CH616938A5 - Process for the preparation of 6beta-acylamino-1-oxadethiapenicillanic acids - Google Patents

Description

The invention relates to a process for the preparation of new 60 6β-acylamido-l-oxadethiapenicilic acids of the formula

H

rnh

(I)

c02h

616 938

wherein A is hydrogen or methoxy and R is an aliphatic, aromatic, heterocyclic, araliphatic or heterocyclic-aliphatic carboxylic acid radical or the 1-aminocyclo-hexylcarbonyl radical, or their salts.

The discovery of penicillin, which has proven to be such an important and effective antibiotic, has generated great interest in this area. Various other antibiotics, such as streptomycin, the tetracyclines, novobiocin and the like, were later found which significantly expanded the medical inventory of pharmaceutical agents for treating infections caused by various pathogens. However, the use of these antibiotics has led to the formation of strains of pathogens which are resistant to these known antibiotics. In addition, the known antibiotics suffer from the disadvantage that they are only effective against certain types of microorganisms, but not against a wide range of pathogens. The search for other antibiotics was therefore continued.

The invention is therefore based on the object of providing a method for producing new penicillins with antibiotic activity.

The compounds of formula 1 obtained according to the invention can be converted into their pharmacologically acceptable salts.

The process according to the invention is characterized in that a compound of the general formula

• N

in which R1 is hydrogen or a protective group and R5 is hydrogen or both radicals R5 together form a benzylidene radical or a substituted benzylidene radical, with an aliphatic, aromatic, heterocyclic, araliphatic or heterocyclic-aliphatic carboxylic acid halide or anhydride or with one of the 1- Reacts aminocyclohexyl carbonyl residue acid derivative, and, if R1 is a protecting group, splits off the protecting group and, if necessary, converts the free acid into a pharmacologically acceptable salt.

The compounds of formula I obtained are converted into corresponding esters on the one hand by reaction with an alcohol.

Amide derivatives of compounds of the formula I can also be prepared by reacting the free acid with an acid halide and then with ammonia, an alkyl, dialkyl or aralkylamine or with a heterocyclic amine.

In the compounds of the formula I obtained according to the invention, R in particular denotes a radical of the formula

O

I!

Y-C-,

where Y is R2R3CH-, where R2 is hydrogen, azide, alkoxy, Ci-Cio alkyl, such as methyl and the like, phenyl, halogen, amino, guanidino, guanylureido, phosphono, hydroxy, tetrazolyl, carboxy, sulfo or sulfamino. R3 means phenyl, a substituted phenyl radical, a 5- or 6-membered monocyclic heterocyclic

Radical having 1 to 4 oxygen, sulfur or nitrogen atoms as heteroatoms in the ring, such as furyl, thienyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl and the like, a substituted heterocyclic thio group, cyano or (2,5-cyclohexadiene-l- yl); Y can also be a substituted phenyl radical

Be 2-substituted 1-naphthyl, a 3-substituted, phenyl-substituted isoxazol-4-yl or a 3-substituted phthalazl-l-yl. The acyl radicals also include 1-aminocyclohexyl and cyclopentyl. The substituents can be halogen, carboxy, carboxymethyl, guanidino, guanidinomethyl, carboxamidomethyl, amino-methyl, nitro, methoxy or methyl. Particularly preferred are those acyl radicals in which R2 is hydrogen, hydroxyl, amino or carboxy and R3 is phenyl or a 5- or 6-membered heterocyclic ring with one or two sulfur, oxygen or nitrogen atoms as heteroatoms. Examples of some preferred radicals are phenylacetyl, 3-bromophenylacetyl, p-aminomethylphenyl-acetyl, 4-carboxymethylphenylacetyI, 4-carboxyamido-methylphenylacetyl, 2-furylacetyl, 5-nitrofurylacetyl,

3-furylacetyl, 5-chlorothienylacetyl, 5-methoxythienyl-acetyl, a-guanidino-2-thienylacetyl, 3-methylisothiazolyl-acetyl, isothiazolylacetyl, 3-chloroisothiazoIyl-

acetyl, 3-methyl-l, 2,5-thiadiazolyl-4-acetyl, 3-chloro-l, 2,5-thiadiazolyl-4-acetyl, 3-methoxy-l, 2,5-thiadiazol-yl-4- acetyl, phenylthioacetyl, 4-pyridylthioacetyl,

Cyanoacetyl, tetrazolylacetyl, a-fluorophenylacetyl, D-phenylglycyl, 4-hydroxy-D-phenylglycyl, 2-TTiienyl-glycyl, 3-thienylglycyl, phenylmalonyl, 3-chlorophenyl-malonyl, 3-thienylmalonyl, 3-thienylmalonyl phonophenylacetyl, a-sulfaminophenylacetyl, a-hydroxy-phenylacetyl, a-tetrazolylphenylacetyl, a-sulfophenyl-acetyl, thienylacetyl, phenoxyacetyl, a-phenoxy-propionyl, a-phenoxyphenylacetyl, 2-phenylnaphthox-3-phenyl-3-phenyl-3-phenyl-3-phenyl-3-phenyl-3-phenyl-3-phenyl-3-phenyl-3-phenyl-3-phenyl-3-phenyl-3-phenyl-3-phenyl-2-phenyl-naphthyl-3-phenyl -4-carbonyl, 5-methyl-3- (2-chlorophenyl) -isoxazole-4-carbonvl, 5-methyl-3- (2-chloro-6-fluorophenyl) -isoxazole-4-carbonyl, a- (3- Guanyl-ureido) -phenylacetyl, a-amino-p-hydroxyphenylacetyl, a-phenyl-ß-aminoporpionyl, a-azidophenyl, 2,6-dimethoxybenzoyl, 2,6-dichlorobenzoyl, 3- (2 ', 6'- Dichloro-phenyl) -5-methylisoxazole-4-carbonyl, 1-aminocyclohexyl-carbonyl, 2- (2,5-cyclohexadien-l-yl) -glycyl and 3-carboxy-phthalazin-l-yl.

The term Ci-Cio alkyl includes straight-chain and branched-chain aliphatic hydrocarbon radicals having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, amyl, hexyl, 2-ethylhexyl, heptyl, Decyl and the like.

The new penicillins obtained according to the invention can be used as antibiotics in the form of derivatives such as metal salts, e.g. Sodium, potassium or aluminum salts, ammonium salts, amine salts, e.g. Procaine or N, N'-dibenzylethylenediamine salts, or of amides and substituted amides, may be used as is known in the art. Unstable esters which are easily metabolized by deacylases contained in body fluids, such as groups of the general formula -CH20C0 (CH2) n-R4, in which n is an integer from 0 to 5 and R4 is an unsubstituted or substituted aliphatic, alicyclic, Aromatic or heterocyclic radical are preferred ester derivatives for use in antibiotic therapy. Other esters of the new penicillins, such as lower alkyl, aralkyl, aryl, silyl or stannyl esters, are suitable as intermediates in the preparation of the free acids and the salts thereof by processes known per se.

When carrying out the following reaction, the 3-position carboxyl group can be protected by an ester group R1, e.g. B. by trichloroethyl, o-nitrobenzyl, p-bromophen

4th

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5

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acyl, p-nitrobenzyl, benzyl, benzhydryl, trimethylsilyl, methoxymethyl and the like. These ester groups can be split off by known methods; e.g. For example, the benzyl and p-nitrobenzyl groups can be split off by hydrogenation in the presence of a catalyst, such as palladium on carbon. The trichloroethyl and p-bromophenacyl groups can also be split off by treatment with zinc and acetic acid or formic acid. The tert-butyl, p-methoxybenzyl, benzhydryl and methoxymethyl group can be split off by treatment with organic or inorganic io acids. Preferred examples of these acids are formic acid, trifluoroacetic acid and the like.

In a preferred embodiment for producing the 6-acylamino-l-oxadethiapenicillanic acids or their esters of the form] I, a corresponding 6-amino-l-oxadethiapenicis is cillanic acid, an ester thereof or a 6-substituted imino-l-oxadethiapenicillanic acid ester of the formula II in the presence of a base, such as a tertiary amine, for example in the presence of trialkylamines or heterocyclic amines, such as triethylamine, pyridine and the like, with an acylation agent]. Appropriate acyl halides or acyl anhydrides, namely aliphatic, aromatic, heterocyclic, araliphatic or heterocyclic aliphatic carboxylic acid halides or anhydrides, are used as acylating agents. Other acylating agents that can also be used 2s are e.g. B. mixed acid anhydrides with other carboxylic acids and in particular Ci-Cio-alkyl esters of carboxylic acids. It is also possible to use carboxylic acids in the presence of a carbodiimide, such as 1,3-dicyclohexylcarbodiimide,

use an activated ester of a carboxylic acid, such as the p-nitro-30-phenyl ester, or carry out the acylation by enzymatic means. The reaction can be carried out at temperatures in the range from 0 to 25 ° C. Any solvent in which the Reak-5 A H

r? nJ_P ° x

J, —N U.CC ^ R1

tion participants are soluble, and that is substantially inert, such as. B. hydrocarbons such as benzene, toluene and the like; solvents such as diethyl ether, methylene chloride, chloroform, tetrahydrofuran, dioxane, acetonitrile and the like can also be used. The reaction is usually carried out in the course of about 5 minutes to a maximum of 3 hours; however, a reaction time of about 0.5 to 1 hour is generally sufficient.

If an imino compound is used, increased yields are obtained if the imino compound is preferably first treated with a metal catalyst. In this first stage of the process, the imino compound is usually dissolved in an inert solvent such as tetrahydrofuran, dimethyl sulfoxide, dioxane, dimethylformamide, methanol, ethanol, methylene chloride or chloroform. Then you usually add some water so that the ratio of solvent to water is about 5-6: 1. The metal catalyst can then be added and the reaction mixture stirred for 1 to 5 hours at room temperature. The solvent can be driven off or the acylating agent can be added directly to the reaction mixture. The preferred catalyst has the general formula MLn, in which M is a metal such as palladium, platinum, nickel, ruthenium, rhodium, cobalt or iron, L the ligand such as halogen, carbonyl, cyclopentadienyl, phenylcyan and the like, and n is an integer means, which depends on the requirements of value. Palladium chloride (PdCte) is preferred as the catalyst.

The following equation illustrates a preferred embodiment of this method using the carboxylic acid halide; however, the same products are obtained using the carboxylic anhydride or another functionally equivalent acylating agent:

0

Ii y-cx

»

II

In the above equation, A and Y have the above meanings, R1 represents hydrogen or a protective group, as described above or otherwise known per se. R5 is hydrogen, or both Rs together form a benzylidene radical or a substituted benzylidene radical,

and X represents halogen, e.g. As chlorine, bromine and the like, azide or anhydride.

Examples of compounds obtainable according to the invention are the following:

6ß- (3-bromophenylacetamido) -6-methoxy-l-oxadethia-penicillanic acid

6β- (p-aminomethylphenylacetamido) -6-methoxy-1-oxadethiapenicillanic acid

6β- (4-carboxymethylphenylacetamido) -1-oxadethiapenicillanic acid

6ß- (4-carboxamidomethylphenylacetamido) -6-methoxy-l-oxadethiapenicillanic acid 6ß- (2-furylacetamido) -6-methoxy-l-oxadethia-penicillanic acid

6ß- (5-Nitrofurylacetamido) -6-methoxy-l-oxadethia-penicillanic acid

6ß- (3-furylacetamido) -6-methoxy-l-oxadethia-

la penicillanic acid

6β- (5-chlorothienylacetamido) -6-methoxy-l-oxadethia-penicillanic acid and 6ß- (5-methoxythienylacetamido) -6-methoxy-l-oxadethia-penicillanic acid

6ß- (a-Guanidino-2-thienylacetamido) -6-methoxy-l-oxadethiapenicillanic acid

6ß- (3-MethylisothiazoIylacetamido) -6-methoxy-l-55 oxadethiapenicillanoic acid

6β- (5-isothiazolylacetamido) -6-methoxy-l -oxadethiapenicillanic acid

6ß- (3-ChloroisothiazolyIacetamido) -6-methoxy-l-oxadethiapenicillanic acid 60 6 ß- (3-methyl-1,2,5-thiadiazoI-4-yl-acetamido) -6-methoxy-l-oxadethiapenicillanic acid 6ß- (3rd -ChIor-l, 2,5-thiadiazol-4-yI-acetamido) -6-methoxy-1-oxadethiapenicillanoic acid 6ß- (3-methoxy-l, 2,5-thiadiazol-4-yl-acetamido) -6-65 methoxy-1-oxadethiapenicillanic acid

6β-phenylthioacetam ido-1-oxadethiapenicillanic acid

6ß- (4-pyridylthioacetamido) -6-methoxy-l-oxadethia-

penicillanic acid

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6β-cyanoacetamido-6-methoxy-1-oxadethiapenicillanic acid

