CH572487A5 - 4,4'-dimethyl-5-thia-2,7-diazabicyclo (4,2,o)- - oct-2-ene-8-one - Google Patents

Abstract

4,2,0 -oct-2-ene-8-one. Title cpd. (I), useful as an intermediate for forming cephalosporins, is prepd. by removing the gp. COX1 and the addition of water to the resulting product from a cpd. (II): (where COX1 is a substd. hydroxy- or mercapto-carbonyl gp.; Ro is H or acyl, both COX1 and the acyl gp. being removed under the reaction conditions).

Description

  

  
 



   The present invention relates to a process for the preparation of a thiadiazabicycloalkenyl compound, namely 4,4-dimethyl-5-thia-2,7-diazabicyclo [4,2, oct-2-en-3-one of the formula
EMI1.1

The new compound is obtained in a surprising manner when using a penam compound of the formula
EMI1.2
 in which the group -NH-C (= O) -X1 is an esterified hydroxycarbonylamino group which can be cleaved off on treatment with reducing agents under neutral or acidic conditions, in which X1 is a group -OR, a or -O-Rob, in which Ro3 is a 2- Halo-lower alkyl radical and Rob is an optionally substituted arylcarbonylmethyl group,

   and Ro represents hydrogen or an acyl radical AcO of an organic acid which can be split off under the conditions of the process, with cleavage of the S-membered ring, rearrangement and ring closure to form the 6-membered nitrogen and sulfur-containing ring and simultaneous splitting off of the -NH-C (= O) -XI group by means of a reducing agent, under neutral or acidic conditions and by means of a simultaneously present or subsequently added at least equimolar amount of water.



   An acylamino group AcO -NH- which can be cleaved under the reaction conditions is e.g. a group of the formula -NH-C (= O) -X1, in which X1 has the meaning given above, in particular a group of the formula -NH-C (= O) -OR, a or -NH-C (= O) - O-Rob wherein ROa and RO have the meanings below, but can also represent any other acylamino group which can be cleaved under the reaction conditions.



   The cleavage of the group —C (O) -X1 depends on the nature of this group, treatment being carried out simultaneously or subsequently with at least one mol, normally an excess, of water. At the same time, acyl residues AcO which can be split off under the reaction conditions are split off.



   Substituted hydroxyl groups X1 are primarily etherified hydroxyl groups which together with the carbonyl grouping under neutral or acidic conditions form functionally modified, primarily esterified, carboxyl groups which can be easily cleaved.



   The group X1 represents the remainder of the formula -O-Ro which, together with the carbonyl group, represents an esterified carboxyl group which can be easily cleaved when treated with chemical reducing agents under neutral or weakly acidic conditions. In this group, ROa denotes a 2-halo-lower alkyl radical in which halogen preferably has an atomic weight of more than 19. The remainder can be one, two or more halogen, e.g. CMor, bromine or iodine atoms, where in particular 2-chlorine, but also 2-bromine-lower alkyl radicals contain several, preferably three chlorine or



  Contain bromine atoms, while a 2-iodine-lower alkyl radical has primarily only one iodine atom. The ROn radical is in particular a 2-polychloro-lower alkyl, such as 2-polychloroethyl radical, primarily the 2,2,2-trichloroethyl radical and the 2,2,2-trichloro-1-methyl-ethyl radical, can but also eg a 2-bromo-lower alkyl, such as 2-polybromo-lower alkyl, such as 2,2,2-tribromoethyl, or a 2-iodo-lower alkyl, e.g.



  in particular the 2-iodoethyl radical.



   Another group X, which, together with the carbonyl grouping, represents an esterified carboxyl group which can be easily cleaved when treated with chemical reducing agents under neutral or weakly acidic conditions, is the group -O-Rob, in which Rob is an optionally substituted arylcarbonylmethyl group. In this, the aryl radical stands for a bi- or polycyclic, but especially a monocyclic, optionally substituted aromatic hydrocarbon radical, e.g. an optionally substituted naphthyl and primarily an optionally substituted phenyl group. Substituents of such groups are e.g. optionally substituted hydrocarbon radicals such as lower alkyl, e.g.

  Methyl, ethyl or isopropyl, furthermore trifluoromethyl, phenyl, or phenyl-lower alkyl, e.g.



  Benzyl or phenylethyl radicals, or functional groups such as free or functionally modified carboxyl groups, e.g. Carboxy, lower alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, furthermore carbamoyl or cyano groups, optionally functionally modified, such as esterified hydroxyl or mercapto groups, e.g. Halogen atoms, or etherified hydroxy or mercapto groups, such as lower alkoxy, e.g. Methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy or tert-butyloxy groups, and / or optionally substituted amino, such as di-lower alkyl, e.g. Dimethylamino or diethylamino, or lower alkanoyl amino, e.g. Acetylamino groups.



   The methyl part of an arylcarbonylmethyl radical Rob is preferably unsubstituted, but can optionally be an organic radical, e.g. an optionally substituted aliphatic hydrocarbon radical such as a lower alkyl, e.g.



  Methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl group, or a cycloaliphatic, aromatic or araliphatic radical such as an aryl, e.g. optionally substituted phenyl group, as well as an optionally substituted cycloalkyl, e.g. Cyclohexyl group, or an optionally substituted phenyl-lower alkyl, e.g. Benzyl group, as a substituent.



   An arylcarbonylmethyl radical RO is preferably the unsubstituted phenacyl radical, but can also be one which is substituted in the aromatic part, such as by lower alkyl, e.g. Methyl groups, lower alkoxy, e.g. Methoxy groups, or halogen, e.g. Be fluorine, chlorine or bromine atoms, substituted phenacyl radical.



   The cleavage of an esterified carboxyl group of the formula -C (= O) -X, which in the starting material of the formula II can also represent the radical AcO, and wherein X represents the group -OR, a or -O-Rob, is carried out by treating with a chemical reducing agents in the presence of at least an equimolar amount, usually in the presence of an excess of water. You work under mild conditions, usually at room temperature or even with cooling.



   Chemical reducing agents are e.g. suitable reducing metals, as well as reducing metal compounds, e.g.



  Metal alloys or amalgams, as well as strongly reducing metal salts. Zinc, zinc alloys, e.g. Zinc copper, or zinc amalgam, and also magnesium, which are preferably used in the presence of hydrogen-releasing agents which are able to generate hydrogen nascent together with the metals, metal alloys and amalgams, zinc e.g. advantageously in the presence of acids such as organic carbonic, e.g. Lower alkanecarboxylic acids, primarily acetic acid, or acidic agents such as ammonium chloride or pyridine hydrochloride, preferably with the addition of water, and in the presence of alcohols, especially aqueous alcohols such as lower alkanols, e.g.

  Methanol, ethanol or isopropanol, which can optionally be used together with an organic carboxylic acid, and alkali metal amalgams such as sodium or potassium amalgam, or aluminum amalgam in the presence of moist solvents such as ethers or lower alkanols.



   Strongly reducing metal salts are primarily chromium II compounds, e.g. Chromium (II) chloride or chromium (II) acetate, which is preferably used in the presence of aqueous media containing water-miscible organic solvents, such as lower alkanols, carboxylic acids such as lower alkanecarboxylic acids, or derivatives such as optionally substituted, e.g. lower alkylated, amides thereof, or ethers, e.g. Methanol, ethanol, acetic acid, dimethylformamide, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether can be used.



   In the above reduction process, care must be taken to ensure that the C = N double bond in the process product is not further reduced and that 3-isopropyl-4-thia-2,6-diazabicyclot3,2,0] -heptan-7-one is formed after rearrangement .



