz), 5.02 (d, 1 , J = 4.5 Hz), 5.82 (dd, 1, J = 4.5 and 9 Hz) and 7.4 to 8 (m, H, ArH).

Analysis for ^c oo ^H 22 ^N 2 ⁰ 6 ^S:

calculated: C, 57.40; H 5.30; N 6.69; 0 22.94 and S 7.66; found: C, 57.70; H 5.20; N 6.52; 0 22.72 and S 7.53%.

The same substance (NMR, IR, melting point) can also be obtained in 94 percent yield from phthalic anhydride and the t-buty ester of 7-ADCA.

Example 6 t -Butyl 7-amino-3-methyl-3-cephem-4-carboxylate

Using the procedure described in Example 2, t-butyl 7- (2-carboxybenzamido) -3-methyl-3-cephem-4-carboxylate is used to t-butyl ^ -amino-S-methyl-S-cephem ^ -carboxylate hydrochloride around. The hydrochloride salt is converted using from ethyl acetate and sodium bicarbonate to the free amino ester um, which is a colorless solid.

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Example 7

p-Methoxybenzyl-7- (2-carboxybenzamido) -S-methyl-S-cephem-

4-carboxylate

A solution of 930 mg (2 mmol) of p-methoxybenzyl-7-phthalimido-3-methyl-3-cephem-4-carboxylate in 25 ml of tetrahydrofuran and 8 ml of water is cooled in an ice-water bath, whereupon 660 mg of Na ₂ S.9H ₂ O is added. The mixture is stirred for 15 minutes and then 10 ml of water and 40 ml of ethyl acetate are added. The layers are separated and 140 mg of a neutral material is obtained from the ethyl acetate layer. The aqueous layer is acidified to pH 4.3 with 1N sulfuric acid and extracted twice with ethyl acetate. The ethyl acetate extract is washed, dried and evaporated to give 660 mg (68%) of phthalamic acid as an amorphous solid. The characteristics of this product are as follows: / alpha / + 85.6 ° (MeCN); IR (CHCl ₃ ), 1781, 1740 and 1710 cm "¹; NMR (CDCl ₃ ) cf2, O8 (s, 3, CH ₃ ), 3.1 and 3.43 (ABq, 2, J = 17 Hz), 3.79 (s, 3, CH ₃ ), 5.0 (d, 1, J = 4.5 Hz), 5.1 (s, 2, CH ₃ ), 5.8 (dd, 1, J = 4.5 Hz), 6.75 to 7.6 (m, 8).

Analysis for C ₂₄ H ₂₂ N ₂ OS:

Calculated: C, 59.74; H 4.60; N 5.81; 0 23.21; S 6.65; Found: C, 59.81; H 4.32; N 6.07; 0 23.34; S 6.51%.

Example 8

p-Methoxybenzyl ^ -amino-S-methyl-S-cephem ^ -carboxylate-p-toluene-

sulfonic acid salt

According to the procedure described in Example 2, p-methoxybenzyl-7- (2-carboxybenzamido) -S-

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carboxylate to p-methoxybenzyl ^ -amino-S-methyl-S-cephem-4-carboxylate-p-toluenesulfonic acid salt by using p-toluenesulfonic acid monohydrate instead of hydrochloric acid in Example 2 in this case used. The product obtained is identical to that of Chauvette et al., J. Org. Former., 36, 1265 (1971).

Example 9

p-Nitrobenzly-7- (2-carboxybenzamido) -3-methyl-3-cephem ~ 4--

carboxylate

A solution, cooled with ice, of 84 mg (1 mmol) of p-nitrobenzyl-7-phthalimido-3-methyl-3-cephem-4-carboxylate in 25 ml of tetrahydrofuran and 5 ml of water is mixed _{with 340 mg of sodium sulfide (Na 2 S.9H_O} ) offset. The mixture is stirred for 7 minutes at pH 11.5, and then 40 ml of ethyl acetate and 10 ml of hasser are added. The layers are separated and the organic layer is washed with 5 ml of water and 5 ml of brine to give 150 mg of a neutral material. The aqueous layer is acidified to pH 4.5 with 1N sulfuric acid and the emulsion obtained is extracted with 25 ml of ethyl acetate. The extract is washed with brine, dried and evaporated to dryness, whereby 290 mg of crude product is obtained, from which 150 mg (30%) of pure product is obtained.

The same connection can also be established by the other variant of the method, namely by 30 minutes Reflux of phthalic anhydride and the p-nitrobenzyl ester of 7-ADCA in acetonitrile.