6ß-tetrazolylacetamido-6-methoxy-l-oxadethia

penicillanic acid

6β- (a-fluorophenylacetamido) -6-rnethoxy-l -oxadethiapenicillanic acid

6 β- (D-a-aminophenylacetamido) -1-oxadethiapenicillanic acid

6ß- [D- (4-hydroxyphenyl) a-aminoacetamido] -l-oxadethia-penicillanic acid

6β- (a-Amino-2-thienylacetamido) -6-methoxy-l-oxadethiapenicillanic acid

6ß- (a-Amino-3-thienylacetamido) -l-oxadethia-penicillanic acid

6β-Benzoylacetamido-6-methoxy-l-oxadethia-penicillanic acid

6ß- (3-chlorobenzoylacetamido) -6-methoxy-l-oxadethia-penicillanic acid

6 β- (2-thienyl-a-carboxylacetamido) -6-methoxy-l-oxadethiapenicillanic acid

6ß- (3-thienyl-a-carboxylacetamido) -6-methoxy-l-oxadethiapenicillanic acid

6β- (a-phosphonophenylacetamido) -6-methoxy-1-oxadethiapenicillanic acid

6β- (a-sulfaminephenylacetamido) -6-methoxy-1-oxadethiapenicillanic acid

6β- (a-Hydroxyphenylacetamido) -6-methoxy-1-oxadethiapenicillanic acid 6β- (a-sulfophenylacetamido) -6-methoxy-1-oxadethiapenicillanic acid

6 β-phenoxyacetamido-1-oxadethiapenicillanic acid

6β- (ci-phenoxypropionamido) -1-oxadethiapenicillanic acid

6β-phenylacetamido-l-oxadethiapenicillanic acid

6ß- (a-phenoxyphenylacetamido) -l-oxadethia-

penicillanic acid

6 β- (a-sulf aminophenylacetamido) -1-oxadethiapenicillanic acid

6ß- (a-Carboxyphenylacetamido) -6-methoxy-l-oxadethia-penicillanic acid

6β- (a-carboxyphenylacetamido) -1-oxadethiapenicillanic acid

6ß- (2,6-Dimethoxybenzamido) -l-oxadethiapenicillanoic acid 6ß- (2,6-dichlorobenzamido) -l-oxadethiapenicillanoic acid 6ß- [3- (2 ', 6'-dichlorophenyl) -5-methylisoxazol-4-amido] - 1-oxadethiapenicillanic acid

6 ß- (1 - aminocyclohexylcarboamido) -1-oxadethiapenicillanic acid

6ß- [l- (2,5-cyclohexadiene) -l-amino-acetamido] -l-oxadethiapenicillanic acid and 6ß- (3-carboxyphthalazin-l-amido) -l-oxadethia-penicillanic acid.

The 6-amino-l-oxadethiapenicillanate (II), in which Rs represent a hydrogen atom, can be prepared in various ways depending on the type of starting material. One method is e.g. B. the treatment of the correspondingly substituted 6-azido-l-oxadethiapenicilIanats with hydrogen in the presence of a noble metal catalyst such as platinum oxide, palladium on charcoal, ruthenium, rhodium and the like. Another way is from chemical reduction, e.g. B.

Al (HgK Zn-HOAc or Cu-HS- ^ ~ ^>, use.

A second method for producing the 6-amino-l-oxadethiapenicillanate (II) is u. a. the treatment of the correspondingly substituted 6-imino compounds with an amine in the presence of an acid catalyst. For this - amines, such as aniline, hydrazine or hydrazine derivatives, such as

Phenylhydrazine and the like. The acid catalyst can be hydrochloric acid, p-toluenesulfonic acid and the like. Solvents that can be used for this purpose are lower alkanols, such as methanol, ethanol and the like, but also other solvents, such as dimethoxyethane, dimethylformamide and the like.

The 6β-substituted imino-l-oxadethiapenicillanate and the 6ß-amino-l-oxadethiapenicillanic acid or the esters thereof used in the acylation process can be obtained by treating a 6a-amino-l-oxa-dethiapenicillanate or a mixture of 6a - and 6β-isomers with an approximately equimolar amount of a substituted or unsubstituted benzaldehyde, the substituents of which may be nitro, halogen, cyano, carboxy or hydroxyl radicals. Any inert or substantially inert solvent such as chloroform, ethanol, dioxane, benzene, toluene or methylene chloride can be used for this. The reaction is preferably carried out at temperatures from 0 ° C. to the reflux temperature of the solvent in question. In order to increase the yields, the water formed in the reaction can be prepared in a manner known per se, e.g. B. by azeotropic distillation, with the aid of molecular sieves or with magnesium sulfate.

The 6a-imino-l-oxadethiapenicillanate thus obtained is then usually in an inert aprotic solvent, e.g. B. tetrahydrofuran. A strong base is preferably added to this solution. As strong bases, lithium alkyls whose alkyl group contains 1 to 4 carbon atoms such as the methyl, ethyl, tert-butyl and n-butyl compounds, and lithium aryls such as phenyllithium and the like, or lithium amides such as lithium diisopropylamide and the like, but sodium hydride or potassium tert-butt lat can also be used. This reaction is usually carried out at temperatures in the range of about -100 to 0 ° C. A polar aprotic solvent, such as dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric acid triamide and the like, and then a source of protons, such as a lower aliphatic carboxylic acid, preferably acetic acid, can then be added to the reaction mixture, whereupon the desired 6β-imino-1- oxadethiapenicillanat receives.

The epimerization described above does not form part of the invention, but is described in another patent of the patent holder relating to "epimerization of penicillin compounds".

This 6ß-imino-l-oxadethiapenicilIanat can be directly acylated or converted into the 6ß-amino compound by the process mentioned. The ester group on this product of the process can be split off by the methods described above, whereupon the 6β-amino-1-oxadethiapenicillanic acid thus obtained is acylated by known methods.

The compounds produced by the process according to the invention are racemates, i.e. H. each compound exists as a pair of enantiomers, the structure of each of the two enantiomers mirroring the structure of the other enantiomer of the pair, and the two enantiomers rotating the polarized light in different ways. These racemic mixtures can be broken down into the pure enantiomers by crystallization of the diastereoisomeric salts with optically active acids or bases, by kinetic asymmetric conversion, by mechanical separation or by other methods known per se. Only one of the enantiomers, namely the 6β-acyl-amido compound (I), of the racemic pair has significant biological activity.

The 6β-amino-6a-methoxy-l-oxadethiapenicillanate can be prepared by using the 6a or the 6ß-amino

6

s

10th

15

20th

25th

30th

35

40

45

50

55

60

65

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bonds converted by reaction with one of the aromatic aldehydes described above in the corresponding imino compounds. The imino compound is then usually activated with a strong base. An inorganic base, e.g. B. an alkali metal hydride or alcoholate such as sodium hydride or sodium tert-butoxide, or an organometallic compound such as phenyllithium, tert-butyllithium, lithium diisopropylamide and the like. The base is typically added to the imino compound solution at temperatures in the range of about i -100 to -60 ° C under an inert atmosphere (e.g., under nitrogen). An inert solvent such as tetrahydrofuran or diethyl ether is preferably used for this.

The activated intermediate is generally not isolated, but directly with a halogenating agent, such as N-bromosuccinimide, N-bromoacetamide, bromine, tert-butylhypochlorite, perchloromethylhypochlorite and the like, to give the 6-substituted imino-6-halogen-1- oxadethiapeniciIlanaten of the general formula

H

B

icooir

20th

halogen

^> - CH = N

0

X "

»-

H

\ I /

H

"C02r R-hn

III

c

-, tJCOOR

implemented in which Z is hydrogen, nitro, halogen, cyano, carboxy or hydroxy. “Halogen” in particular chlorine or bromine and R1 has the above meaning.

This compound typically goes into treatment with methanol in the presence of a base such as silver oxide, barium oxide, calcium oxide, copper (I) oxide or triethylamine, into the 6β-substituted in the presence of an acid catalyst or with water in the presence of a metal catalyst (e.g. B. PdCL2), as described above, can be reacted to the 6β-amino-6-l-oxadethiapenicil lanates.

Another method of epimerization that can be used to convert the oa-acylamino-l-oxadethiapenicillin to the 6β-acylamino-l-oxadethiapenicillin is described below. This epimerization process described below also does not form part of the invention, but is described in another patent filed in the name of inventor Lovji Cama. In the following flow diagram, the substituents R and R1 have the above meanings.

Flow chart

40

45

SCH, H 3

R-HN

kW

A

- .. COOR

The process starts from the 6cc-acylamino-6-methylthio-penicillin A. This starting material can be prepared in solution in an inert solvent such as tetrahydrofuran, chloroform or the like, and the solution is cooled to below about 0 ° C, preferably to a temperature between about -100 and 0 ° C. It is most advantageous to cool the solution with solid carbon dioxide or a mixture thereof with a solvent such as alcohol, chloroform, acetone or ether, so that the temperature of the solution drops to - 60 to - 100 ° C.

Then chlorine is added to the solution of A in a solvent such as carbon tetrachloride or the like. The chlorine is added in a molar excess based on the amount of Compound A (1 to 5 times the amount of A).

The mixture consisting of two components is stirred for a few minutes at the low temperature; however, this is not absolutely necessary. Then an active hydride is added in solution, also at the same low temperature.

Various inorganic compounds with a hydrogen anion, such as lithium aluminum tri-tert-butoxy hydride, lithium aluminum hydride, sodium borohydride, lithium borohydride and others, can be used as the “active hydride”. The active hydride is used in a molar excess (1 to 5 times the amount of A). After the addition of the hydride, the mixture is stirred for a few minutes, after which it is allowed to assume room temperature or a temperature between 0 ° C. and room temperature. After washing and evaporation, the pure product C according to normal metho-65 den, z. B. can be obtained by preparative thin layer chromatography.

In the above brief description, the intermediate acylamine B is not mentioned. This intermediate 60

616 938

8th

product is not isolated from the reaction mixture; its existence is probable, if only hypothetical.

The 6cx-azido-l-oxadethiapeniciIlanate are prepared by a 10-step synthesis process, the last step of which is the ring closure. In this process, 2-formamido-3-hydroxy-3-methylbutyric acid ethyl ester is used and the following process steps are carried out: (a) preparation of the free 2-formamido-3-hydroxy-methylbutyric acid by elimination of the ester group; (b) Preparation of the corresponding amino compound 2-amino-3-methyl-3-hydroxybutter-io acid in the form of the hydrochloric acid salt thereof by hydrolysis of the formamido group of the acid; (c) esterification with the protective group Ri given above to protect the carboxyl function in subsequent reactions; (d) reacting the protected 2-amino-3-hydroxy-3-methylbutyric acid with a lower alkyl ester of thionoformic acid, such as ethyl thio-formate, in the presence of hydrogen sulfide; this reaction is generally carried out in an inert solvent, such as benzene, carbon tetrachloride, methylene chloride or hexane, at temperatures from 0 to 40 ° C. and leads to the formation of the ester of 2-thioformamido-3-hydroxy-3- methyl butyric acid; (e) Protection of the hydroxyl function by reaction of the hydroxy compound with a suitable known protective agent, such as dihydropyran in the presence of an acid, such as p-toluenesulfonic acid or trisz methylsilyl chloride, to form the ester of the 2- substituted in the 3-position by the protective group Thioformamido-3-hydroxy-3-methylbutyric acid; (f) Preparation of the ester of the 2- (S-methylthioformimidato) -3-hydroxy-3-methylbutyric acid substituted in the 3-position by reacting the compound protected on the 3-position hydroxyl group with a methylating agent, such as methyl iodide, in Presence of a base such as potassium carbonate in a suitable solvent such as acetone or dimethylformamide; (g) reaction of the S-methyl-substituted compound with azi- 3s doacetyl chloride and an acid-binding agent, e.g. B.

a tertiary amine, which also catalyzes the cycloaddition, to form the compound of the general formula containing the lactam ring

40

N.

H

Protecting group

IV

50

(h) Preparation of the free hydroxy compound l-fT-R1-2'-hydroxypropyl) -3-azido-4-methylthio-2-azetidinone by cleaving off the 55 protecting the hydroxyl group

Group in a known manner, e.g. By treating with an acid such as hydrochloric acid, perchloric acid and the like; (i) Replacement of the 4-methylthio group by chlorine by reacting the azetidinone with a chlorinating agent, such as chlorine, in a suitable inert solvent, such as methylene chloride or benzene, at temperatures in the range from about 0 to 40 ° C. to form the corresponding substituted 4-chloroazetidinones and (j) treating the 4-chloro compound with a halogen releasing agent such as silver fluoroborate, silver oxide or silver trifluoromethanesulfonate in a suitable solvent such as methylene chloride, toluene or chloroform to form the desired ester of 6a-azido-1 -oxadethiapenicillanic acid of the general formula

J_N 1.

* # C0oR1

«£»

in which R1 has the meaning given above.

The nomenclature used here is as follows: The connection

A H

knh

—R V

• «-c02h is called 6ß-acylamido-6-A-l-oxadethiapenicillanic acid.

In formula I, the dotted lines leading to "A" and "H" indicate that the substituents are below the level of the β-lactam ring, while the line leading to "RNH" indicates that the nitrogen atom is above the level of the ring located. It is not necessary to specify the configuration of both substituents on the 6-position carbon atom; because if the configuration of the nitrogen atom is given, the other substituent, ie «A», must of course be in the other possible configuration.