   The 4,4-dimethyl-5-thia-2,7-diazabicyclo [4.2.0] oct-2-en-8-one can be separated from mixtures obtained according to the process according to known separation methods, e.g. isolated by fractional crystallization, adsorption chromatography (column or thin layer chromatography) or other suitable separation methods and, for example, separated from the 3-isopropyl-4-thia-2,6-diazabicyclo [3,2,0] heptan-7-one which may be formed.



   The above process also includes those Ausfüh approximate forms, according to which compounds obtained as an intermediate product are used as starting materials and the remaining process steps are carried out with these, or the process is terminated at any stage; furthermore, starting materials in the form of derivatives can be used or formed during the reaction.



   The starting materials of the formula II used according to the process can e.g. can be prepared by adding a penam-3-carboxylic acid compound IIIa having the formula
EMI2.1
 in which Aca represents the acyl residue of an organic carboxylic acid, in which free functional groups such as hydroxyl, mercapto and especially amino and carboxyl groups, optionally, e.g. by acyl groups or

   are protected in the form of ester groups, and Ro stands for a carboxyl group = = O) -OH (compound IIIa), or a salt thereof into the corresponding acid azide compound @ with the formula III, in which Ro represents the azidocarbonyl radical -C (= O) -N3 represents (compound IIIb), converted, this with the elimination of nitrogen to the corresponding isocyanate compound with the formula III, in which Ro is the isocyanato group -N = C = O (compound IIIc), converted and simultaneously or subsequently with a compound of the formula H- X1 (1V) treated,

   and in a compound obtained an acyl radical Aca which cannot be cleaved under the conditions of the process according to the invention is replaced by hydrogen, and, if desired, a compound obtained is converted into another of the formula II, and / or, if desired, a mixture of isomers obtained into the separates individual isomers
An acyl group Aca occurring in the compounds of the formula III can represent any acyl radical of an organic carboxylic acid with optionally protected functional groups, primarily a naturally occurring or biosynthetically produced N-acyl derivative of 6-aminopenam-3-carboxylic acid or 7-amino -ceph -3-em-4-carboxylic acid compounds containing acyl radical,

   such as a monocyclic arylacetyl- or aryloxyacetyl-, furthermore an optionally substituted lower alkanoyl- or medealkenoyl-, e.g. the 4-hydroxyphenylacetyl, hexanoyl, octanoyl, 3-hexenoyl, 5-amino-5-carboxy-valeroyl, n-butylmercapto-acetyl or allylmercaptoacetyl, especially the phenylacetyl or phenyloxyacetyl radical, or then one preferably under acidic conditions, easily cleavable acyl radical, especially the acyl radical of a half ester of carbonic acid, such as one under acidic conditions, e.g. by treatment with trifluoroacetic acid, easily cleavable acyl radical, especially the acyl radical of a half-ester of carbonic acid, such as one under acidic conditions, e.g.

   by treatment with trifluoroacetic acid, easily cleavable lower alkoxy carbonyl, e.g. tert-butyloxycarbonyi- or tert-pentyloxycar bonyl radical, cycloalkoxycarbonyl, e.g. Adamantyloxycarbonyl radical, phenyl-lower alkoxycarbonyl, e.g. Diphenylmethoxycarbonyl, as well as α-4-diphenyl-α-methyl-ethoxycarbonyl radical, or furyl-lower alkoxycarbonyl, e.g. Furfurylocarbo.



  nylrest.



   The conversion of an acid compound purple or a suitable salt, in particular an ammonium salt, into the corresponding acid azide IIIb can e.g. by converting it into a mixed anhydride (for example by treating with a lower alkyl haloformate, such as ethyl chloroformate, or with trichloroacetic acid chloride in the presence of a basic agent such as triethylamine or pyridine) and treating such an anhydride with an alkali metal azide, such as sodium azide, or an ammonium azide, e.g. Benzyltrimethylammonium azide.

  The acid azide compound ilib obtainable in this way can be used in the absence or absence of a compound of the formula IV under the reaction conditions, e.g. on heating, are converted into the desired isocyanate compound IIIc, which usually does not need to be isolated and can be converted directly into the desired starting material in the presence of a compound of the formula IV.

 

   The reaction with a compound of the formula IV, in particular with an alcohol of the formula ROa -OH or Rob -OH such as with a 2-haloethanol ROa -OH, e.g. with 2,2,2-trichloro- or 2-bromoethanol, or with an arylcarbonylmethyl Rob -OH, e.g. Rhenacyl alcohol is optionally dissolved in an inert solvent, e.g. in a halogenated hydrocarbon such as carbon tetrachloride, chloroform or methylene chloride, or in an aromatic solvent such as benzene, toluene or chlorobenzene, preferably with heating.



   An acyl group Aca which cannot be split off under the reaction conditions of the process according to the invention, in particular an acyl group different from the remainder of the formula -C (= O) -X1, can, if desired, after protection of free functional groups (e.g. by acylation, Esterification, such as silylation, etc.) or after the release of protected functional groups (e.g. by hydrolysis, reduction or treatment with an acid), such as by treatment with an imide halide-forming agent, such as a suitable inorganic acid halide, e.g.



  Phosphorus pentachloride, preferably in the presence of a basic agent such as pyridine, reacting the resulting imide halide with an alcohol such as lower alcohol, e.g. Methanol, and cleavage of the imino ether formed in an aqueous medium, preferably under acidic conditions. The acyl radical of a suitable half ester of carbonic acid, such as a carbo-lower alkoxy-, e.g. the carbo-tert-butyloxy, as well as carbo-tert-pentyloxy, carbo-idamantyloxy or carbodiphenylmethoxy radical can be split off by treatment with a suitable acidic agent such as trifluoroacetic acid.



   Starting materials of the formula II obtainable according to the process can be converted into one another. E.g. an aliphatically bonded chlorine, especially bromine, atom in the radical X1, as in the 2-bromoethyloxy radical, e.g. by treating with a suitable iodized salt such as an alkali metal, e.g.



  Potassium iodide, replaced by an iodine atom in a suitable solvent such as acetone, e.g. the 2-bromoethyl radical can be converted into the 2-iodoethyl radical.



   Furthermore, in starting materials of the formula II in which Ro is hydrogen, this can be exchanged in a manner known per se for an acyl group AcO which can be split off under the reaction conditions and replaced by hydrogen.



  The usual acylating agents are used, especially reactive derivatives of suitable acids, if necessary in the presence of a basic agent such as an organic tertiary base, e.g. Triethylamine or pyridine. Reactive derivatives of acids are anhydrides, including mixed ones, in particular with haloformic acid esters, e.g. Ethyl chloroformate, anhydrides which can be prepared, also halides, primarily fluorides or chlorides, or reactive esters, such as esters of acids with alcohols or phenols containing electron-attracting groups, and with N-hydroxy compounds, e.g. Cyanmethanol, p-nitrophenol or N-hydroxysuccinimide. The acylation can also be carried out in stages, e.g.



  by treating a compound of the formula II obtained, in which Ro is hydrogen, with a carbonic acid dihalide, in particular phosgene, and a compound of the formula II obtained, in which R1 is a halocarbonyl group, with a suitable alcohol, e.g. an optionally substituted lower alkanol, such as tert-butanol, 2,2,2 trichloroethanol, or phenacyl alcohol.