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A sample is recrystallized from dioxane / water, and the result is faultless crystals having the following characteristics: melting point 192-193 ⁰ C NMR (DMSO-dg) cf2, O4 (s, 3, CH _3), 3.35 and 3, 68 (ABq, 2, J = 18 Hz), 5.2 (d, 1, J = 4 Hz, H-6), 5.4 (s, 2, CH ₂ ), 5.8 (dd, 1, J = 4.5 and 9 Hz) 8 (m, 8 ArH).

Analysis for C ₂₃ H ₁₉ N ₃ OgS:

calculated: C, 55.53; H 3.85; N 8.45; 0 25.73; S 6.45; Found: C, 55.67; H 3.94; N 8.49; 0 25.89; S 6.47%.

The subsequent acidification of the aqueous solution to pH 2.0 and subsequent extraction with ethyl acetate gives 120 mg of p-nitrobenzyl-7- (2-carboxybenzamido) -S-methyl ^ -cephem-4 -carboxylate ..

Example 10

p ~ nitrobenzl-7-amino-3-methyl-3-cephem-4-carboxylate-p-toluene-

sulfonate salt

A solution of 1.0 g (2 mmol) of p-nitrobenzyl 7- (2-carboxybenzamido) -3-methyl-3-cephem-4-carboxylate in 30 ml of dry tetrahydrofuran is cooled in an ice-salt bath and with 0.28 ml (2 mmol) of triethylamine and 0.20 ml (2 mmol) of ethyl chloroformate offset. After cooling and stirring for 20 minutes, 0.15 ml of 85 percent hydrazine hydrate is added and stir for another 10 minutes. The Ät-N.HCl-SaIz is filtered off, and the Fitlrat is evaporated to dryness. The residue is dissolved in a mixture of 25 ml of ethyl acetate and 10 ml of water. The organic extract is made from the aqueous layer separated and washed with sodium bicarbonate solution, Washed with water and brine. After drying, steams one off the solvent. The residue is dissolved in 10 ml of acetonitrile, and the solution is heated to for 50 minutes

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Reflux and then cool. The solution thus obtained is mixed with 380 mg of p-toluenesulfonic acid hydrate and 2.5 ml of water, whereupon the precipitate (160 mg) is filtered off and most of the acetonitrile is evaporated from the filtrate. Crystallization begins on cooling and scratching. 2 hours later, 680 mg (63%) of the title compound are collected. The purity of the product is examined by thin layer chromatography using silica plates and methanol / benzene (1: 3). A sample is recrystallized from methanol / ether and it then shows the following characteristics; Melting point 170 to 174 ⁰ C (decomposition), NMR (DMSO _3-6 ) d ~ 2.2O (s, 3, CH ₃ ), 2.30 (s, 3, CH ₃ ), 3.6 (s, 2 , SCH ₂ ), 5.22 (s, 2, CH ₃ ester), 5.4 (s, 2, azetidinone hydrogens) and 7.1 to 8.25 (m, 8 Ar hydrogens); IR (KBr) 1780 (azetidinone-CO) and 1730 cm ester-CO).

Analysis for ^C ₂ 2 ^H 23 ^N 3 ^O 8 ^S 2 ^:

Calculated: C, 50.66; H 4.45; N 8.06; S 12.30; Found: C, 51.03; H 4.27; N 8.19; S 11.91%.

Example 11 p-Nitrobenzyl ^ -phenylacetamido-S-methyl-S-cephem ^ -carboxylate

A suspension of p-nitrobenzyl 7- (2-carboxybenzamido) -3-methyl-3-cephem-4-carboxylate (462 mg., 1 mmol) in tetrahydrofuran at 0 ⁰ C with triethylamine (0.14 ml, 1 mmol). After 15 minutes, ethyl chloroformate (0.1 ml, 2 mmol) is added and the whole is kept at 0 ° C. for 0.5 hours and anhydrous hydrazine (0.03 ml, 1 mmol) is then added to the reaction mixture. After 15 minutes the reaction mixture is filtered and the filtrate is evaporated in vacuo

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2Ί29166

dry up. The residue is taken up in acetone (15 ml) and tetrahydrofuran (15 ml) and phenylacetyl chloride (0.13 ml, 1 mmol) is then added. After refluxing for 30 minutes, the mixture is cooled and evaporated to dryness in vacuo. The product obtained is taken up in chloroform (50 ml), whereupon it is washed in succession in 1N hydrochloric acid (30 ml), 10 percent sodium bicarbonate (40 ml) and brine (40 ml), dried over magnesium sulphate and dried in vacuo Evaporate dry. The colorless product obtained is slurried with ethyl acetate (12 ml). Filtration gives p-nitrobenzyl-V-phenylacetamido-S-methyl-S-cephem ^ -carboxylate. Recrystallization from ethyl acetate leads to an analytical sample, melting at 227-230 ⁰ C.