The products (I) obtained according to the invention form a large number of pharmacologically usable salts with inorganic and organic bases; these include e.g. B. metal salts derived from alkali or alkaline earth metal hydroxides, carbonates or bicarbonates, and salts of primary, secondary or tertiary amines, such as monoalkyl amines, dialkylamines, trialkylamines, lower alkanolamines, lower dialkanolamines, lower Alkylenediamines, N, N'-diaralkyl-lower-alkylenediamines, aralkylamines, amino-substituted lower alkanols, by lower alkylamino groups N, N-disubstituted alkanols, amino-, polyamino- and guanidino-substituted lower aliphatic carboxylic acids and nitrogen-containing heterocyclic amines. Representative examples are of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium hydroxide, calcium carbonate, trimethylamine, triethylamine, piperidine, morpholine, quinine, lysine, protamine, arginine, procaine, ethanolamine, morphine, benzylamine, ethylenediamine, N, N ' -Diben-cylethylenediamine, diethanolamine, piperazine, dimethylamino-ethanol, 2-amino-2-methyl-1-propanol, theophylline, N-methylglucamine, trishydroxymethylmethylamine and the like derived salts.

The salts can be mono salts, such as the monosodium salt obtained by reacting 1 equivalent of sodium hydroxide with 1 equivalent of product (I); mixed disalts are obtained by reacting 1 equivalent of a monosal with 1 equivalent of another base. Similarly, salts can be obtained by reacting 1 equivalent of a base having a divalent cation such as calcium hydroxide with 1 equivalent of the product (I). Mixed salts and mixed esters, such as z. B. by implementing the product (I) with

9

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1 equivalent of sodium hydroxide and then obtained with 1 equivalent of lactic acid are within the scope of the invention.

The salts mentioned are pharmacologically usable non-toxic derivatives which can be used as active ingredients in suitable pharmaceutical unit dosage forms. They can also be combined with other pharmaceutical agents to obtain a wide range of activities. In addition, these salts and also the corresponding esters and amides are suitable as intermediates for the preparation of the carboxylic acid corresponding to general formula I.

The products (I) are also converted into the corresponding mono- and diesters as well as mono- and diamides. So you can z. B. the trimethylacetoxymethyl or dibenzhydryl ester or alkyl, cycloalkyl, aryl or aralkyl ester, e.g. B. the methyl, ethyl, cyclohexyl, phenyl and benzyl esters, or amides, diamides, Ci-Cio-alkylamides, N, N-di-Ci-Cio-alkylamides, N-aralkylamides, N, N- Diaralkylamides or heterocyclic amides, such as the N-methyl and the N-ethyl amide, the NN-dimethyl amide, the N, N-diethyl amide, the N-benzyl amide, the N, N-dibenzyl amide, the piperidide, the pyrrolidide, the morpholide and the like.

Processes for the preparation of the ester and amide derivatives are in particular the reaction of the carboxylic acid (I) or the corresponding acid halide with an alcohol or phenol, e.g. B. with methanol, ethanol, cyclohexanol, phenol, benzyl alcohol, dibenzhydrol and the like. The amide derivatives can be obtained by reacting the corresponding acid halide with ammonia or a corresponding alkylamine, dialkylamine, aralkylamine or heterocyclic amine. These and other conventional methods of

The preparation of the esters and amides is familiar to the person skilled in the art.

The examples below serve to explain the methods by which the new products can be manufactured. However, these examples are not to be interpreted as restrictive; the invention also includes the production of functionally equivalent products. Therefore, any modification of the systems described here that leads to the formation of the same product is to be regarded as an analogous method. The process can be modified in many ways.

example 1

Sodium 6ß-phenylacetamido-l-oxadethiapenicillanate stage A:

2-formamido-3-hydroxy-3-methylbutyric acid

37.8 g of 2-formamido-3-hydroxy-3-methylbutyric acid ethyl ester are mixed with 200 ml of water, after which a solution of 8.0 g of sodium hydroxide in 100 ml of water is added dropwise at such a rate that the temperature does not exceed 35 ° C. After the addition has ended (about 1 hour), the reaction mixture is stirred at 35 ° C. for another hour. The solvent is removed under reduced pressure and the remaining sodium 2-formamido-3-hydroxy-3-methylbutyrate is dissolved in 200 ml of water and the solution is treated with a cation exchange resin, namely a polystyrene (Dowex in the hydrogen ion form) substituted by sulfonic acid groups in the core until the pH is 1. The ion exchange resin is filtered off and the filtrate is freeze-dried. This gives 2-formamido-3-hydroxy-3-methyl-butyric acid.

Level B:

2-amino-3-methyl-2-hydroxybutyric acid hydrochloride

15.9 g of 2-formamido-2-hydroxy-3-methylbutyric acid are dissolved in 150 ml of 5N hydrochloric acid, and the mixture is heated at reflux temperature for V2 hours. The solution is concentrated to 50 ml and then freeze-dried. 2-Amino-3-methyl-3-hydroxybutyric acid hydrochloride is obtained.

Level C:

2-Amino-3-methyl-3-hydroxybutyric acid benzyl ester

16.6 g of 2-amino-3-methyl-3-hydroxybutyric acid hydrochloride are mixed with 160 ml of benzyl alcohol and 32 g of polyphosphoric acid. The mixture is heated at 100 ° C for 6 hours and then poured into 2500 ml of water containing 25 ml of concentrated hydrochloric acid. The mixture is extracted twice with 1300 ml ether and the ether extract is extracted twice with 500 ml hydrochloric acid. The combined aqueous extracts are adjusted to a pH of 9.6 and extracted five times with 750 ml of diethyl ether each. The ether extract is dried over magnesium sulfate and evaporated to give 2-amino-3-methyl-3-hydroxybutyric acid benzyl ester.

Level D;

Benzyl 2-thioformamido-3-hydroxy-3-methylbutyrate 2.23 g of benzyl 2-amino-3-hydroxy-3-methylbutyrate are dissolved in 25 ml of carbon tetrachloride and the solution is cooled to 0 ° C. After the addition of 10 g of ethyl thionoformate, the mixture is stirred for V2 hours. The mixture is passed into the mixture of hydrogen sulfide for 10 minutes and the reaction mixture is then stirred for a further 5 hours at room temperature. The solvent is removed under reduced pressure and 2-thioformamido-3-hydroxy-3-methyl-butyric acid benzyl ester is obtained from the residue by chromatography on silica gel.

Level E:

Benzyl 2-thioformamido-3-trimethylsilyloxy-3-methylbutter

2.67 g of 2-thioformamide-3-hydroxy-3-methyl-butyric acid benzyl ester are dissolved in 30 ml of methylene chloride, and the solution is mixed with 8.0 ml of 1,1,1,3,3,3-hexamethyldisilazane and 4, 0 ml of trimethylsilyl chloride are added and the reaction mixture is stirred under nitrogen overnight. The solvent and excess of reagents are stripped off under reduced pressure and the residue is dissolved in methylene chloride and filtered. The filtrate is evaporated. This gives benzyl 2-thioformamido-3-trimethylsilyloxy-3-methylbutter.

Level F:

2- (S-methyl-thioformimidato) -3-trimethylsilyloxy-3-methylbutyric acid benzyl ester

3.51 g of benzyl 2-thioformamido-3-trimethylsiIyIoxy-3-methylbutyrate are dissolved in 25 ml of anhydrous acetone. After adding 3 g of powdered potassium carbonate and 1.38 g of methyl iodide, the reaction mixture is stirred for 3 hours under nitrogen, then filtered and evaporated. The residue is dissolved in chloroform, the solution is filtered and concentrated. This gives benzyl 2- (S-methyl-thioformimidato) -3-trimethylsilyloxy-3-methylbutyrate.

Level G:

1- (l / -Benzyloxycarbonyl-2'-methyl-2'-trimethylsilyloxypropyl) -3-azido-4-methylthio-2-azetidinone

3.65 g of benzyl 2- (S-methyl-thioformimidato) -3-trimethylsilyl-oxy-3-methylbutyrate are dissolved in 50 ml of dry methylene chloride. 1.2 g of azidoacetyl chloride are added dropwise in the course of 2 minutes, and the mixture is stirred for a further 5 minutes. Then 1.01 g of triethylamine in 10 ml of methylene chloride are added in the course of 10 minutes and the mixture is stirred for a further 5 minutes. The reaction mixture is washed with 5 percent sodium bicarbonate solution, dried and evaporated. The backlog at s

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Chromatography on silica gel 2.25 g 1- (1'-

Benzyloxycarbonyl-2'-methyl-2'-trimethylsilyloxypropyl) -3-

azido-4-methylthio-2-azetidinone.

Level H:

1 - (1-Benzyloxycarbonyl-2'-methyl-2'-hydroxypropyl) -3-azido-4-methylthio-3-azetidinone

2.24 g of l- (l'-benzyloxycarbonyl-2'-methyl-2'-trimethylsilyloxypropyl) -3-azido-4-methylthio-2-azetidinone are dissolved in 40 ml of dioxane, the solution is dissolved in 10 ml of water and then 3 ml of 2.5N hydrochloric acid were added and the mixture was stirred at room temperature for 15 minutes. The pH is adjusted to 7 with sodium bicarbonate, the reaction mixture is diluted with methylene chloride, washed with brine, dried and evaporated. The crude product thus obtained is chromatographed on silica gel. 1- (1'-Benzyl-oxycarbonyl-2 '-methyl-2'-hydroxypropyl) -3-azido-4-methyl-thio-2-azetidinone is obtained.

Level I:

l- (l'-Benzyloxycarbonyl-2'-methyl-2'-hydroxypropyl) -3-azido-4-chloro-2-azetidinone

1.82 g of l- (l'-benzyloxycarbonyl-2'-methyl-2'-hydroxypropyl) -3-azido-4-methylthio-2-azetidinone are dissolved in 20 ml of methylene chloride and the solution is dissolved in a solution of 0.47 g of chlorine in methylene chloride. The reaction mixture is left to stand at room temperature for 10 minutes and the solvent is then stripped off under reduced pressure. This gives l- (r-benzyloxycarbonyl-2'-methyl-2 / -hydroxypropyl) -3-azido-4-chloro-2-azetidinone.

Level J:

6cx-azido-l-oxadethiapenicillanic acid benzyl ester

1.76 g of 1- (1-benzyloxycarbonyl-2'-methyl-2'-hydroxypropyl) -3-azido-4-chloro-2-azetidinone are dissolved in 20 ml of methylene chloride. 0.6 g of silver oxide and 0.95 g of silver tetrafluoroborate are added to the solution. The mixture is stirred for 45 minutes at room temperature. The silver salts are filtered off and the filtrate is washed with 5 percent sodium bicarbonate solution and then with water, dried and evaporated to dryness. This gives benzyl 6a-azido-l-oxa-dethiopenicillinate.

Level K:

Benzyl 6a-amino-l-oxadethiapenicillate

0.632 g of benzyl 6a-azido-l-oxadethiapenicillin are dissolved in 20 ml of dioxane. After adding 0.3 g of platinum oxide, the mixture is reduced with hydrogen under a pressure of 2.8 kg / cm 2 until the complete reduction of the azide results from the infrared spectrum of a sample. The catalyst is filtered off and the filtrate is evaporated. 6a-Amino-1-oxadethiapenicillanic acid benzyl ester is obtained.

Level L:

Benzyl 6a-benzaldimino-l-oxadethiapenicillanate

0.29 g of benzyl 6a-amino-l-oxadethiapenicillanate are mixed with 0.106 g of benzaldehyde. The mixture is dissolved in 20 ml of benzene, the solution is dried over magnesium sulfate, filtered and evaporated. This gives benzyl 6a-benzaldimino-l-oxadethiapenicillanate.

Level M:

6 ß-Benzaldimino-1-oxadethiapenicillanoic acid benzyl ester

0.378 g of 6a-benzaldimino-l-oxadethiapenicillanic acid benzyl ester are dissolved in 1 ml of anhydrous tetrahydrofuran and the solution is cooled to -78 ° C. under nitrogen. 1 ml of a 1 molar solution of phenyllithium in a mixture of benzene and ether is added dropwise in the course of 2 minutes, and 10 ml are then added in the course of 2 minutes

Dimethylformamide and then a mixture of 0.03 ml of water and 0.08 g of acetic acid in 20 ml of tetrahydrofuran. The reaction mixture is allowed to reach room temperature, diluted with benzene, washed with phosphate buffer solution (pH 8), dried and evaporated. The residue is a mixture of the starting material and 6β-benzaldimino-l-oxadethiapenicillanic acid benzyl ester.

Stages:

6 ß-Amino-1-oxadethiapenicillanoic acid benzyl ester

0.198 g of 2,4-dinitrophenylhydrazine are dissolved in 10 ml of ethanol, 0.190 g of p-toluenesulfonic acid monohydrate is added to the solution and the mixture is stirred at room temperature for V2 hours. After adding a solution of 0.378 g of benzyl 6-benzaldimino-1-oxadethiapenicillanate (mixture of the C-6 epimers) in 10 ml of ethanol, the reaction mixture is stirred for 2 hours at room temperature, filtered and the filtrate evaporated. The residue is taken up in methylene chloride, washed with phosphate buffer solution (pH 8), dried and evaporated. The 6β-amino-l-oxadethiapenicillanoic acid ester is predominantly obtained.