   The compound of the formula I is a valuable intermediate which can be easily converted into starting materials which are particularly useful for the production of pharmacologically valuable compounds, e.g. of the 7-N-acylaminocephalosporanic acid type, with effects against microorganisms such as gram-positive and gram-negative bacteria. can be convicted
For example, the compound of the formula I can be converted into 3-isopropyl-4-thia-2,6-diazabicyclo (3, 2, oiheptan-7-one of the formula) by reducing the -N = CH double bond
EMI3.1
 in which R1 is hydrogen, and in this the hydrogen R1 is replaced by an acyl radical Ac, primarily an acyl radical Ac ', such as the tert-butyloxycarbonyl radical, which can be easily split off, in particular under acidic conditions.

  If a compound of the formula IV, in which R 1 is an acyl radical Ac, in particular an acyl radical Ac ', is used, usually in the absence of a condensing agent, with a 3,3-Diformyi.acrylic acid.R2A.ester of the formula
EMI3.2
 wherein R2A represents an organic residue which forms an easily cleavable esterified carboxyl group together with the carboxyl group, or a tautomer thereof, and treats an obtained 2- (2-Ac-3-isopropyl-7-oxo-2,6-di aza-4- thia-6-bicyclo [3, 2.0] heptyl) -3, 3 -diformyl-propionic acid -R2-ester of the formula
EMI3.3
 with an acidic agent, a 7-amino-3-formyl-ceph-2-em-4-carboxylic acid R2A-ester of the formula is obtained
EMI3.4
   This can e.g. according to the Austrian patent no.



  264 537 described method, are converted into 7-aminocephalosporanic acid and its N-acyl derivatives.



   In a compound of the formula the -N = CH-double bond is removed by exhaustive reduction, e.g. by treating with an excess of a chemical reducing agent such as a reducing metal or a reducing metal compound, e.g. Metal alloy or amalgam, preferably in the presence of a hydrogen-donating part, such as one of the reducing agents described above, in particular zinc in the presence of acetic acid, preferably aqueous acetic acid, reduced.



   A hydrogen atom R1 in a compound of formula IV is used in a manner known per se, e.g. after the acylation reaction described above, replaced by an acyl group Ac. A tert-butyloxycarbonyl group can e.g. by treatment with fluoroformic acid tert-butyl ester, or then by treatment with phosgene and reacting a compound of the formula IV, in which R1 represents the chlorocarbonyl group, with tert-butanol.



   In a compound of the formula V, an organic radical R2A, together with the carboxyl group, forms an easily cleavable esterified carboxyl group. A2A stands in particular for a radical ROa with the meanings given above, in particular for the 2,2,2-trichloroethyl or 2-iodoethyl group, also for one with the carboxyl group being hydrolytically, optionally under weakly acidic or weakly basic conditions Cleavable esterified carboxyl group-forming organic radical R ', such as for a hydrocarbon, in particular aliphatic, aromatic or araliphatic hydrocarbon radical substituted by electron-attracting groups, where electron-attracting groups are, for example

  Nitro groups, optionally functionally modified carboxyl or sulfo groups, such as cyano or sulfamoyl groups, halogen atoms or acylamino groups, e.g. the 4-nitrophenyl, 2,4-dinitrophenyl, 4-nitrobenzyl, 2,5,6-trichlorophenyl, 2,3,4,5,6-pentachlorophenyl, phthaliminomethyl or succinimomethyl, or for one together with the carboxyl group forming an organic radical R0g which can be cleaved under physiological conditions and which forms an esterified carboxyl group, such as an acyloxy, e.g. a lower alkanoyloxy, in particular acetyloxy group, substituted methyl radical.



   The reaction of a compound of the formula IV, in which Rl represents an acyl radical Ac, in particular an acyl radical Ac 'which can easily be split off under acidic conditions, with a diformyl acrylic acid R 1 ester of the formula V is carried out in a manner known per se, e.g. by heating the reaction mixture to temperatures at which decomposition of the olefin of formula V, which is also in hydrated form, i. as 3,3-diformyllactic acid-R, A-ester of the formula
EMI4.1
 can be used and loses water under the reaction conditions, is largely avoided, i.e.

   at about 50 "C to about 1200C, usually in the presence of a solvent such as a suitable, optionally halogenated, aliphatic or aromatic hydrocarbon, e.g.



  n-octane or xylene, or a suitable ether, e.g. 1,2-dimethoxyethane, and / or in an inert gas such as nitrogen atmosphere and / or under increased pressure.



   Acidic agents which cause the ring opening of the S-membered ring and the ring closure to the 6-membered sulfur-stick material ring in a compound of the formula VI are primarily inorganic or strong organic, oxygen-containing acids, as well as aprotic Lewis acids of the boron trifluoride type and their complexes . Inorganic acids containing oxygen are e.g. Sulfuric acid, phosphoric acid or perchloric acid, while strong organic oxygenated acids strong organic carboxylic acids such as substituted lower alkanecarboxylic acids, e.g. Halogen-lower alkanecarboxylic acids, and especially trifluoroacetic acid, or strong organic sulfonic acids, such as p-toluenesulfonic acid.

  Aprotic Lewis acids of the boron trifluoride type are e.g. the boron trifluoride itself, as well as its complexes, e.g. with ether, i.e.



  Boron trifluoride etherate, or with hydrofluoric acid, i.e.



  Hydrofluoric acid and tin tetrachloride. Suitable mixtures of acids can also be used.



   The above ring splitting and ring closing reaction is carried out in the absence or presence of suitable solvents (although certain acidic agents, such as trifluoroacetic acid, can also serve as solvents), with cooling, at room temperature or with heating, if necessary, in a nitrogen atmosphere and / or in a closed Vessel carried out.



   An acyl group Ac 'which can easily be split off under acidic conditions, e.g. the tert-butyloxycarbony radical, usually also split off under the reaction conditions.



   In contrast to the known 2-R1-4-thia-2,6-diazabicyclo [3,2,0] -heptan-7-one compounds which can also be used in the above reaction sequence for the preparation of compounds of the formula VII, the carbon atom of which in 4-position e.g. is disubstituted by lower alkyl, especially methyl groups, the compounds of the formula 1 can be prepared in a simple manner from readily available starting materials of the 6-N-acylamino-penicillanic acid series, thereby providing synthetic access to compounds of the 7-N-acylaminocephalosporanic acid type is simplified significantly.



   A compound of the formula IV, in which Rl stands for hydrogen, can also be used as a starting material for the production of new compounds with antibiotic effects against gram-positive and gram-negative bacteria, as follows:
If the compound of the formula IV, in which R 1 is hydrogen, is oxidized with a mercaptan disulfide oxidizing agent, a disulfide compound of the formula is obtained, if appropriate after treatment with water
EMI4.2
 wherein R1a and R1b represent hydrogen or together represent an 1-isobutylidene group, or an acid addition salt thereof.

  In a compound of formula VIII the amino group, e.g. acylated by the acylation process described above, an l-isobutylidene group formed by the radicals Rln and Rlb, optionally in modified form, being cleaved off simultaneously or subsequently. A compound of the formula VIII obtainable in this way, in which R18 is an acyl radical Ac and R1b is hydrogen, is reacted with ethylene oxide with simultaneous treatment with a reducing agent, and a compound of the formula is thus obtained
EMI5.1
 wherein the primary hydroxyl group is converted into a hydroxyl group esterified by the acyl radical of the formula -C (= O) -X2.

  X stands for an etherified hydroxy or mercapto group which, together with the carbonyl group, forms an esterified carboxyl group which can be cleaved under mild conditions.



   The thus obtainable compound of the formula
EMI5.2
 is made with a compound of the formula
EMI5.3
 where R2A is an organic radical of an alcohol, preferably easily replaceable by hydrogen, or a reactive derivative thereof. In the addition compound of the formula
EMI5.4
 the secondary hydroxyl group is converted into a reactive esterified hydroxyl group.