Example 12

t-Butyl-7- (2'-carboxy) acrylamido-S-acetoxymethyl-S-cephem-

4-carboxylate

A solution of 656 mg (2 mmol) of t-butyl ^ -amino-S-acetoxymethyl-3-cephem-4-carboxylate and 196 mg (2 mmol) of maleic anhydride in 20 ml of benzene is refluxed for 0.5 hours, cooled and then evaporated to dryness in vacuo. The thin-layer chromatogram shows no starting material and a slowly moving product that has the following characteristics: NMR (CDCl ₃ ) 94 (s, 9, t-Bu), 127 (s, 3, OAc), 207 and 216 (ABq, 2 , J = 20 Hz), 293 and 307 (ABq, J = 14.0, CH ₂ 305 (1, d, J = 4.5, azetidinone-H), 350 (1, q, J = 4.5 and 8.0 Hz, azetidinone-H), 390 (2H, q, J = 12 and 2.0 Hz), 534 (1, d, J = 8.0, NH) and 806 Hz (1, broad s, COOH ).

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Example 13 t-Buty 1-7-amino-3-acetoxymethyl 1-3-cephem-4-carboxylate

According to the procedure described in Example 2, t-butyl-7- (3'-carboxy) acrylamido-S-acetoxymethyl-S-cephem is used 4-carboxylate to t-butyl-T-amino-S-acetoxymethyl-S-cephem-4-carboxylate hydrochloride around. The reaction mixture containing the hydrochloride is treated with ethyl acetate and Sodium bicarbonate to give a tan amorphous product. The NMR spectrum and thin layer chromatography show that the product obtained is identical to authentic t-butyl-T-amino-S-acetoxymethyl-3-cephem-4-carboxylate.

Example 14

Benzhydryl 7- (2-carboxybenzamido) -3- (5-methyl-1,3,4-thiadiazol-2-y1) thiomethyl 1-3-cephem-4-carboxylate

A solution of benzhydryl 7-phthalimido-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylate (2 mmol) in 25 ml of tetrahydrofuran and 8 ml of water is made cooled in an ice-water bath, whereupon 660 mg Na ₃ S.9H ₂ O are added. The mixture obtained is stirred for 15 minutes and then 10 ml of water and 40 ml of ethyl acetate are added. The layers are separated and a neutral material is obtained from the ethyl acetate layer. The aqueous layer is acidified to pH 4.3 with 1N sulfuric acid and extracted twice with ethyl acetate. The ethyl acetate extract is washed, dried and evaporated to give the title compound.

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Example 15

Benzhydryl 7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylate

A solution of benzydryl 7- (2-carboxybenzamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylate (2 mmol) in 30 ml of dry tetrahydrofuran is cooled in an ice-salt bath, whereupon 0.28 ml (2 mmol) of triethylamine and 0.20 ml (2 mmol) of ethyl chloroformate are added. After cooling and stirring for 20 minutes, 0.106 ml (2 mmol) of N-methylhydrazine in 5 ml of tetrahydrofuran are added. Stirring is continued for about 10 minutes. The At ₃ N.HCl salt is filtered off and the filtrate is evaporated to dryness. The residue is taken up in about 15 ml of chloroform, and the mixture obtained is left to stand for about 1 hour at room temperature, and methyl phthalhydrazide is precipitated (melting point 243 to 245 ^° C.). By filtering off and evaporating the filtrate in vacuo, crude benzydryl-7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylate is obtained.

Example 16

2,2,2-trichloroethyl-7- (2-carboxybenzamido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl 1-3-cephem-4-carboxylate

The procedure described in Example 14 is used to employ 2,2,2-trichloroethyl-7-phthalimido-3- (1-methyl-IH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate to 2,2,2-trichloroethyl-7- {2-carboxybenzamido) -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylate around.