Level O:

Benzyl 6β-phenylacetamido-l-oxadethiapenicillanate 0.290 g benzyl 6ß-amino-l-oxadethiapenicillanate is dissolved in 20 ml of methylene chloride, and the solution is cooled to 0 ° C. and 0.250 g of pyridine is added. After the dropwise addition of 0.154 g of phenylacetyl chloride, the solution is stirred at 0 ° C. for 30 minutes. The reaction mixture is washed once with water, then with buffer solution (pH 2) and then with buffer solution (pH 7), dried and evaporated. Chromatography of the residue on silica gel gives 6β-phenylacetamido-l-oxadethiapeniciIlansäure-benzyl ester.

Level P:

Sodium 6β-phenylacetamido-l-oxadethiapenicillanate

0.409 g of 6β-phenylacetamido-l-oxadethiapenicillanoic acid benzyl ester are dissolved in 10 ml of dioxane. 2 ml of water, 0.084 g of sodium bicarbonate and 0.05 g of 10% palladium on carbon are added and the mixture is reduced for 1 hour under a hydrogen pressure of 2.8 kg / cm 2. The catalyst is filtered off and washed with a little water. The filtrate and the washing liquids are freeze-dried and sodium 6β-phenylacetamido-1-oxadethiape-nicillanate is obtained.

Example 2

6β-phenylacetamido-6-methoxy-1-oxadethiapenicillanic acid and the sodium salt thereof

Level A:

6-bromo-6-benzaldimino-1-oxadethiapenicillanoic acid benzyl ester

0.378 g of benzyl 6-benzaldimino-l-oxadethiapenicillanate are dissolved in 10 ml of anhydrous tetrahydrofuran and the solution is cooled to -78 ° C. under nitrogen,

whereupon 1 ml of a 1 molar solution of phenyllithium in a mixture of benzene and ether is added dropwise over the course of 2 minutes. Then 0.211 g of N-bromosuccinimide in 5 ml of tetrahydrofuran are added dropwise over the course of 2 minutes. The reaction mixture is stirred at -78 ° C for 5 minutes, after which it is allowed to warm to 0 ° C. The solvent is stripped off under reduced pressure, the residue is taken up in methylene chloride and the solution is washed once with phosphate buffer solution (pH 7), then with water, dried and concentrated to 5 ml. This gives a solution of 6-bromo-6-benzaldimino-l-oxa-

s

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benzyl dethiapenicillanate, which is used immediately in the next process step.

Level B:

6a-methoxy-6-benzaldimino-l-oxadethiapenicilic acid benzyl ester

0.2 g of silver oxide are suspended in 20 ml of methanol. The solution of 6-bromo-6-benzaldimino-l-oxadethiapenicilIansäu rebenzyl ester is added dropwise to the silver oxide suspension within 10 minutes. The reaction mixture is then stirred for a further 15 minutes, the silver salts are filtered off, the filtrate is evaporated and the residue is taken up in benzene. The solution is washed twice with phosphate buffer solution (pH 7), then dried and evaporated. Chromatography of the residue on silica gel gives 6a-methoxy-6-benzaIdimino-l-oxadethiapenicillanoic acid benzyl ester.

Level C:

6 ß-PhenyIacetamido-6-methoxy-l-oxadethiapenicillanic acid benzyl ester

0.204 g of benzyl 6a-methoxy-6-benzaldimino-l-oxadethiapenicillanate are dissolved in 6 ml of tetrahydrofuran, 1 ml of water and then 0.066 g of palladium chloride are added and the mixture is stirred for 3 hours at room temperature. The solvent is evaporated off under reduced pressure. The residue is stirred with petroleum ether and the material soluble in petroleum ether is discarded. The residue is then taken up in 25 ml of methylene chloride and the solution is dried over magnesium sulfate and evaporated. The residue is again taken up in methylene chloride, the solution is cooled to 0 ° C. and 0.21 g of pyridine and then 0.077 g of phenylacetyl chloride are added. The mixture is stirred at 0 ° C for 15 minutes, after which it is allowed to reach room temperature over the next 15 minutes. The reaction mixture is diluted with methylene chloride, washed once with buffer solution (pH 2) and then with buffer solution (pH 7). The organic phase is dried and evaporated. Chromatography of the residue on silica gel gives benzyl 6β-phenylacetamido-6-methoxy-1-oxadethiapenicillanate.

Level D:

6β-phenylacetamido-6-methoxy-l-oxadethiapenicillanic acid and its sodium salt

According to the step P procedure of Example 1, the 6β-phenylacetamido-6-methoxy-1-oxadethiapenicillanic acid benzyl ester is converted into 6ß-phenylacetamido-6-methoxy-l-oxadethiapenicillanic acid and the sodium salt thereof.

Example 3

6ß-phenylacetamido-l-oxadethiapenicillanic acid stage A:

Benzyl 2-oxazoline-5,5-dimethyl-4-carboxylate

10.0 g of 2-oxazoline-5,5-dimethyl-4-carboxylic acid ethyl ester are prepared by the method of H.D. Hoffe and U. Schollkopf (Angewandte Chemie International Edition, Volume 9, 1970, page 300).

The 2-oxazoline-5,5-dimethyl-4-carboxylic acid ethyl ester is dissolved in 20 ml of benzyl alcohol. After adding 0.150 g of NaH, the mixture is left to stand at room temperature for 2 hours. Then 100 ml of benzene are added and the mixture is evaporated under reduced pressure (at a temperature below 30 ° C.). The residue is left to stand for a further 2 hours, then benzene is added and the mixture is evaporated again. After evaporation of this type five times, 100 ml of benzene are added, the mixture is washed once with buffer solution (pH 3),

then with saline, evaporate and distill

0.3 mm Hg. After a flow of benzyl alcohol, which passes at 50-65 ° C, benzyl 2-oxazoline-5,5-dimethyl-4-carboxylate is obtained in a yield of 8.1 g (bp 125-130 ° C) .

1st row (Movie); 5.70 (ester C = 0), 6.1 (C = N).

H

NMR x (CDCb); 2.66 (CeHs); 3.25 (C = N, J = 2 Hz) 6.86 (C6H5CH2); 5.73 (N-C-C, J = 2 Hz); 8.56 and 8.83

H O

(CH3-C).

Level B:

Benzyl 2-amino-3-hydroxy-3-methylbutyrate

8.1 g of benzyl 2-oxazoline-5,5-dimethyl-4-carboxylate are mixed with 0.9 ml of water and 0.3 ml of triethylamine. The reaction mixture is heated at 100 ° C. for 3 hours with stirring. Then 15 ml of 5N hydrochloric acid are added, the mixture is cooled, diluted with 50 ml of water and extracted twice with 25 ml of methylene chloride. The aqueous layer is adjusted to a pH of 10 with 50 percent sodium hydroxide solution and extracted four times with 30 ml of methylene chloride each time. The combined methylene chloride extracts are washed once with brine, then dried and evaporated. This gives 5.9 g of benzyl 2-amino-3-hydroxy-3-methylbutyrate.

I.R. (x: 3.95 (NH and OH); 5.75 (Ester-C = O).

H

I.

NMR T (CCh); 2.7 (COH5); 4.9 (CÖHSCHZ); 6.78 (N-C-C) 7.75 (NH and OH); 8.83 and 9.0 (CH3-C).

Level C;

2-Thioformamido-3-hydroxy-3-methylbutyric acid benzyl ester

5.9 g of benzyl 2-amino-3-hydroxy-3-methylbutyrate are mixed in a thick-walled tube with 5 ml of ethyl thionoformate. The tube is cooled to -78 ° C, after which 5 ml of hydrogen sulfide is condensed into the tube. The tube is melted, whereupon the contents are allowed to assume room temperature and mixed thoroughly and the tube is left overnight at room temperature. The tube is then cooled to -78 ° C again and the seal is broken. The hydrogen sulfide is allowed to evaporate, the residue is taken up in methylene chloride and filtered. The filtrate gives 6.1 g of 2-thioformamido-3-hydroxy-3-methylbutyric acid benzyl ester on evaporation.

S

I.R. [a: 3.0 (NH and OH); 5.75 (ester); 6.65 and 6.92 (HC)

S

NMRx (CCU); 0.6 (HC); 0.86 (NH); 2.7 (CoHS); 4.86 (C6H5CH2); 6.53 (OH); 8.73 and 9.0 (CHa-C).

Level D:

* 2-Thioformamido-3-trimethylsilyloxy-3-methyl-butter-acidic acid benzyl ester

8.1 g of 2-thioformamido-3-hydroxy-3-methylbutyric acid benzyl ester are dissolved in 100 ml of methylene chloride, and the solution is mixed with 12 m! Trimethylsilyl chloride and 16 ml s

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12

1,1,1,3,3,3, -hexamethyldisilazane were added and the mixture was stirred at room temperature overnight. The solution is then filtered and the filtrate evaporated under reduced pressure. The residue gives 6.62 g of 2-thioformamido-3-trimethylsilyl-oxy-3-methylbutyric acid benzyl ester when chromatographed on silica gel using a mixture of 25% ethyl acetate in benzene as eluent.

I.R. [x, 3.0 (NH); 5.75 (ester); 6.68 and 6.95 (HC and 11.8 (Si-O).

S

S

); 9.7

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NMR x 0.55 (H-C); 2.0 (NH); 2.66 (CeHs); 4.86 (CeHsCHa); 8.62 and 8.7 (CHbC); 9.93 (CHa-Si).

Level E:

Benzyl 2- (S-methylthioimidato-3-trimethylsilyloxy-3-methylbutyrate 20

20 g of benzyl 2-thioformamido-3-trimethylsilyloxy-3-methylbutter are dissolved in 200 ml of anhydrous acetone, and 9 g of powdery anhydrous potassium carbonate and 4.6 ml of methyl iodide are added to the solution. The reaction mixture is stirred under nitrogen for 24 hours and then evaporated under reduced pressure. The residue is taken up in 100 ml of carbon tetrachloride, the solution is filtered and the residue is washed with 50 ml of carbon tetrachloride. The combined filtrates and washing liquids are evaporated to 20.15 g of 2- (S-methylthioimidato) -3-trime-so thylsiIyloxy-3-methylbutyric acid benzyl ester.

I.R. (Movie); 5.75 (ester); 6.26 (C = N); 9.6 and 8.85 (SiO). NMRx (CCl-0; 1.93 (H-C = N); 2.73 (CeH5); 4.92 (C6H5CH2);

6.16 (N-C-C); 7.63 (CHa-S); 8.67 and 8.73 (CH3-C); 35

I.

H

9.93 (CHs-Si).

Level F: 40

1 - (1-Benzyloxycarbonyl-2-methyl-2-trimethylsilyloxy) propyl-3-azido-4-methylthio-2-azetidinone

2.42 ml (1.5 equivalents) of azidoacetyl chloride are added to 25 ml of dry methylene chloride under nitrogen, and the mixture is cooled to -78 ° C. After the addition of a solution of 3.74 ml (1.5 equivalents) of triethylamine in 25 ml of methylene chloride over the course of 15 minutes, the mixture is stirred at -78 ° C. for 1 hour.

A solution of 6.67 g of 2- (S-methylthioimidato) -3-trimethylsilyloxy-3- so methyl-4-butyric acid benzyl ester in 25 ml of methylene chloride is then added dropwise over the course of 15 minutes. The reaction mixture is stirred for a further 10 minutes at -78 ° C, whereupon it is allowed to assume room temperature in the course of 3 hours and then stirred for a further V2 hour. The reaction mixture is washed once with water and then with sodium chloride solution, dried and evaporated to the crude product. Chromatography on silica gel while eluting with a 5 percent ethyl acetate solution in benzene gives 2.81 g of l- (l-benzyloxycarbonyl-2-methyl-2-trimethylsilyloxy) propyl-3-azido-4-methylthio-2-azetidinone; Yield 60% 37%.

LR. (j. (film): 4.70 (N3); 5.61 (β-lactam); 5.70 (ester);

9.6 and 11.85 (Si-O);

NMR x (CCU); 2.68 (CôHs); 4.88 (C6H5CH2); 5.46 and 5.63

(β-lactam protons); 5.92 (N-C-CO); 7.96 (CH3-S); 65

I.

H

8.56 and 8.6 (CH3-C); 9.90 (CHa-Si).

Level G:

1 - (1-Benzyloxycarbonyl-2-methyl-trimethyIsilyloxy) propyl-3-azido-4-chloro-2-azetidinone

2 g of l- (l-benzyloxycarbonyl-2-methyl-2-trimethylsilyl-oxy) -propyI-3-azido-4-methyIthio-2-azetidinone are dissolved in 20 ml of carbon tetrachloride, and the solution is mixed with 4.69 g ( 1.3 equivalents) of a solution of 2 g of chlorine in 20 ml of carbon tetrachloride. The reaction mixture is left to stand at room temperature for 1 minute and then evaporated under reduced pressure. The residue is dissolved in 20 ml of benzene, evaporated again and the process repeated again. The residue consists of 1.9 g of 1- (1-benzyloxycarbonyl-2-methyl-2-trimethylsilyloxy) propyl-3-azido-4-chloro-2-azetidinone.