  The reactive ester of the formula
EMI5.5
 wherein Z is a reactive esterified hydroxyl group, primarily a halogen, especially chlorine or bromine atom, and an organic sulfonyloxy, e.g. 4-methylphenylsulfonyloxy or methylsulfonyloxy group, is set with a phosphine compound of the formula
EMI5.6
 wherein each of the radicals Ra, Rb and Rc stands for an optionally substituted hydrocarbon radical, and thus obtained, if necessary, after cleavage of the elements of an acid of the formula H-Z (XVb) from a phosphonium salt compound of the formula available as an intermediate
EMI5.7
 the phosphoranylidene compound of the formula
EMI5.8
 in which the esterified carboxyl group -C (= O) - -X2 is cleaved.

  Is oxidized in such a obtainable compound of the formula
EMI5.9
 the carbinol group of the formula -CH2-OH to a formyl group of the formula -CHO is obtained with simultaneous ring closure of an aldehyde compound of the formula formed as an intermediate product
EMI6.1
 the ceph-3-ner compounds of the formula
EMI6.2
 where R1 stands for an acyl radical Ac, and R2 represents the organic radical R2A of an alcohol, where, if desired,

   the acyl group Ac is split off and, if appropriate, the free amino group is acylated in a compound obtainable in this way and / or an ester grouping of the formula -C (= O) -O-R2A in the free carboxyl group or in another ester grouping of the formula -C (= O) - O-R2 converted and optionally a free carboxyl group converted into an esterified carboxyl group of the formula -C (= O) -O-R2, and / or a compound obtained with a salt-forming group in a salt or a salt obtained in the free compound or in a another salt can be converted and / or a mixture of isomers obtained can be separated into the individual isomers.



   The compounds of the formula XVIII have valuable pharmacological properties or can be used as inter mediate products for the preparation of such. Compounds of the formula XVIII in which R1 is an acyl radical occurring in pharmacologically active N-acyl derivatives of 6-amino- - -penam-3-carboxylic acid or 7-amino-ceph-3-em-4-carboxylic acid compounds and R2 is hydrogen or one Organic residue of an alcohol which can be split off easily under physiological conditions means are against microorganisms such as gram-positive bacteria, e.g. Staphylococcus aureus, in particular also against penicillin-resistant bacteria of this type, e.g. in dilutions up to 0.0001 γ / ml and against gram negative bacteria, e.g. Escherichia coli, effective.



   An acyl radical contained in pharmacologically active N-acyl derivatives of 6-amino-penicillanic acid or 7-amino-cephalosporanic acid is primarily 2,6-dimethoxybenzoyl, tetrahydronaphthoyl, 2-methoxy-naphthoyl, 2-ethoxy-naphthoyl, Cyclopentylcarbonyl-,? -Amino-cyclo-pentylcarbonyl- or?

  ; -Amino-cyclohexylcarbonyl- (optionally with substituted amino, e.g. a sulfoamino group, optionally present in salt form), benzyloxycarbonyl, hexahydrobenzyloxycarbonyl, 2-phenyl-5-methyl -4-isoxazolylcarbonyl, 2- (2-chlorophenyl) -5-methyl-4-isoxazolylcarbonyl-, 2- (2,6-dichlorophenyl) -5-methyl-4-isoxazolylcarbonyl-, phenylacetyl-, phenacylcarbonyl-, phenyloxyacetyl-, phenylthioacetyl-, bromophenylthioacetyl-, 2-phenyloxypropionyl- , α-phenyloxy-phenylactyl-,, methoxy-phenylacetyl-, α-ethoxy-phenylacetyl-, α-methoxy-3,4-dichloro-phenylacetyl-,?

  ; -Cyan-phenylacetyl-, phenylglycyl- (optionally with substituted amino, such as a sulfoamino group, optionally present in salt form), benzylthioacetyl, benzylthio-propionyl, sc-carboxyphenylacetyl (optionally with a functionally modified one, for example in salt form present, carboxyl group), 2-pyridylacetyl-, 4-aminopyridiniumacetyl-, 2-thienylacetyl-, sG-carboxy-2-tbienylacetyl- or -carboxy -3-thienylacetyl- (possibly with a functionally modified, e.g. present in salt form, carboxyl group ), a-cyano- -2-thienylacetyl-,?

  ; -Amino-2-thienylacetyl- or ec-aniino-3-thienylacetyl- (optionally with substituted amino, e.g. sulfonamino group, optionally present in salt form), 3-thienylacetyl, 2-furylacetyl, 1 -imidazolylacetyl, l-methyl-5-tetrazolylacetyl, 3-methyl-2-imidazolylthioacetyl, 1,2,4-thiazol-3-yl-thioacetyl, propionyl, butyryl, hexanoyl, octanoyl, acrylyl, crotonoyl , 3-butenoyl, 2-pentenoyl, methoxyacetyl, methylthioacetyl, butylthioacetyl, allylthioacetyl, chloroacetyl, bromoacetyl, dibromoacetyl, 3 chloropropionyl, 3-bromopropionyl, aminoacetyl,

   5-Amino -5-carboxy-valeryl- (optionally with substituted amino and / or optionally functionally modified carboxyl group), azaoacetyl-, carboxyacetyl-, methoxycarbonylacetyl-, ethoxycarbonylacetyl-, bismethoxycarbonylacetyl-, pro-phenyl-cyano-acetyl-, N-phenylcarbamoylacetyl-, N-phenylcarbamoylacetyl- -, 2-Cvan-3-dimethylacrylyl or N-2-chloroethylcarbamoyl radical.



   Compounds of the formula XVIII in which both radicals R1 and R2 are hydrogen, or in which R1 is hydrogen or an acyl radical Ac and R2 is an organic, together with the -C (= O) -O grouping, which forms an esterified carboxyl group which is preferably easily cleavable The remainder of an alcohol R, A represents, are valuable intermediates which in a simple manner, e.g. as described below, can be converted into the above-mentioned pharmacologically active compounds.



   The oxidation of compounds of the formula IV can be carried out with the aid of oxidizing agents usually used for the preparation of disulfide compounds, such as oxygen or hydrogen peroxide (preferably in the presence of heavy metal salts such as copper-IL or iron-III salts, e.g.



  halides or sulfates, as catalysts), halogens, especially iodine, hypohalites, such as alkali metal hypohalites, iron (III) chloride, or heavy metal, such as lead acylates, e.g. Lead tetraacetate, usually in the presence of a suitable diluent such as benzene, ethanol, acetone or acetic acid, and optionally water.

 

   Usually the disulfide obtained is acylated in the crude state, e.g. by the acylation procedure described above, such as by treatment with an acid or a derivative thereof such as an acid halide, e.g. chloride, optionally gradually and / or in the presence of a suitable condensing agent or basic agent.



   As reducing agents which are used simultaneously in the treatment of a disulfide compound of the formula VIII with ethylene oxide, e.g. the above-mentioned chemical reducing agents in question, the reaction being carried out in a neutral or weakly acidic medium. A particularly suitable reducing agent is zinc, which is used in the presence of aqueous acetic acid.