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Example 17

2, 2, a-trichloroethyl-y-amino-a- (1-methyl-IH-tetrazol-5-yl) thiomethyl 3-cephem-4-carboxylate

The procedure described in Example 15 gives 2,2,2-trichloroethyl-7- (2-carboxybenzamido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate to 2,2,2-trichloroethyl-y-amino-S- (1-methyl-IH-tetrazol-5-yl) -thiomethyl-3 -cephem-4-carboxylate reacted, but instead of N-methylhydrazine, N, N'-dimethylhydrazine is used,

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Claims (11)

P a te η ta η s ρ r ü ehe '1, Process for the cleavage of the amide acid function of a 7- (amic acid) cephalosporins of the formula 0 Il R -CC-NH, ^a Il ^R "" ^C "" -CHsRh COOH COOR1 wherein R and R stand for hydrogen or R and R together a a with the carbon atoms to which they are attached represent an ortho-phenylene ring, R _{1 is} a carboxy protecting group, and R _{2 represents} hydrogen, acetoxy, methoxy, methylthio, (5-methyl-1,3,4-thiadiazol-2-yl) thio or (1-methyl-1H-tetrazol-5-yl) thio, characterized in that one (T) the above 7- (amic acid) cephalosporin with a Alkyl chloroformate in the presence of a tertiary amine to form the corresponding mixed anhydride of the formula II COOR1 409882/1160 where R. is alkyl having 1 to 4 carbon atoms, implements, (2) the product mixture obtained from the above chloroformate treatment with a hydrazine of the formula R ₃ HNNHR ₄ , wherein R ₃ and R _{4 are} independently hydrogen or methyl, reacts, and (3) a) the reaction mixture obtained from the above hydrazine treatment with an acyl halide to form the corresponding 7-acylamidocephalosporin, or b) the corresponding 7-aminocephalosporin is obtained from the reaction mixture of the abovementioned hydrazine treatment if at least one of the substituents R ₃ and R- is methyl, or c) heating the reaction mixture obtained from the above hydrazine to produce the corresponding 7-Arainocephalosporins to a temperature of about 50 to about 1OO ⁰ C, if the substituents R ₃ and R ₄ are Nasser substance, or d) the reaction mixture obtained from the above hydrazine treatment to produce the corresponding 7-aminocephalosporin in the form of its acid addition salt is reacted with acid if the substituents R ₃ and R are hydrogen. 409882/1160 2. The method according to claim 1, characterized in that that the reaction mixture obtained from the hydrazine treatment to produce the corresponding 7-acylamidocephalosporin with an acyl halide. 3. The method according to claim 1, characterized in that the product mixture obtained from the chloroformate treatment with a hydrazine, in which at least one
the substituents R., and R. is methyl, reacted and the 7-aminocephalosporin recovered from the reaction mixture. 4. The method according to claim 1, characterized in that the product mixture obtained from the chloroformate treatment with a hydrazine, in which R_ and R _{4 are} hydrogen, is reacted and the reaction mixture obtained to produce the 7-aminocephalosporin to a temperature of about 50 heated to about 100 ^{° C.} 5. The method according to claim 1, characterized in that the product mixture obtained from the chloroformate treatment is reacted with a hydrazine of the formula R ₃ HNNHR ₄ , in which R ₃ and R _{4 are} hydrogen, and the reaction mixture obtained is used to produce the 7-aminocephalosporin reacts with acid in the form of its acid addition salt. 6. A method according to any one of claims 1 to 5, characterized in that a tertiary amine at a temperature of about -20 ⁰ C reacting the Amidsäurecephalosporin with an alkyl chloroformate in the presence of up to about +5 C. 409882/1160 7. The method according to any one of claims 1 to 6, characterized characterized in that ethyl chloroformate is used as the alkyl chloroformate. 8. The method according to claim 5, characterized in that the product mixture obtained from the chloroformate treatment first with up to 1 equivalent of a hydrazine of the formula R ₃ HNNHR ₄ R ₃ and R _{4 are} hydrogen, treated per equivalent of the amic acid at a temperature of about -10 C up to about room temperature for a period of about 1 to about 10 minutes, the resulting reaction mixture then with about 1 to about 2 equivalents of one Acid from the group of hydrochloric acid, hydrobromic acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid or sulfuric acid per equivalent of the original amic acid is reacted over a period of about 5 to about 10 minutes, whereby the corresponding 7-aminocephalosporin is obtained in the form of its acid addition salt. 9. The method according to claim 3, characterized in that the product mixture obtained from the chloroformate treatment is first treated with up to one equivalent of a hydrazine of the formula R ₃ HNNHR ₄ , wherein at least one of the substituents R- and &. are methyl, per equivalent of the amic acid at a temperature of about -10 ⁰ C to about room temperature for a period of about 1 to about 10 minutes, and thus arrives at the corresponding 7-aminocephalosporin « 10. The method according to any one of claims 1 to 9, characterized in that the amic acid function of a compound of formula I in which R and R are hydrogen, splits. 409882/1160 11. The method according to any one of claims 1 to 9, characterized characterized in that the amidic acid function of a compound of the formula I in which R and R together with the carbon atoms to which they are attached for an ortho-phenylene ring stand, splits. 409882/1160