I.R. (A (film); 4.7 (Na); 5.59 (β-lactam-C = O); 5.70 (ester-carbonyl).

Cl

NMRx (CDCb): 2.6 (CôHs); 3.72 (ice H

(trans

-H); 4.33

Cl); 4.8 (C6H5CH2); 5.26 H

(trans and ice N3 -

5.75 (N-C-C); 8.53 and 8.6 (CH3-C); 9.85 (CHb-SÌ).

I I!

H O

Level H:

1 - (1-Benzyloxycarbonyl-2-methyl-2-hydroxy) propyl-3-azido-4-chloro-2-azetidinone

1.9 g of l- (l-benzyloxycarbonyl-2-methyl-2-trimethyl-silyloxy) propyl-3-azido-4-chloro-2-azetidinone are dissolved in 20 ml of dioxane and 10 ml of water. After adding 2.5 ml of 2.5N hydrochloric acid, the mixture is left to stand at room temperature for 15 minutes. The reaction mixture is neutralized with phosphate buffer solution (pH 7) and extracted with chloroform. The chloroform extract is washed once with brine, dried and evaporated. 1.57 g of 1- (1-benzyloxycarbonyl-2-methyl-2-hydroxy) propyl-3-azido-4-chloro-2-azetidinone are obtained.

LR. | A (film); 2.9 (OH); 4.7 (N3); 5.60 (β-lactam) 5.75 (Ester-C = O).

H

NMRx (CDCb); 2.58 (C6H5); 3.88 (cisr H

Cl);

4.48 (trans r

-Cl); 4.72 (C6H5CH2); H

5.25 (ice and trans N3 ■

8.6 and 8.66 (CHa-C).

j); 5.92 (N-C-C = 0); H O

Level I:

6a-azido-l-oxadethiapenicillanic acid benzyl ester

1.25 g of l- (l-benzyloxycarbonyl-2-methyl-2-hydroxy) propyl-3-azido-4-chloro-2-azetidinone are dissolved in 120 ml of tetrahydrofuran, and the solution is cooled to 5 ° C. Then

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If 0.900 g of silver trifluoromethyl sulfonate in 10 ml of tetrahydrofuran is added dropwise in the course of 1 minute, the reaction mixture is stirred for 5 minutes, diluted with benzene and washed once with saline-containing buffer solution (pH 7). The organic phase is separated off. The aqueous phase is extracted once with benzene and the combined organic phases are washed once with brine, then dried and evaporated to the crude product. Chromatography on silica gel while eluting with 5 percent ethyl acetate solution in benzene gives 0.115 g of 6cc-azido-l-oxadethiapenicillanic acid benzyl ester.

I.R. | x (film); 4.7 (N3); 5.6 (β-lactam); 5.71 (ester).

NMR t (CDCb); 2.64 (CôHs); 4.79 (CôHsCHi); 4.91 (C-5H) (J = 1 Hz); 5.5 (C-6H) (J = 1 Hz); 6.3 (C-3 H), 8.63 and 8.8 (preferably CH3).

Level J:

Benzyl 6a-amino-l-oxadethiapenicillanate

0.115 g of 6 a-azido-1-oxadethiapenicillanoic acid benzyl ester 20 are dissolved in 8 ml of benzene. After adding 0.050 g of platinum oxide, the mixture is reduced for 1 hour under a hydrogen pressure of 2.8 kg / cm 2. Then the catalyst is filtered off through a layer of silica gel G, which is washed with ethyl acetate. The filtrate gives 0.102 g of 6a-amino-l-oxadethiapenicillanic acid benzyl ester on evaporation.

stirred and then mixed with a solution of 0.015 g of methylsulfonyl chloride in 0.15 ml of tetrahydrofuran. The mixture is stirred at -78 ° C for 5 minutes, after which it is allowed to warm to -20 ° C. After adding 20 ml of benzene, the mixture is washed once with buffer solution (pH 7) and then four times with water, dried and evaporated. The residue is purified by preparative thin layer chromatography on silica gel G using 5% ethyl acetate in benzene for elution, and xo 0.017 g of 6-p-nitrobenzaldimino-6-methylthio-l-oxadethiapenicillic acid benzyl ester is obtained.

LR. (x (film); 5.59 (β-lactam-C = O); 5.72 (ester-C = O); 6.1 (C = N).

H H H

NMRx (CDCb); 0.16 (C = N); 1.86 (02N - <(C);

iHh

30th

I.R. (Movie); 3.0 (NH); 5.6 (β-lactam-C = O); 5.72 (Ester-C = O).

NMR t (CDCb); 2.6 (CeHs); 4.8 (CeHsCHz); 4.95 (C-5H, J = 1 Hz); 5.8 (C-6H, J = 1 Hz); 6.23 (C-3H); 7.3 (NH2); 8.61 and 8.75 (preferably CHa).

Level K: 35

6a-p-nitrobenzaldimino-1-oxydethiapenicillanic acid benzyl ester

0.102 g of 6a-amino-l-oxadethiapenicillanoic acid benzyl ester are dissolved in 10 ml of methylene chloride, 0.050 g of p-nitrobenzaldehyde and 2 g of magnesium fullfate 40 are added, and the mixture is stirred at room temperature for 2 hours and then filtered. The filtrate is evaporated and the residue is purified by preparative thin layer chromatography. 0.069 g of benzyl 6a-p-nitrobenzidimino-1-oxadethiapenicillanate is obtained. 45

I.R. (x (film); 5.59 (β-lactam-C = O); 5.72 (ester-C = O); 6.1 (C = N).

H H

NMRt (CDCb); 1.4 (-C = N-); 1.86 (NO *

2.6 (CeHs); 4.58 (C-6H, J = 1 Hz); 4.76 (C6H5-CH2); 5.1 (C-5H, J = 1 Hz); 6.2 (C-3H); 8.53 and 8.71 (preferably CH3).

Level L:

p-Nitrobenzaldimino-6-methylthio-l-oxadethia-penicillanic acid benzyl ester

0.080 g of 6a-p-nitrobenzaldimino-l-ocadethiapenicillanic acid rebenzyl ester is dissolved in 4 ml of tetrahydrofuran, and the solution is cooled to -78 ° C. under nitrogen. 0.082 ml of a 2.3 molar solution of phenyllithium in a mixture of benzene and ethyl ether is added dropwise and the mixture is stirred at -78 ° C. for 1 minute. After adding 4 ml of dimethylformamide, the mixture is kept at -78 ° C for 1 minute

2.65 (CoHs); 4.68 (C-5H); 4.8 (C6H5CH2);

6.1 (C-3H); 7.53 (S-CH3); 8.53 and 8.79 (preferably CHs).

Level M:

p-Toluenesulfonic acid salt of 6-amino-6-methylthio-l-oxadethiapenicillanoic acid benzyl ester

0.111 g of the crude, unpurified p-nitrobenzal-dimino-6-methylthio-l-oxadethiapenicilic acid benzyl ester are dissolved in 1 ml of tetrahydrofuran. 0.045 g of 2,4-dinitrophenylhydrazine and 0.0425 g of p-toluenesulfonic acid monohydrate are mixed in 2 ml of tetrahydrofuran for 1 hour at room temperature. The Schiff base solution is added to the mixture and stirred at room temperature for 15 to 20 minutes. The reaction mixture is filtered and the residue washed with 1 ml of tetrahydrofuran. The filtrate and the washing liquids are evaporated. The residue obtained is the p-toluenesulfonic acid salt of 6-amino-6-methylthio-1-oxadethiapenicillanoic acid benzyl ester.

Stages:

Benzyl 6-phenylacetamido-6-methylthio-1-oxadethiapenicil

The p-toluenesulfonic acid salt of 6-amino-6-methylthio-1-oxadethiapenicillanic acid benzyl ester obtained from benzene, which is obtained from 0.111 g of the crude 6-p-nitrobenzimino-6-methylthio-1-oxadethiapenicillanate, is dissolved in 4 ml of methylene chloride and the solution is cooled to 0 ° C. and cooled. After adding 0.068 ml of pyridine and 0.034 ml of phenylacetyl chloride, the mixture is stirred for 15 minutes, then diluted with methylene chloride, washed once with buffer solution (pH 7), then with buffer solution (pH 3) and again with buffer solution (pH 7). The methylene chloride solution is dried and evaporated. The residue is purified by thin layer chromatography on silica gel G using 25 percent ethyl acetate in benzene as the eluent, and 0.032 g of 6-phenylacetamido-6-methylthio-1-oxa-dethiapenicillanic acid benzyl ester is obtained.

LR. [x (film); 2.95 (NH; 5.59 (β-lactam-C = O); 5.75

(Ester-C = 0); 5.95 (amide C = 0); 6.72 (amide II). NMRx (CDCb); 2.6 and 2.7 (CeHs); 3.63 (NH); 4.7 (C-5H); 4.81 (C6H5-CH2O); 6.19 (C-3H); 6.45 (C6HsCH2C = 0); 3.75 (S-CHa; 8.6 and 8.86 (preferably CH3).

Level O:

6β-phenylacetamido-l-oxadethiapenicillanoic acid benzyl ester 0.080 g 6-phenylacetamido-6-methylthio-l-oxadethiapeni-

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Benzyl cillanate is dissolved in 2 ml of tetrahydrofuran and the solution is cooled to -78 ° C under nitrogen. A solution of 1.3 equivalents of chlorine in 0.162 ml of carbon tetrachloride is then added and the mixture is stirred for 3 minutes. After adding 0.151 g (3.0 equivalents) of lithium tributoxyaluminium hydride in 1 ml of tetrahydrofuran, the mixture is stirred for a further 5 minutes, whereupon the temperature is allowed to reach 0 ° C. You add chloroform

washes the mixture with buffer solution (pH 3) and then with buffer solution (pH 7) and evaporates to 0.076 g of crude product. Purification by means of preparative thin layer chromatography on silica gel G using 25 percent ethyl acetate in benzene for elution gives 0.017 g of 6β-phenylacetamido-1-oxadethiapenicillanic acid benzyl ester.

LR. | A (film); 2.95 (NH); 5.57 (β-lactam-C = O); 5.73 (ester-C = O); 5.97 (amide-C = O); 6.59 (amide II). NMR t (CDCb); 2.63 and 2.73 (CôHs); 3.84 (NH, J = 9 Hz); 4.63 (C-6H, J = 9 and J = 3 Hz); 4.79 (C-5H, J = 3 Hz); 4.86 (CôHsCHz); 6.19 (C-3H); 6.42 (CôHsCH2-C = O); 8.62 and 8.87 (preferably CHs).

Level P:

Sodium 6β-phenylacetamido-l-oxadethiapenicillanate

0.007 g of benzyl 6β-phenylacetamido-1-oxadethiapenicillanate are dissolved in 1 ml of dioxane and 0.5 ml of water. 0.0015 g of sodium bicarbonate and 0.003 g of 10 percent palladium on carbon (Bolhofer's catalyst) are added and the mixture is reduced for 0.5 hours under a hydrogen pressure of 2.8 kg / cm 2. The catalyst is filtered off and the filtrate is extracted with chloroform. The product is biologically active in vitro against both Bacterium subtilis and Proteus vulgaris. The aqueous layer is freeze-dried and sodium 6β-phenylacetamido-l-oxadethiapenicillanate is obtained.

Example 4

Sodium 6ß-phenoxyacetamido-l-oxadethiapenicillanate stage A:

Sodium 2-formamido-3-hydroxy-3-methylbutyrate

2-Oxazoline-5,5-dimethyl-4-carboxylic acid ethyl ester is mixed with 0.9 ml of triethylamine and 3 ml of water and heated to 100 ° C. for 3 hours. The reaction mixture is then cooled to room temperature and diluted with 100 ml of water, whereupon 56 ml of 2.5N sodium hydroxide solution are added dropwise over the course of 15 minutes. The reaction mixture is stirred overnight at room temperature and then evaporated under reduced pressure. By recrystallizing the residue from a mixture of ethanol and isopropanol, 20.5 g of sodium 2-formamido-3-hydroxy-3-methylbutyrate are obtained.

O H

II I

NMR (D2O) 1.70 (H-C-N); 5.59 (N-C-COO);

8.6 (preferably dimethyl).

Level B:

2-Formamido-3-hydroxy-3-methylbutyric acid-o-nitro-benzyl ester

18.3 g of sodium 2-formamido-3-hydroxy-3-methylbutyrate are dissolved in 100 ml of dimethylformamide, and the solution is mixed with 19 g of o-nitrobenzyl chloride. The reaction mixture is stirred under nitrogen at 50 ° C. overnight, then poured into 200 ml of water and extracted three times with 150 ml of chloroform. The combined chloroform extracts are washed twice with water, then with brine, dried, first concentrated in a rotating evaporator.

to drive off the benzene, and then further evaporated on the high vacuum pump to drive off the dimethylformamide. 2-Formamido-3-hydroxy-3-methylbutyric acid-o-nitrolbenzyl ester is obtained.