   In a compound of the formula IX, the primary hydroxyl group is converted in a manner known per se by acylating into the acyloxy group of the formula -OC (= O) -X2, in particular into one of the groups of the formulas -OC (= O) -Q-Ro, -OC (= O) -OR, b, -0-C (= Q) -O-ROe, -OC (= O) -O-Rod, -OC (= O) -O-Ro @ or -C} -C (= O) -O-Ror converted, in which red, Rob, Roc, Rod, RJe and Rof have the meanings given above, and primarily for the 2,2,2-trichloroethyl, 2-bromo ethyl , 2-iodoethyl,

   Phenacyl, 4,5-dimethoxy-2-nitro-benzyl, 4-methoxy-benzyl or tert-buty radical
The above acylation reaction is carried out e.g. carried out as described above.



   In a compound of the formula XI, a radical R2A is primarily one of the groups R0a, R0b, R0c, R0d, R0e, Rof or R0g, such as one of the above-mentioned groups of this type and in particular for the 2,2,2-trichloroethyl , 2-iodoethyl (or the 2-bromoethyl-), phenacyl-, 4,5-dimethoxy-2-nitro-benzyl-, 4-methoxybenzyl- or tert. Butyl radical.



   The addition of the glyoxylic ester compound of the formula XI to the nitrogen atom of the lactam ring of a compound of the formula X takes place preferably at elevated temperature, primarily at about 50 ° C. to about 1500 ° C., in the absence of a condensing agent and / or without the formation of a salt. Instead of the free glyoxylic acid ester compound, it is also possible to use a reactive oxo derivative thereof, primarily a hydrate, it being possible, if necessary, to remove water formed when using the hydrate by distillation, for example azeotropically.



   It is preferred to work in the presence of a suitable solvent, e.g. Dioxane or toluene, or solvent mixture, if desired or necessary, in a closed vessel under pressure and / or in the atmosphere of an inert gas such as nitrogen.



   In a compound of the formula XII, the secondary hydroxyl group can be converted in a manner known per se into a reactive hydroxyl group esterified by a strong acid, in particular into a halogen atom or into an organic sulfonyloxy group. One uses e.g. suitable halogenating agents such as a thione halide, e.g. chloride, a phosphorus oxyhalide, especially chloride, or a halophosphonium halide, such as triphenylphosphonium dibromide or -diiodide, and a suitable organic sulfonic acid halide, such as chloride, the reaction preferably in the presence of a basic, primarily an organic basic agent, such as an aliphatic tertiary amine, e.g. Triethylamine or diisopropylethylamine, or a heterocyclic base of the pyridine type, e.g.

  Pyridine or collidine.



  It is preferred to operate in the presence of a suitable solvent, e.g. Dioxane or tetrahydrofuran, or a solvent mixture, if necessary, with cooling and / or in the atmosphere of an inert gas such as nitrogen.



   In a compound of formula XIII obtained, a reactive esterified hydroxyl group Z can be converted into another reactive esterified hydroxyl group in a manner known per se. So you can e.g. replace a chlorine atom by treating the corresponding chlorine compound with a suitable bromine or iodine reagent, in particular with an inorganic bromide or iodide salt such as lithium bromide, preferably in the presence of a suitable solvent such as ether, for a bromine or iodine atom.



   In a phosphine compound of formula XIV, each of the groups Ra, Rb and Re means primarily an optionally, e.g. by etherified or esterified hydroxy groups, such as lower alkoxy groups or halogen atoms, substituted lower alkyl radical or an optionally, z. B.



  Phenyl radical substituted by aliphatic hydrocarbon radicals, such as lower alkyl groups, or etherified or esterified hydroxyl groups, such as mederalkoxy groups or halogen atoms, or nitro groups.



   The reaction of a compound of the formula XIII with the phosphine compound of the formula XIV, in which each of the groups Ra, Rt and Re is primarily phenyl and a lower alkyl, especially the n-butyl test, is preferably carried out in the presence of a suitable inert solvent such as an aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. Hexane, cyclohexane, benzene or toluene, or an ether, e.g. Dioxane, tetrahydrofuran or diethylene glycol dimethyl ether, or a solvent mixture made. If necessary, one works with cooling or at elevated temperature and / or in the atmosphere of an inert gas, such as plastic.



   A phosphonium salt compound of the formula XVa formed as an intermediate usually spontaneously loses the elements of the acid of the formula H-Z (xVb); if necessary, the phosphonium salt compound can be prepared by treating with a weak base such as an organic base, e.g. Diisopropylethylamine or pyridine, decomposed and converted into the phosphoranylidene compound of the formula XV.



   The cleavage of the esterified carboxyl group of the formula -C (= O) -X2 in a compound of the formula XV can be carried out in various ways, depending on the nature of the group X2. Thus, a grouping of the formula -C (=O) -X2, in which X2 is the group of the formula O-ROa and -OR, b, can be converted into a grouping of the formula -C (O) by treatment with a chemical reducing agent ) -X2, in which X2 is the group of the formula .0.R0e, by irradiation, and a grouping of the formula -C (= O) -X2, in which X2 is the group of the formula -O-RO or ROe, by treatment with split an acid.

  These reactions can e.g. be carried out as described above, it being possible to work in the absence of water. An esterified carboxyl group of the formula -C (= O) -O-red can under weakly basic conditions, e.g. at a pH of from about 7 to about 9, e.g. by treatment with a weakly basic agent such as an alkali metal hydrogen carbonate such as sodium hydrogen carbonate, or a suitable buffer solution (pH about 7 to about 9) such as a dipotassium hydrogen phosphate buffer, preferably in the presence of water and an organic solvent such as methanol or acetone.



   In a compound of the formula XV, the esterified carboxyl groups of the formulas -C (= O) -X2 and .C (= O) O.R2A preferably differ from one another in such a way that under the conditions of cleavage of the esterified carboxyl group of the formula -C ( = O) -X2 the esterified carboxyl group of the formula -C (= O) -O-RA remains intact.

  For example, the esterified carboxyl group of the formula -C (= O) -X2 is one of the esterified carboxyl groups which can be cleaved upon treatment with a chemical reducing agent such as zinc in the presence of aqueous acetic acid, e.g. a grouping of the formula -C (= O) -O-R0a or -C (= O) -O-R0b, in which, R0a is preferably easy for the 2,2,2-trichloroethyl or 2-iodoethyl or the latter convertible 2-bromoethyl radical and RO are primarily the phenacyl group, the esterified carboxyl group of the formula -C (= O) -O-R2A, for example for one of the esterified carboxyl groups -C (= O) -O-RA which can be cleaved on treatment with a suitable acid such as trifluoroacetic acid, e.g. for a grouping of the formula -C (= O) -O-R0e, in which ROe is preferably the tert-butyl group.

 

   The oxidation of a primary carbinol group into a formyl group in a compound of the formula XVI can surprisingly be carried out by treatment with an oxidizing organic sulfoxide compound in the presence of agents with dehydrating or water-absorbing properties. As oxidizing sulfoxide compounds are primarily aliphatic sulfoxide compounds in question, such as di-lower alkyl sulfoxides, primarily dimethyl sulfoxide, or lower alkylene sulfoxides, e.g. Tetramethylene sulfoxide. Agents with dehydrating or absorbing properties are primarily acid anhydrides, in particular anhydrides of organic, such as aliphatic or aromatic carboxylic acids, e.g.

  Anhydrides of lower alkanecarboxylic acids, in particular acetic anhydride, also propionic anhydride, or benzoic anhydride, and anhydrides of inorganic acids, in particular phosphoric acids, such as phosphorus pentoxide.



  The above anhydrides, primarily from organic carboxylic acids, e.g. Acetic anhydride, are preferably used in about a 1: 1 mixture with the sulfoxide oxidizing agent. Further dehydrating or absorbing agents are carbodiimides, primarily dicyclohexylcarbodimide, also diisopropylcarbodiimide, or ketenimines, e.g.