I.R. | x (film); 2.96 (NH and OH); 5.75 (Ester-C = O);

5.95 (amide-C = O); 6.51 (NO2).

NMRx (CDCb): 1.70 (HC-NH); 1.8-2.8 (ArH); 3.0 (NH);

II

O

4.39 (Ar-CH2O); 5.30, d (NH-CH-COO); 6.93 (OH); 8.66 and 8.72 (preferably dimethyl).

Level C:

2-Amino-3-hydroxy-3-methylbutyric acid o-nitro-benzyl ester

26 g of 2-formamido-3-hydroxy-3-methylbutyric acid o-nitrobenzyl ester are dissolved in 60 ml of 5N hydrochloric acid, and the solution is heated to 90-100 ° C. for 45 minutes. The reaction mixture is cooled, diluted with 60 ml of water and extracted twice with methylene chloride. The aqueous layer is adjusted to a pH of 10 with sodium hydroxide solution and then extracted with methylene chloride. The methylene chloride extract is dried and evaporated to 18 g of 2-amino-3-hydroxy-3-methylbutyric acid o-nitrobenzyl ester.

I.R. n (film); 2.97 (NH and OH); 5.75 (Ester-C = O); 6.52 (NO2).

NMR (CDCb): 1.80-2.8 (ArH): 4.41, s (Ar-CH2-0); 6.46 (N-CH-COO); 7.60 (NH and OH); 8.7 and 8.82 (preferably dimethyl).

Level D:

2-Thioformamido-3-hydroxy-3-methylbutyric acid o-nitrobenzyl ester

18.0 g of 2-amino-3-hydroxy-3-methylbutyric acid-o-nitro-benzyl ester are mixed in a thick-walled tube with 5 ml of ethyl thionoformate. The tube is cooled to -78 ° C, after which 5 ml of hydrogen sulfide are condensed. Then the tube is melted, the contents are allowed to reach room temperature, mixed thoroughly and the tube is left to stand at room temperature overnight. The tube is then cooled to -78 ° C and the closure broken. The hydrogen sulfide is allowed to evaporate, the residue is taken up in methylene chloride and filtered. The filtrate gives 18.5 g of 2-thioformamido-3-hydroxy-

3-methylbutyric acid o-nitrobenzyl ester.

LR. n (film): 3.0 (NH and OH); 5.75 (Ester-C = O); 6.51 (NO2) 6.6 and 6.92 (H-C = S).

S

II

NMR (CDC1); 0.4, d (H-C); 1.4 (NH); 1.7-2.75 (ArH); 4,4, s (Ar-CHz-O); 4.73, d (N-C-COO); 7.35, s (OH) 8.6

H

and 8.66 (like dimethyl).

Level E:

2-Thioformamido-3-trimethyIsilyloxy-3-methylbutyric acid o-nitrobenzyl ester

18.5 g of 2-thioformamido-3-hydroxy-3-methylbutyric acid o-nitrobenzyl ester are dissolved in 100 ml of methylene chloride and the solution is mixed with 12 ml of trimethylsilyl chloride and 16 ml of 1,1,1,3,3,3-hexamethyldisilazane added and stirred overnight at room temperature. The solution is then filtered and the filtrate is reduced to a residue under reduced pressure

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evaporated, which by chromatography on silica gel using 25% ethyl acetate in benzene to elute 16.5 g of 2-thioformamido-3-trimethyIsilyloxy-3-methylbutyric acid o-nitrobenzyl ester.

I.R. (Film): 3.0 (NH); 5.72 (Ester-C = O); 6.51 (NO2); 6.65 and 6.95 (HC = S); 9.6 and 11.75 (SiO).

S

II

NMR (CDCb): 0.39, d (HC); 1.7-2.75 (ArH); 4.36;

(ArCH2Ü); 4.8, d (N-C-COO); 8.53 and 8.63

H

(likes dimethyl); 9.90 (CHs-Si).

Level F:

2- (S-methylthioimidato) -3-trimethylsilyloxy-3-methyl-butyric acid o-nitrobenzyl ester

16.0 g of 2-thioformamido-3-trimethylsilyloxy-3-methylbutyric acid o-nitrobenzyl ester are dissolved in 200 ml of anhydrous acetone, and the solution is mixed with 9 g of powdery anhydrous potassium carbonate and 4.6 ml of methyl iodide. The reaction mixture is stirred under nitrogen for 24 hours and then evaporated under reduced pressure. The residue is taken up in 100 ml of carbon tetrachloride, the solution is filtered and the residue is washed with 50 ml of carbon tetrachloride. The combined filtrates and washing liquids provide 16.1 g of 2- (S-methyl-thioimidato) -3-trimethylsilyloxy-3-methylbutyric acid-o-nitro-benzyl ester on evaporation.

LR. (x (film): 5.75 (ester-C = O); 6.25 (C = N); 6.51 (NO2). NMRx (CDCb); 1.70, s (C = N); 1 , 8-2.7 (ArH); 4.4, s

H

(ArCH2-0); 6.01, s (N-CH-COO); 7.55, s (CH3-S-); 8.60 and 8.67 (preferably dimethyl).

Level G: 40

1 - (1-o-Nitrobenzyloxycarbonyl-2-methyl-2-trimethylsilyloxy) propyl-3-azido-4-methylthio-2-azetidinone

2.42 ml (1.5 equivalents) of azidoacetyl chloride are added to 25 ml of dry methylene chloride under nitrogen, and the mixture is cooled to -78 ° C. A solution of 3.74 ml (1.5 equivalents) of triethylamine in 25 ml of methylene chloride is added over the course of 15 minutes and the mixture is stirred at -78 ° C. for 1 hour.

A solution of 16.0 g of 2- (S-methylthioimidato) -3-trimethylsilyl-so-oxy-3-methylbutyric acid-o-nitrobenzyl ester in 25 ml of methylene chloride is then added dropwise over the course of 15 minutes. The reaction mixture is stirred for a further 10 minutes at -78 ° C., whereupon it is allowed to assume room temperature within 3 hours and the mixture is stirred for a further V2 hour. The reaction mixture is washed once with water and then with brine, dried and evaporated to the crude product. Chromatography on silica gel using 5% ethyl acetate in benzene as the eluent gives 8.2 g of l- (lo-nitrobenzyloxycarbonyl-2-methyl-2-trimethylsilyloxy) -propyl-3-azido-4-methyl-60 thio-2-azetidinone.

I.R. | x (film); 4.72 (Ns); 5.60 (β-lactam-C = O); 5.71

(Ester-C = O); 6.51 (NO2).

NMRx (CDCb); 1.8-2.8 (ArH); 4.40, d (ArCH2-0); 5.27, d

H H 65

H.

5.70, s (N-C-COO) 7.86, s (CH3-S); 8.5 and 8.54 (preferably dimethyl).

Level H:

1- (lo-nitrobenzyloxycarbonyl-2-methyl-2-trimethylsilyloxy) propyl-3-azido-4-chloro-2-azetidinone 8.0 g of 1- (lo-nitrobenzyloxycarbonyl-2-methyl-2-tri -methylsilyloxy) -propyl-3-azido-4-methylthio-2-azetidinone are dissolved in 20 ml of carbon tetrachloride and treated with 4.69 ml (1.3 equivalents) of a solution of 2 g of chlorine in 20 ml of carbon tetrachloride. The reaction mixture is left to stand at room temperature for 1 minute and then evaporated under reduced pressure. The residue is dissolved in 20 ml of benzene and evaporated again, whereupon the process is repeated once more. 7.85 g of l- (l-o-nitrobenzyloxycarbonyl-2-methyl-2-trimethyl-20 silyloxy) -propyl-3-azido-4-chloro-2-azetidinone are obtained as the residue.

I.R. [x (film); 4.71 (N3); 5.58 (β-lactam-C = O); 5.71 (ester C = 0); 6.51 (NO2).

Cl

NMR x (CDCb); 1.8-2.8 (ArH); 4.36, d (J = 1) (r

N3

"H); 4.40,

s (ArŒteO); 5.25, d (J = 1) (H-U); 5.73.

H

s (N-C COO); 8.53 and 8.60 (preferably dimethyl).

Level I:

1- (l-o-nitrobenzyloxycarbonyl-2-methyl-2-hydroxy) propyl-3-azido-4-chloro-2-azetidinone

7.85 g of l- (l-o-nitrobenzyloxycarbonyl-2-methyl-2-tri-methylsilyloxy) propyl-3-azido-4-chloro-2-azetidinone are dissolved in 20 ml of dioxane and 10 ml of water. After adding 2.5 ml of 2.5N hydrochloric acid, the mixture is left to stand at room temperature for 15 minutes. The reaction mixture is neutralized with phosphate buffer solution (pH 7) and extracted with chloroform. The chloroform extract is washed once with brine, then dried and evaporated. 6.26 g of l- (l-o-nitrobenzyloxycarbonyl-2-methyl-

2-hydroxy) propyl-3-azido-4-chloro-2-azetidinone.

I.R. fx (film); 2.91 (OH); 4.70 (Ns); 5.60 (β-lactam-C = O)

5.71 (ester C = 0); 6.52 (NO2).

NMR 1.8-2.8 (ArH); 4.37, s (ArCHaO); 4.50, d (J = 1)

H H

JC1.

(r

); 5.23, d (J = 1) (N3-

); 5.9, s (N-C-COO)

I.

H

(J = 2Hz) N3-

; 5.46 (J = 2 Hz) (-

-S — CH2);

8.4 (OH); 8.56 and 8.66 (preferably dimethyl).

Level J:

6cc-azido-l-oxadethiapenicillanoic acid o-nitrobenzyl ester

6.25 g of l- (l-o-nitrobenzyloxycarbonyl-2-methyl-2-hydroxy) propyl-3-azido-4-chloro-2-azetidinone are dissolved in 120 ml of tetrahydrofuran and the solution is cooled to 5 ° C. 0.900 g of silver trifluoromethylsulfonate in 10 ml of tetrahydrofuran are added dropwise in the course of one minute, and the reaction mixture is then stirred for a further 5 minutes, diluted with benzene and washed once with saline-containing buffer solution (pH 7). The organic phase is with once

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Extracted benzene and washed the combined organic phase once with brine, then dried and evaporated to the crude product. Chromatography on silica gel using 5% ethyl acetate in benzene for elution gives 1.01 g of 6a-azido-l-oxadethiape-nicillanic acid-o-nitrobenzyl ester.

LR. \ i (film); 4.71 (Na); 5.58 (β-lactam-C = O); 6.52 (NO2).

NMR t (CDCb); 1.8-2.7 (ArH); 4.39, s (ArCmO); 6.83, d (J = 1 Hz) (C-5-H); 5.8, d (J = 1 Hz) (C-6 H); 6.12, s (C -3 H); 8.53 and 8.65 (preferably dimethyl).

Level K:

6'-Amino-1-oxadethiapenicillanoic acid o-nitrobenzyl ester

0.200 g of 6a-azido-l-oxadethiapenicillanoic acid-o-nitrobenzyl ester are dissolved in 4 ml of methylene chloride, and the solution is mixed with 0.152 ml of triethylamine and cooled to 0 ° C. Hydrogen sulfide is introduced into the solution for 10 minutes and the reaction mixture is stirred for a further 10 minutes until the infrared spectrum of a sample no longer shows any azide. The solvent is stripped off under reduced pressure and the residue is taken up in methylene chloride, washed once with monopotassium phosphate solution, then dried and evaporated. This gives 0.201 g of 6a-amino-1-oxad-thiapenicillanoic acid-o-nitrobenzyl ester.

LR. n (film); 3.0 (NH); 5.59 (β-lactam-C = O); 5.71

(Ester-C = 0); 6.51 (NO2).

NMR x (CDCb); 1.8-2.7 (ArH); 4.40, s (Ar-CHz-O); 4.92 d (J = 1.5) (C-5H); 5.80, d (J = 1.5) (C-6H); 6.15, s (C -3 H); 7.74 (NH2); 8.56 and 8.66 (preferably dimethyl).

Level L:

6a- (p-nitrobenzaldimino) -l-oxadethiapenicillanoic acid-o-nitrobenzyl ester

0.201 g of 6a-amino-l-oxadethiapenicillanoic acid-o-nitro-benzyl ester are dissolved in 4 ml of ethyl acetate, whereupon 0.060 g of p-nitrobenzaldehyde is added and the mixture is left to stand at room temperature for 10 minutes. The solvent is stripped off under reduced pressure and the residue is taken up in ethyl acetate. The solution is filtered through a small column of silica gel G, which is eluted with ethyl acetate. The solvent is stripped off under prevented pressure, and 0.155 g of 6a- (p-nitrobenzalimino) -l-oxadethiapenicillanoic acid-o-nitrobenzyl ester is obtained.

LR. left (film): 5.58 (β-lactam-C = O); 5.71 (Ester-C = O);

6.1 (C = N); 6.52 (NO2).