  Diphenyl-N-p-tolylketenimine; these reagents are preferably used in the presence of acidic catalysts such as phosphoric acid or pyridinium trifluoroacetate or phosphate. Sulfur trioxide can also be used as a dehydrating agent, usually in the form of a complex, e.g. with pyridine.



   The sulfoxide oxidizing agent is usually used in excess. Sulphoxide compounds liquid under the reaction conditions, especially dimethyl sulphoxide, can e.g. also serve as a solvent; inert diluents such as benzene or mixtures of solvents can also be used as solvents.



   The above oxidation reaction is carried out if desired. carried out under cooling, but mostly at room temperature or at a slightly elevated temperature.



   In a compound of the formula VIII, an acyl group Ac, in particular an easily cleavable acyl group, in a manner known per se, a tert-butyloxycarbonyl group, e.g. by treating with trifluoroacetic acid, a 2.2.2-trichloroethoxycarbonyl group by treating with a suitable metal or metal compound, e.g. Zinc, or a chromium-II compound, such as chloride or acetate. advantageously in the presence of a hydrogen-generating, hydrogen-releasing agent, preferably of hydrous acetic acid, which nascent together with the metal or the metal compound. Furthermore, in a compound of formula VIII in which a carboxyl group of formula -C (= O) -O-R2 is preferably a e.g.



  by esterification, including by silylation or stannylation, e.g. carboxyl group protected with a suitable organic halosilicon or halotin IV compound such as trimethylchlorosilane, a suitable acyl group Ac, in which any free functional groups present are preferably protected, by treatment with an imide halide forming agent. such as a suitable inorganic acid halide, e.g. Phosphorus pentachloride. preferably in the presence of a basic agent such as pyridine. Reacting the imide halide formed with an alcohol, such as lower alkanol. e.g. Methanol, and cleavage of the imino ether formed in an aqueous or alcoholic medium, preferably under acidic conditions, are split off.



   In a compound of formula XVIII thus obtained, the unsubstituted amino group can be purified by acylation methods known per se, e.g. as described above, are acylated, it being possible to introduce an acyl group in stages. So you can in the free amino group of a compound of formula XVIII a halogen-lower allcanoyl, e.g. Bromoacetyl group, and a N-halo-lower alkanoylamino compound thus obtainable with suitable exchange reagents, such as basic compounds, e.g. Tetrazole, thio compounds e.g. 2-mercapto-1-methyl-imidazole, or metal salts, e.g. Sodium azide, react; in this way substituted lower alkanoylamino compounds are obtained.



   In a compound of formula XVIII having an esterified carboxyl group, the latter e.g. represents an esterified carboxyl group of the formula -C (= O) -O-RA which can easily be converted into the free carboxyl group, this can be converted in a manner known per se, e.g. depending on the type of esterifying radical R2A can be converted into the free carboxyl group, a grouping of the formula -C (= O) -O-RO or C (= 0) -3-Rob e.g. by treating with a chemical reducing agent such as a metal, e.g. Zinc, or a reducing metal salt such as a chromium-II salt, e.g.

  Chromium (II) chloride, usually in the presence of a hydrogen-donating agent that is able to generate nascent hydrogen together with the metal, such as an acid, primarily acetic acid, or an alcohol, preferably adding water, a group of the formula - C (= O) -O-ROe e.g.



  by irradiation, preferably with ultraviolet light, using shorter-wave ultraviolet light, e.g. below 290 m, works when R, C e.g. an optionally in the 3, 4 and / or 5 position, e.g. represents arylmethyl radical substituted by lower alkoxy and / or nitro groups, or with longer-wave ultraviolet light, e.g. over 290 to if ROe e.g. is an arylmethyl radical substituted in the 2-position by a nitro group, a grouping of the formula -C (= O) -O-Rod or -C (= O) -O-Roe e.g.

   by treatment with an acidic agent such as formic acid or trifluorosic acid and a grouping of the formula -C (= 0) -O- -R, 'hydrolytically, optionally under weakly acidic or basic conditions, e.g. by treating with a weakly basic agent such as aqueous sodium hydrogen carbonate or an aqueous potassium phosphate buffer from pH about 7 to about 9.



   In a compound of the formula XVIII, a grouping of the formula -C (= O) -O-R2A can be converted into another of these formulas, e.g. a 2-bromoethoxycarbonyl group -C (= O) -O-Roa by treatment with an iodine salt such as sodium iodide in the presence of a suitable solvent such as acetone into a 2-iodoethoxycarbonyl group.



   E.g. carboxyl group protected by silylation can be obtained in a conventional manner, e.g. can be released by treatment with water or an alcohol.



   In a compound of the formula XVIII with a group of the formula -C (= O) -O-R2, where R2 is hydrogen, the free carboxyl group can be added in a manner known per se, e.g. by treating with a diazo compound such as a diazo lower alkane, e.g. Diazomethane or diazoethane, or a phenyl-diazo-lower alkane, e.g. Phenyldiazomethane or diphenyldiazomethane, or by reaction with an alcohol suitable for esterification in the presence of an esterifying agent such as a carbodiimide, e.g. Dicyclohexylcarbodiimide, as well as carbonyldiimidazole, or by any other known and suitable esterification process, such as reaction of a salt of the acid with a reactive ester of an alcohol and a strong inorganic acid, as well as a strong organic sulfonic acid.

  Acid halides, such as chlorides (produced e.g. by treatment with oxalyl chloride), or activated esters, e.g. those with N-hydroxy nitrogen compounds, or e.g. with haloformic acid lower alkyl esters, such as ethyl chloroformate, or with haloacetic acid halides, such as trichtoroacetic acid chloride, formed.



  mixed anhydrides are converted into esters by reaction with alcohols, optionally in the presence of a base such as pyridine.



   Salts are in particular those of compounds of the formula XVIII in which R2 stands for hydrogen and primarily metal or ammonium salts, in particular corresponding pharmaceutically acceptable, non-toxic salts such as alkali metal and alkaline earth metal, e.g. Sodium, potassium, magnesium or calcium salts, as well as ammonium salts with ammonia or suitable organic amines, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic and aliphatic primary, secondary or tertiary mono-, di- or polyamines for the salt formation in question come, such as lower alkylamines, e.g.

  Triethylamine, hydroxy-lower alkylamines, e.g. 2-hydroxyethylamine, bis (2-hydroxyethyl) amine or tri- (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, e.g. 4-aminobenzoic acid-2-diethylamino-ethyl ester, alkylene amines, e.g. l-ethyl piperidine, cycloalkylamines, e.g. Bicyclohexylamine, or benzylamines, e.g. N, N'-dibenzyl-ethylenediamine. Compounds of formula XVIII in which e.g. Rl stands for hydrogen or which have a basic group in an acyl radical Rl can also be acid addition salts, in particular pharmaceutically usable, non-toxic acid addition salts, for example. with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids.

  Compounds of the formula XVIII in which R2 is hydrogen and in which R is hydrogen or which contain a basic group in an acyl radical Rl can also be in the form of an inner salt, i.e. in second-terionic form.



   Salts of compounds of the formula XVIII can be prepared in a manner known per se. Thus, one can use salts of compounds of formula XVIII in which Ra is hydrogen, e.g. by treating with metal compounds such as alkali metal salts of suitable carboxylic acids, e.g. the sodium salt of cc-ethyl-caproic acid, or with ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent. Acid addition salts are usually obtained e.g. by treatment with an acid or a suitable anion exchange reagent.

  Salts can be converted into the free compounds in the usual way, metal and ammonium salts e.g. by treatment with suitable acids, and acid addition salts e.g. by treating with a suitable basic agent.



   The new compound of the formula I can also be used as starting material for the preparation of pharmacologically active compounds as follows:
If the compound of the formula I is reacted with a glyoxylic acid ester of the formula XI or an aldehyde derivative, in particular the hydrate thereof, preferably at elevated temperature and in the presence of an inert solvent, a compound of the formula is obtained
EMI9.1
 in which the free hydroxyl group is converted into a reactive esterified hydroxyl group.

  A compound of the formula which can be obtained in this way
EMI9.2
 where Z is a reactive esterified hydroxyl group, in particular a halogen atom and primarily a chlorine and a bromine atom, is reacted with a phosphine compound of the formula XIV, and the phosphoranylidene compound of the formula
EMI9.3
 obtained, which is left to stand in an aqueous medium, preferably at a pH of about 5 to about 8, and thereby into a Ceph-3-em compound of the formula
EMI10.1
 in which R1 is hydrogen and R2 is the organic radical R2A, transferred.

  In such a compound, either the free amino group can first be converted into an acylamino group in a manner known per se, in which acyl represents the acyl radical Ac of an organic carboxylic acid, primarily for the pharmacologically active N-acyl derivative of 6-amino-penicillanic acid or 7-amino-cephalosporanic acid which occurs or then stands for an acyl radical of a carbonic acid half-derivative which can easily be split off, especially under acidic conditions, and then the carboxyl group is released or the esterified carboxyl group is first converted into the free carboxyl group and then the free amino group is acylated.



   Compounds of the formula XXIII, in particular those in which Rl is an acyl radical of an organic carboxylic acid occurring in pharmacologically active N-acyl derivatives of 6-amino-penicillanic acid and 7-amino-cephalosporanic acid compounds, and R2 is hydrogen or a physiologically cleavable one together with the carboxyl group represents esterified carboxyl group-forming organic radical, are, similar to the corresponding compounds of the formula XVIII, against microorganisms such as gram-positive bacteria, e.g. Staphylococcus aureus, in particular also against penicillin-resistant bacteria of this type, e.g. in dilutions up to 0.0001 / ml, and against gram negative bacteria, e.g. Escherichia coli, effective.

  Other compounds of formula XXIII, e.g. those in which Rl represents hydrogen and / or R2 represents an organic radical easily replaceable by hydrogen, e.g. similar to the corresponding compounds of formula XVIII and as shown above, can be used as intermediates for the preparation of the above pharmacologically active compounds.



   Ceph-3-em compounds of the formula XXIII can also be obtained if a phosphoranylidene compound of the formula XXII is treated with a suitable acylating agent, such as a carboxylic acid halide which provides the radical Ac, e.g. Chloride, N-acylated in the absence of a basic agent; after treating the intermediate product formed with water, a Ceph-3-em compound of the formula XXIII, in which R1 is an acyl radical Ac and R2 is the organic radical R2A, and in which the free carboxyl group from the esterified carboxyl group is obtained and, in a manner known per se, any functional groups present in the acyl radical Ac can be released from protected functional groups and / or the acyl radical Ac can be split off and the free amino group acylated.



   The condensation of the compound of the formula I with the glyoxylic acid ester of the formula XI, the conversion of the secondary hydroxyl group in a compound of the formula XX into a reactive esterified hydroxyl group Z, primarily into a halogen atom, and the reaction of a compound of the formula XXI, wherein the Group Z represents a reactive esterified hydroxy group with a phosphine compound of the formula XIV, in which each of the groups Ra, Rb and Re is primarily an optionally substituted one
Lower alkyl or phenyl, e.g. n-butyl or phenyl radical, are carried out according to the processes described above.



   The conversion of a phosphorus alkylidene compound of Formula XXII to a compound of Formula XXIII, which occurs at a pH of from about 5 to about 8, is preferably carried out in a suitable buffer solution, e.g. in an aqueous di-alkali metal hydrogen phosphate tri-alkali metal phosphate such as an aqueous, e.g. 0.05 to 0.5 molar potassium hydrogen phosphate-tripotassium phosphate buffer solution, preferably made at room temperature or with cooling.



   In a compound of formula XXIII, if desired, the amino group, e.g. acylated by the acylation process described above and an esterified carboxyl group easily convertible into the free carboxyl group into that, e.g. by the ester cleavage process described above.



   An acylating agent which can be used for the direct conversion of a phosphoranylidene compound of the formula XXII into a compound of the formula XXIII, in which R1 is an acyl radical and R2 is an organic radical R2A, is primarily a halide, in particular the chloride, of an organic carboxylic acid of the formula Ac- OH (XXIV), and also a corresponding, optionally mixed anhydride. The acylation reaction is carried out in the absence of an otherwise customary basic agent, preferably in the presence of an inert solvent such as dioxane.



  The N-acylated intermediate is treated, usually without isolating it, with at least one mole, but not an excessively large excess, of water, heating, if necessary, for a short period.



  After removing the water, e.g. by treating with an anhydrous drying agent such as sodium sulfate, the reaction mixture is e.g. heated to about 50 "C to about 100" C to ensure complete formation of the compound of formula XXIII. In this, if desired, in the usual way, e.g. according to the processes described above, the esterified carboxyl group and any protected functional groups present in the acyl radical Ac are released, and an acyl group is acylated.



   The abovementioned acyl groups Ac, as well as Aca, primarily represent the acyl radicals of organic carboxylic acids occurring in pharmacologically active N-acyl derivatives of 6-amino-penam-3-carboxylic acid or 7-amino-ceph -3-em-4-carboxylic acid compounds , such as the acyl radicals mentioned above, furthermore easily cleavable acyl radicals, e.g. when treated with a chemical reducing agent such as zinc in the presence of aqueous acetic acid, or by acid treatment, e.g. with trifluoroacetic acid, cleavable acyl residues of carbonic acid half-esters, e.g.

   the tert-butyloxycarbonyl, tert-pentyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl radical or a radical which can be converted into the latter, such as the 2-bromoethoxycarbonyl radical, as well as the phenacyloxycarbonyl, adamantyloxycarbonyl, diphenylmethoxycarbonyl, cc-4 -Biphenylyl-a-methyl-ethyloxycarbonyl or furfuryloxycarbonyl radical.



   Compounds of formulas XVIII and XXIII with pharmacological effects can e.g. can be used in the form of pharmaceutical preparations which contain them in admixture with a solid or liquid pharmaceutical carrier material and which are suitable for enteral, parenteral or topical administration. Suitable carrier substances which are inert towards the active substances are e.g. Water, gelatin, saccharides such as lactose, glucose or sucrose, starches such as corn, wheat or arrowroot starch, stearic acid or salts thereof such as magnesium or calcium stearate, talc, vegetable fats and oils, alginic acid, benzyl alcohols, glycols or other known ones Carriers.

  The preparations can be in solid form, e.g. as tablets, dragees, capsules or suppositories, or in liquid form, e.g. as solutions, suspensions or emulsions. They can be sterilized and / or contain auxiliaries such as preservatives, stabilizers, wetting agents or emulsifiers, solubilizers, salts for regulating the osmoic pressure and / or buffers. They can also contain other pharmacologically usable substances. The pharmaceutical preparations which are also encompassed by the present invention can be produced in a manner known per se.



   The invention is described in the following examples. The temperatures are given in degrees Celsius.