NMRx (CDCb); 1.43 (C = N); 1.53-2.7 (ArH); 4.40.

I.

H

s (ArCHzO); 4.50 (C-6H); 5.05 (C-5H); 6.07, s (C-3H); 8.52 and 8.63 (preferably dimethyl).

Level M:

6-p-NitrobenzaIdimino-6-methylthio-l-oxadethia-penicillanic acid o-nitrobenzyl ester

0.155 g of 6a- (p-nitrobenzaldimino) -l-oxadethiapenicil-lanoic acid-o-nitrobenzyl ester, as described for the corresponding benzyl ester, with phenyllithium and methylsulfenyl chloride to 0.176 g of crude 6-p-nitrobenzal-dimino-6-methylthio- 1-oxadethiapenicillanoic acid o-nitro-benzyl ester implemented.

I.R. n (film); 5.58 (β-lactam-C = O); 5.71 (Ester-C = O); 6.09 (C = N); 6.56 (NO2).

H

I.

NMRx (CDCb); 1.2, s (C = N); 4.4, s (ArCmO); 4.64, s (C-5H); 6.03, s (C-3H); 7.73 (CHaS).

Stages:

p-Toluenesulfonic acid salt of 6-amino-6-methylthio-1-oxadethiapenicillanoic acid o-nitrobenzyl ester

0.176 g of 6-p-nitrobenzaldimino-6-methylthio-l-oxade-thiapenicillanoic acid-o-nitrobenzyl ester are dissolved in 2 ml of methyl chloride and the solution is diluted with ether until a slight turbidity remains. 0.060 g of p-toluenesulfonic acid monohydrate are dissolved in 3 ml of ethyl ether, and the solution is added dropwise to the solution of the Schiff base. The salt which precipitates out is centrifuged off, and the p-toluenesulfonic acid salt of 6-amino-6-methylthio-1-oxadethiapenicillanoic acid o-nitribenzyl ester is obtained, which is converted directly into the amide.

Level O:

6-Phenoxyacetamido-6-methylthio-l-oxadethiapenicillanic acid o-nitrobenzyl ester

The p-toluenesulfonic acid salt of 6-amino-6-methyl-thio-l-oxadethiapenicillanoic acid-o-nitrobenzyl ester obtained from 0.176 g of the crude 6-p-nitrobenzidimino-6-methylthio-l-oxadethiapenicillanoic acid o-nitrobenzyl ester is converted into 4 ml dissolved and the solution cooled to 0 ° C. First, 0.130 ml of pyridine and then 0.056 ml of phenoxyacetyl chloride are added. The reaction mixture is stirred for 15 minutes at 0 ° C., then diluted with methylene chloride, washed once with buffer solution (pH 7), then with buffer solution (pH 3) and then again with buffer solution (pH 7). The organic phase is dried and evaporated. Purification of the residue by preparative thin layer chromatography on silica gel while eluting with 25% ethyl acetate in benzene gives 0.038 g of 6-phenoxyacetamido-6-methylthio-l-oxadethiapenicillanoic acid-o-nitrobenzyl ester.

LR. (x (film): 3.0 (NH); 5.58 (β-lactam-C = O); 5.72

(Ester-C = 0); 5.95 (amide C = 0); 6.52 (NO2).

NMRx (CDCb): 1.8-3.2 (ArH); 4.42, s (ArCmO); 4.67, s (C-5H); 5.43, s (CeHsO-CTfc-); 6.1, s (C-3H); 7.7 (CH3-S); 8.53 and 8.73 (preferably dimethyl).

Level P:

6 ß-phenoxyacetamido-1-oxadethiapenicillanoic acid o-nitrobenzyl ester.

0.073 g of 6-phenoxyacetamido-6-methylthio-1-oxadethia-penicillanic acid-o-nitrobenzyl ester are dissolved in 5 ml of tetrahydrofuran, and the solution is cooled to -78 ° C. and with a solution of 13 mg of chlorine in 0.26 ml of carbon tetrachloride transferred. After 5 minutes, 0.140 g of lithium tri-butoxyaluminium hydride in 2 ml of tetrahydrofuran is added, the mixture is stirred for 5 minutes at -78 ° C. and then allowed to reach a temperature of 0 ° C. The mixture of Rekatìons is poured into pH 3 buffer solution and extracted with choroform. The chloroform extract is dried and evaporated to 0.072 g of crude product. Purification by preparative thin layer chromatography on silica gel while eluting with 25% ethyl acetate solution in benzene gives 0.019 g of 6-phenoxy-acetamido-1-oxadethiapenicillanoic acid-o-nitro-benzyl ester.

LR. M. (film): 3.0 (NH); 5.55 (β-lactam-C = 0); 5.72 (ester C = 0); 5.91 (amide C = 0); 6.51 (NO2).

NMR x (CDCb): 1.8-3.2 (ArH); 4.42 (ArCmO); 4.52 (J = 10, J = 3) 2 (C-6 H); 4.69, d (J = 3) (C-5H); 5.48, s (C6H5O-CH2); 6.08, s (C-3H); 8.52 and 8.66 (preferably dimethyl).

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Level Q:

Sodium 6β-phenoxyacetamido-1-oxadethiapenicillanate

0.010 g of 6β-phenoxyacetamido-1-oxadethiapenicillanoic acid o-nitrobenzyl ester are dissolved in 4 ml of dioxane and 2 ml of water containing 0.018 g of sodium bicarbonate. The mixture is photolysed for 1/2 hour in a Pyrex glass vessel with cooling in a cooling batch using a Hanovia lamp as an ultraviolet radiation source. The solvent is removed under reduced pressure, and sodium 6β-phenoxyacetamido-l-oxadethiapenicillanate is obtained.

Example 5

6ß- (2,6-Dimethoxy) -benzamido-l-oxadethiapenicillanic acid stage A:

6-Benzyloxycarbonylamino-6-methylthio-oxadethia-penicillanic acid benzyl ester

0.508 g of p-toluenesulfonic acid salt of 6-amino-6-methyl-thio-l-oxadethiapenicillanoic acid benzyl ester are dissolved in 10 ml of methylene chloride, and the solution is cooled to 0 ° C., firstly with 0.300 ml of pyridine and then with 0.200 g of benzyl-oxycarbonyl chloride . The reaction mixture is stirred for 15 minutes at 0 ° C. and then for 1 hour at room temperature, then washed with buffer solution (pH 7), then with buffer solution (pH 3) and again with buffer solution (pH 7). The organic phase is dried and evaporated. Chromatography on silica gel while eluting with 25% ethyl acetate solution in benzene gives benzyl 6-benzyloxy-carbonylamido-6-methylthio-1-oxadethiapenicillanate.

Level B:

Benzyl 6β-benzyloxycarbonylamino-l-oxadethiapenicillan

0.321 g of benzyl 6-benzyloxycarbonylamino-6-methylthio-l-oxade-thiapenicillanate are dissolved in 15 ml of tetrahydrofuran, and the solution is cooled to - 780 ° C. under nitrogen and a solution of 0.047 g of chlorine in 0.47 ml of carbon tetrachloride is added. After 5 minutes, a solution of 0.420 g of lithium tri-tert-butoxyaluminium hydride in 4 ml of tetrahydrofuran is added, the mixture is stirred at -78 ° C. for 5 minutes and then allowed to reach room temperature. The reaction mixture is diluted with chloroform, washed once with buffer solution (pH 3), then with buffer solution (pH 7) and then dried and evaporated. The residue is obtained by chromatography on silica gel using 25% ethyl acetate solution in benzene to elute benzyl 6β-benzyloxycarbonylamino-l-oxadethiapenicillanate.

Level C:

6β-amino-1-oxadethiapenicillanic acid

0.100 g of benzyl 6β-benzyloxycarbonylamino-1-oxadethiapenicillanate are dissolved in 5 ml of dioxane and 5 ml of water. After adding 0.020 g of 10% palladium on carbon, the mixture is reduced for V2 hours under a hydrogen pressure of 2.8 kg / cm 2. The catalyst is filtered off and the filtrate is freeze-dried. 6β-Amino-l-oxadethiapenicillanic acid is obtained.

Level D:

6ß- (2,6-dimethoxy) benzamido-l-oxadethiapenicillanic acid

An ice-cooled suspension of 200 mg of 6β-amino-l-oxadethiapenicillanic acid in 25 ml of 67% aqueous acetone is first mixed with 168 mg of sodium bicarbonate and then with 200.5 mg of 2,6-dimethoxybenzoyl chloride. After stirring for 1 hour at 0 ° C, the solution is freeze-dried. 6 ß- (2,6-Dimethoxy) -benzamido-l -oxadethiapenicillanic acid is obtained in the form of its sodium salt.

In a similar manner, the sodium salt of 6β- (3-phenyl-5-methyl-4-isoxazoloylamido) -l-oxadethiapenicillanic acid is obtained from 6ß-amino-l-oxadethiapenicillanic acid and 3-phenyl-5-methyl-4-isoxazololyl chloride in the presence of sodium bicarbonate.

In an analogous manner, 6 ß-amino-1-oxadethiapenicillanoic acid and 3- (2,6-dichlorophenyl) -5-methyl-4-isoxazoloyl chloride in equimolecular amounts with sodium bicarbonate give the sodium salt of 6β [3- (2,6-dichlorophenyl I ) -5-methyl-4-isoxazoloylamido] -1-oxadethiapenicillanoic acid.

The sodium salt of 6ß- [3- (2-chloro-6-fluorophenyl) -5-methy] -4-isoxazoloylamido] -1-oxadethiapenicillanic acid is obtained from 6ß-amino-l-oxadethiapenicillanic acid and 3- (2-chloro -6-fluorophenyl) -5-methyl-4-isoxazole-oyl chloride.

Example 6

Disodium 6β- (D-a-sulfophenylacetamido) -1-oxadethiapenicillanate

A solution of 0.6 g of D-a-sulfophenylacetyl chloride in 5 ml of dry ether is added dropwise with stirring to an ice-cooled suspension of 0.5 g of 6β-amino-1-oxadethiapenicillanic acid and 0.8 g of sodium bicarbonate in 4 ml of water. The mixture is allowed to react at 0 to 5 ° C. for 30 minutes, the organic layer is separated off, the aqueous solution is adjusted to a pH of 6.5 and it is chromatographed in a column (2.0 × 70 cm) is charged with neutral polystyrene resin («Amberlite XAO-2»), eluting with water. The eluate is monitored for ultraviolet absorption at 253.7 mu. After an initial fraction containing inorganic salt and unreacted α-sulfophenylacetic acid, the product fraction corresponding to the absorption maximum is collected and freeze-dried. Disodium 6ß- (D-a-sulfophenylacetamido) -l-oxadethiapenicillanate is obtained.

Example 7

Disodium 6β- (a-carboxyphenylacetamido) -l-oxadethiapenicillanate 0.3 ml of triethylamine is added to a suspension of 210 mg of 6ß-amino-l-oxadethiapenicil-lanoic acid in 5 ml of methylene chloride. The mixture is stirred at room temperature for 15 minutes and then cooled to 0 ° C. A solution of 170 mg of phenylchlorocarbonyl ketene in 1 ml of methylene chloride is then added and the mixture is allowed to react at 0 to 5 ° C. for 15 minutes. The methylene chloride is stripped off under reduced pressure and the residue is taken up in a mixture of ethyl acetate and phosphate buffer solution (pH 2). The ethyl acetate solution is stirred at 5 ° C. with water and the pH is adjusted to 7 with sodium bicarbonate solution. The aqueous layer is separated off and converted into the disodium salt of 6ß- (a-carboxyphenylacet-amido) -l-oxadethiapenicillanic acid by freeze-drying.

If the above procedure is carried out using 3-thienylchlorocarbonyl ketene, the disodium salt of 6β - («- carboxy-3-thienylacetamido) -l-oxadethia-penicillanic acid is obtained.

Example 8

6ß- (2-phenyl-2-aminoacetamido) - 1-oxa-1-dethiapenicillanic acid

Level A:

Sodium 6ß- (2-phenyl-2-azidoacetamido) -l-oxa-l-dethiapenicillanate

17.0 g of 6β-amino-l-oxa-l-dethiapenicilicanoic acid are dissolved in 300 ml of 30% acetone by adding an equivalent amount of sodium bicarbonate with stirring at 00.degree. A solution of 16.6 g of phenylazidoacetyl chloride is dropped in

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1 tì ml of acetone, keeping the mixture neutral by adding a total of 21 g of sodium bicarbonate. The reaction mixture is stirred for a further 2 hours at 0 ° C., washed twice with ether, acidified to pH 2 with hydrochloric acid and extracted twice with ether. The ether solution is washed twice with water and then extracted with 85 ml in sodium bicarbonate solution. The aqueous solution is washed with ether and freeze-dried. This gives sodium 6β- (2-phenyl-2-azidoacetamido) -l-oxa-l-dethiapenicillanate.

Level B:

6β- (2-phenyl-2-aminoacetamido) -l-oxa-l-dethia-penicillanic acid

A solution of 4 g of sodium 6β- (2-phenyl-2-azidoacet-amido) -l-oxa-l-dethiapenicillanate in 30 ml of water becomes 30. Minutes hydrogenated using 1 g of Raney nickel under a pressure of 3.5 at. The catalyst is filtered off and washed. The filtrate is adjusted to a pH of 2, washed with ether, then adjusted to a pH of 5 and concentrated in vacuo. The precipitate of 6ß- (2-phenyl-2-aminoacetamido) -l-oxa-l-dethiapenicillanic acid is filtered off and dried.

Example 9

6ß- (a-Amino-p-hydroxyphenylacetamido) -l-oxa-1 -dethiapenicillanic acid

Level A:

Sodium 6ß- (a-BenzylIoxycarbonyIamino-p-hydroxy-phenyI-acetamido) -l-oxa-l-dethiapenicillanic acid

A solution of 20 g of a-benzyloxycarbonylamino-p-hydroxy-phenylacetic acid and 8.3 ml of 2,6-luthidine in 140 ml of acetone is mixed with 6.3 ml of ethyl chloroformate at 0 ° C. After 30 minutes at 0 ° C., a solution of 13.2 g of 6β-amino-l-oxa-dethia-penicillanic acid and 10.5 ml of 2,6-lutidine in 140 ml of water, precooled to 0 ° C., is quickly added. The mixture is stirred at 0 ° C. for 30 minutes and at 25 ° C. for 1 hour, concentrated in vacuo, acidified to a pH of 2 and extracted three times with 50 ml each of methyl isobutyl ketone. The organic layers are combined, washed with water and extracted with 50 ml of water containing 1 equivalent of sodium bicarbonate. Freeze-drying of the aqueous solution gives sodium 6β- (a-benzyl-oxycarbonylamino-p-hydroxyphenylacetamido) -1-oxa-dethia-penicillanate.

Level B:

6 ß- («- Amino-p-hydroxyphenylacetamido) -1-oxa-1 -dethiapenicillanic acid

A solution of 15 g sodium 6ß - (<x-benzyloxycarbonyl-amino-p-hydroxyphenylacetamido) -l-oxa-dethiapenicillanat in

250 ml of water is hydrogenated for 1 hour at 1 atm with 40 g of 5% palladium on calcium carbonate, then filtered and adjusted to a pH of 1.9. The solution is washed with methyl isobutyl ketone, adjusted to a pH of 5.1 and concentrated in vacuo to 50 ml. The 6ß- (a-amino-p-hydroxyphenylacetamido) -l-oxa-l-dethiapenicillanic acid crystallizes out and is filtered off.

Example 10

6ß- (a-Amino- [3-thienyl] acetamido) -1-oxa-1 -dethiapenicillanoic acid

A solution of 3.8 g of 6β-amino-l-oxa-dethiapenicillanic acid in 400 ml of a mixture of 80% acetone and 20% water is at -5 ° C while maintaining a pH of 2.5 in the course of 20 minutes with 5.9 g of a- (3-thienyl) glycyl chloride hydrochloride. The solution is adjusted to a pH of 4.8, concentrated in vacuo, filtered, adjusted to a pH of 2 and washed twice with methyl isobutyl ketone. Then it is extracted at 0 ° C with a 10% solution of 5.3 g of sodium dioctyl sulfosuccinate in methyl isobutyl ketone. The methyl isobutyl ketone solution is dried with sodium sulfate and neutralized to a pH of 5.3 with triethylamine. The crystallizing 6ß- (a-amino- [3-thienyl] -acetamido) -l-oxa-dethiapenicillanic acid is filtered off.

The products obtained according to the invention can be used alone or together with other active ingredients in a wide variety of pharmaceutical preparations. These antibiotics and their corresponding salts can be used in the form of capsules, tablets, powders, liquid solutions, suspensions or elixirs. They can be administered orally, intravenously or intramuscularly. Suitable carriers are e.g. B. mannitol, sucrose, glucose or sterile liquids such as water, saline, glycols, animal, vegetable, synthetic or petroleum-derived oils, e.g. Peanut oil, mineral oil or sesame oil. In addition to the carrier, the agents can contain other constituents, such as stabilizers, binders, antioxidants, preservatives, lubricants, suspending agents, viscosity regulators or flavoring agents. Furthermore, the pharmaceutical preparations can contain other active ingredients in order to give them a further spectrum of antibiotic activity.

The dose to be administered depends largely on the condition and weight of the patient or animal to be treated; parenteral administration is preferred for general infections, oral administration for intestinal infections. In general, the daily dose consists of approximately 15 to 600 mg of active ingredient per kg of body weight and is administered in one application or in two applications per day.

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Claims (8)

616 938 1-oxadethiapenicillanat or the disodium 6ß- (a-carb-oxyphenylacetamido) -l-oxadethiapenicillanat produces. 17. The method according to claim 10, characterized in that 6ß- (D-a-sulfophenylacetamido) -l-oxade- 55 produces thiapenicillanic acid. R2R3CHCX implemented in which R2 and R3 have the above meanings and X is halogen. 2-thienylglycyl, 3-thienylglycyl, phenylmalonyl, 20 3-chlorophenylmalonyl, 2-thionylimonyl, 3-thenylmalonyl, a-phosphonophenylacetyl, a-sulfaminoacetyl, a-hydroxyphenylacetyl, a-tetrazolylphenylacetyl, a-sulfophenylacetyl, 2-thienyoxetylyl, phenoxyacylyl, phenoxyacylyl, phenoxyacetyl, phenoxyacylyl -SuIfamino-25 phenylacetyl, 2,6-dimethoxybenzoyl, 2,6-dichlorobenzoyl, 2 3 "r r chcnh- a h 0. he -N • co2h in which A is hydrogen or methoxy, R2 is hydrogen, hydroxy, amino or carboxy and R3 is phenyl or a 5- or 6-membered heterocyclic ring having 1 to 4 sulfur, oxygen or nitrogen heteroatoms, characterized in that a compound of the formula r- r \ 2 3 "r r chcnh 60 in which A is hydrogen or methoxy, R2 is hydrogen, Ci-Cio alkyl, phenyl, halogen, amino, guanidino, phosphono, hydroxy, tetrazolyl, carboxy, sulfo or sulfamino and R3 is phenyl, substituted phenyl, a 5- to 6-membered monocyclic Heterocyclic ring with 1 to 4 oxygen, sulfur or nitrogen heteroatoms, a substituted heterocyclic thio radical, cyano or 2,5-cyclohexadien-l-yl, characterized in that a compound of the formula 616 938 in which the two radicals R5 together form a benzylidene radical or a substituted benzylidene radical, treated with a metal catalyst of the general formula MLn, in which M is palladium, platinum, nickel, ruthenium, rhodium, cobalt or iron, L halogen, carbonyl, cyclopentadienyl or phenylcyan and n is an integer corresponding to the valency requirements, whereupon the mixture with an acylating agent of the general formula O R2R3CHCX implemented, in which X means halogen. 2. A process for the preparation of ester derivatives of compounds of the formula wherein A is hydrogen or methoxy and R is an aliphatic, aromatic, heterocyclic, araliphatic or heterocyclic-aliphatic carboxylic acid radical or the 1-aminocyclo-hexylcarbonyl radical, characterized in that first according to the process according to Claim 1 produces the compounds of formula I and then esterifies them with an alcohol. 2nd PATENT CLAIMS 1. Process for the preparation of compounds of formula h rnh (I) • • «co2h in which A is hydrogen or methoxy and R is an aliphatic, aromatic, heterocyclic, aliphatic or heterocyclic-aliphatic carboxylic acid radical or the 1-amino-cyclo-hexylcarbonyl radical, and their salts, characterized in that a compound of the general Formula ah lì \ '■' ■ (II) H rnh •. .co2H (I) 3- (2 ', 6'-dichloro) phenyl-5-methylisoxazole-4-carbonyl, l-aminocyclohexylcarbonyl, l- (2,5-cyclohexadien-l-yl) -glycyl, phenylglycyl or 3-carboxyphthalazin-l- yI means. 11. The method according to claim 10, characterized in that 6ß-phenylacetamido-l-oxadethiopeniciI- lanoic acid or sodium 6ß-phenylacetamido-6-methoxy-l ~ oxadethiapenicillinat. 12. The method according to claim 10, characterized in that 6ß-phenylacetamido-6-methoxy-l-oxadethia- 35 penicillanic acid or 6ß- (a-aminophenylacetamido) -1-oxadethiapenicillanic acid. 13. The method according to claim 10, characterized in that 6ß- (a-carboxyphenylacetamido) -l-oxadethia-penicillanic acid or 6ß- (phenoxyacetamido) -l-oxadethia- 40 produces penicillanic acid. 14. The method according to claim 10, characterized in that 6ß- (2,6-dimethoxybenzamido) -l-oxadethia-penicillanic acid or 6ß- (D-4-aminophenylacetamido) -l-oxadethiapenicillanic acid is prepared. 45 15. The method according to claim 10, characterized in that 6ß- (a-amino-p-hydroxyphenylacetamido) -l-oxadethiapenicillanic acid or 6ß- (a-amino- [3-thienyl] -acetamido) -l-oxa-dethiapenicilanoic acid manufactures. 16. The method according to claim 10, characterized in that one disodium-6ß- (D-a-sulfophenylacetamido) - 3. Use of the compounds of the formula I prepared by the process according to claim 1 for the preparation of corresponding amide derivatives, characterized in that the free acids of the formula I mentioned first with an acid halide and then with ammonia, an alkyl, dialkyl or aralkylamine or reacted with a heterocyclic amine. • co2r in which R5 is hydrogen or both R5 together form a benzylidene radical or a substituted benzylidene radical, with a compound of the formula O Y-CX 45 converts, where X is halogen. 4. The method according to claim 1 for the preparation of compounds of the formula (I) in which A is hydrogen or methoxy, Y is a 1-aminocyclo-hexyl radical, a substituted phenyl radical, a 3-substituted-is, phenyl-substituted isoxazoI-4-yI radical, a 3-substituted-phthalazin-l-yl radical or a radical of the general formula R2R3CH-, where R2 is hydrogen, Ci-Cio alkyl, phenyl, halogen, amino, guanidino, phosphono, hydroxy, tetrazolyl, carboxy, sulfo or sulfamino and R3 20 phenyl, substituted phenyl, a 5- or 6-membered monocyclic heterocyclic ring having 1 to 4 oxygen, sulfur or nitrogen heteroatoms, a substituted heterocyclic thio radical, cyano or 2,5-cyclohexadien-l-yl, characterized in that a compound 25 of the formula in which R1 is hydrogen or a protective group and R5 is hydrogen or both R5 together form a benzylidene radical or a substituted benzylidene radical, with an aliphatic, aromatic, heterocyclic, aliphatic or heterocyclic-aliphatic Chen carbonic acid halide or anhydride or with an acid derivative releasing the 1-aminocyclohexylcarbonyl radical, and, if R1 is a protective group, splits off the protective group and, if appropriate, converts the free acid into a pharmacologically acceptable salt. 5 ^ a h: O / -N_ ♦ c02R in which A and Ri have the above meanings and Rs is hydrogen or the two Rs together form a benzylidene radical or a substituted benzylidene radical, with a compound of the general formula O 9. The method according to claim 7, characterized in that in the compounds obtained R2 hydrogen, hydroxy, amino or carboxy and R3 phenyl or a 5- or 6-membered heterocyclic ring with 1 or 2 sulfur, s means oxygen or nitrogen heteroatoms. 10. The method according to claim 1, characterized in that in compounds obtained R Phenylacetyl, 3-bromophenylacetyl, p-aminomethylphenylacetyl, 4-carboxymethylphenylacetyI, 4-carboxyamido-i'methylphenylacetyl, 2-furylacetyl, 5-nitrofurylacetyl, 3-furylacetyl, 5-chlorothienylacetyl, 5-methoxyethylacetyl, 5-methoxyethylacetyl, 5-methoxythylacetyl 2-thienylacetyl, 3-methylisothiazolylacetyl, 5-isothiazolylacetyl, 3-chloroisothiazolyl-acetyl, 3-methyl-l, 2,5-thiadiazoIyI-4-acetyl, 3-chloro-isl, 2,5-thiadiazolyl-4 -acetyl, 3-methoxy-l, 2,5-thia-diazolyl-4-acetyl, phenylthioacetyl, 4-pyridylthio-acetyl, cyanoacetyl, tetrazolylacetyl, a-FIuorphenyl-acetyl, D-phenylglycyl, 4-hydroxy-D-phenylglycyl , 5. The method according to claim 1 for the preparation of compounds of the formula 50 0 6. The method according to claim 5, characterized in that palladium chloride is used as the metal catalyst. 7. The method according to claim 4 for the preparation of compounds of the form] 0 8. The method according to claim 1 for the preparation of sodium 6ß-phenylacetamido-l-oxadethiapenicillanate, characterized in that 6β-amino-l-oxadethiape-nicillanic acid benzyl ester is reacted with phenylacetyl chloride, by splitting off the benzyl group, the free 6β-phenylaceta-mido-1-oxadethiapenicillanic acid is produced and the latter is converted into its sodium salt by reaction with sodium bicarbonate.