   Example I.
A solution of 5 g of 6-amino-2,2-dimethyl-3- (N-2,2,2-trichloroethyloxycarbonyl-amino) -penam in 100 ml of dimethylformamide becomes 65 ml of a 1.7 molar aqueous chromium (II) chloride Solution given, keeping it at 0 and working under a nitrogen atmosphere. After the exothermic reaction has subsided, the reaction mixture is stirred for 30 minutes under a nitrogen atmosphere at 22 "and then brought to a pH of 7.5 by adding 50% strength aqueous tripotassium phosphate solution. The mixture is evaporated under a pressure of 0.1 mm Hg and digested the residue with methylene chloride. The insoluble residue is separated off, the solution is dried over sodium sulfate and evaporated under reduced pressure.

  The residue is crystallized from a mixture of tetrahydrofuran and diethyl ether and gives 4,4-dimethyl-5-thia-2,7-diaza-bicyclo [4.2.0] oct-2-en-8-one of the formula
EMI11.1
 which melts at 152-1530C; Thin-layer chromatogram (silica gel): Rf = 0.09 (system: toluene-acetone 8: 2) and Rf = 0.25 (system: toluene-acetone 6: 4); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.01, 3.49} 1,, 5.63 p, 6.07 +, 7.33 7.48, 8.52 hL, @, 9.27 p and 10 , 39.



   The starting material can be made as follows:
A slurry of 30 g of the potassium salt of 2,2-dimethyl-6- (N-phenylacetylamino) -penam-3-carboxylic acid in a mixture of 150 ml of anhydrous dimethylformamide and 12 ml of pyridine is under a nitrogen atmosphere at -15 "with 9 ml Trichloroacetyl chloride is added and the mixture is stirred for 15 minutes at -15 .. 6.5 g of solid sodium azide are added to the clear yellow solution and again stirred for 15 minutes at -15, then poured onto a mixture of 400 ml of toluene and 400 ml of ice water with stirring. The phases are separated, the aqueous solution is extracted in the cold twice with 250 ml of toluene each time The three organic solutions are washed twice with 250 ml of ice water each time, combined, dried over sodium sulfate and evaporated under reduced pressure.

  The residue contains the 2,2-dimethyl-6- (N-phenylacetyl-amino) -penam-3-carboxylic acid azide; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.02, 4.69 z, 5.60, 5.93, 6.70 and 8.54; Thin-layer chromatogram (silica gel): Rf = 0.49 (system: toluene / acetone 8: 2) and Rf = 0.69 (system: toluene / acetone 6: 4); which still contains solvent and converts into 3-isocyanato-2,2-dimethyl-6- (N-phenylacetyl-amino) -penam on further drying.



   24.3 g of the 2,2-dimethyl-6- (N-phenylacetyl-amino) -penam-3-carboxylic acid azide obtained as evaporation residue are dried at 200 for 24 hours under high vacuum. This gives 3-isocyanato-2,2-dimethyl-6- (N -phenylacetylamino) -penam as a light brown foam; Infrared spectrum (in methylene chloride): characteristic bands at 3.00 x, 4.44, 5.59 p, 5.93, 6.69 lt, 7.98 4 and 8.35 x; Thin-layer chromatogram (silica gel): Rf = 0.23 (system toluene / acetone 8: 2), and Rf = 0.52 (system toluene / acetone 6: 4).

  The 3-isocyanato-2,2-dimethyl-6- (N-phenylacetyl-amino) -penam is also obtained by heating a benzene solution of 2,2-dimethyl-6- (N-phenylacetyl-amino) -penam-3 for half an hour -carboxylic acid azides to 70 under a nitrogen atmosphere.



   A solution of 19.3 g of 3-isocyanato-2,2-dimethyl-6- (N- -phenylacetyl-amino) -penam in 200 ml of benzene is mixed with 14.1 ml of 2,2,2-trichloroethanol and the exotherm Reaction initiated by adding 0.9 ml of triethylamine; the temperature is kept at 20 by cooling.



  The mixture is left to stand for one hour at 20 and one hour at 0, the precipitate is filtered off and washed with 50 ml of a cold 1: 1 mixture of benzene and hexane and with hexane (room temperature). The 2,2-dimethyl-6- (N-phenylacetyl-amino) -3- (N-2,2,2-trichtorethoxycarbonyl-amino) - -penam thus obtained melts at 200-202 "(corr.); Thin-layer chromatogram (Silica gel) Rf = 0.35 (system toluene / acetone 8: 2), and Rf = 0.66 (system toluene / acetone 6: 4).



   A solution of 11.0 g of 2,2-dimethyl-6- (N-phenylacetylamino) -3- (N-2,2,2-trichloroethoxycarbonyl-amino) -penam in a mixture of 240 ml of anhydrous methylene chloride and 25.6 166 ml of a 10% solution of phosphorus pentachtoride in methylene chloride are added at 100 ml of pyridine under a nitrogen atmosphere and the mixture is then stirred at 0 for 30 minutes. Then 120 ml of absolute methanol are added with strong cooling (-100) and stirring is continued for 2 hours.

  80 ml of water are added, the pH value (measured in samples diluted with water) is adjusted with about 9 ml of a 2-n. aqueous sodium hydroxide solution to 3.3 and allowed to react for one hour at 0 and for a further hour at 200. It is then poured into 500 ml of a l-m while stirring. aqueous dipotassium hydrogen phosphate buffer solution and the pH value is adjusted from 6.5 to 7.0 by adding 50% aqueous tripotassium phosphate solution. The aqueous phase is separated off and washed twice with 200 ml of methylene chloride each time; the three organic solutions are each washed twice with water, combined, dried over sodium sulfate and evaporated under reduced pressure.

  The crystalline residue is taken up in 40 ml of a 1: 1 mixture of benzene and hexane; the mixture is during
Cooled at 0 for 15 minutes and filtered off the precipitate.

 

  6-Amino-2,2-dimethyl-3- (N-2,2,2-trichloroethoxycarbonyl-amino) -penam is obtained, which melts at 179-1800 (corr.); Infrared absorption spectra: characteristic bands (in methylene chloride) at 2.90 u, 5.58, 6.62, 7.17 p "7.27, 8.32 {, 8.46, 8.82, 9.25 and 9, 62 x; (in Nujol) at 2.95 tt. 3.01 s, 3.11, 5.64, u ,, 5.80, 6.35 e, 7.60 u, 7.87 z, 8, 00, 8.27, 8.65, 8.70, 9.16 and 9.57; thin layer chromatogram (silica gel):

  Rf = 0.17 (in the toluene / acetone system 8: 2) and Rf = 0.43 (in the toluene / acetone system 6: 4); characteristic yellow coloration with ninhydrin colidin (free amino group).



   Example 2
A solution of 0.26 g of 6-amino-3- (N-2-iodäthyloxycar- bonyl-amino) -2,2-dimethyl-penam in 5 ml of tetrahydrofuran is diluted with 15 ml of 90% aqueous acetic acid and cooled to zero and 2 g of zinc dust are added with vigorous stirring. The reaction mixture is stirred for a further 10 minutes at 0 and then filtered through a filter with an attachment of a diatomaceous earth preparation. The filter residue is suspended in tetrahydrofuran, filtered again and washed thoroughly with methylene chloride.

  The combined filtrates are evaporated under reduced pressure and at low temperature and the residue is taken to dryness several times with toluene under high vacuum to remove the acetic acid, then taken up in 80 ml of methylene chloride and 30 ml of a saturated aqueous sodium chloride solution and shaken well. The organic phase is separated off and washed with 40 ml of a 0.5 molar aqueous dipotassium hydrogen phosphate solution saturated with sodium chloride and 30 ml of a saturated aqueous sodium chloride solution.

  The aqueous solutions are washed twice with 70 ml of methylene chloride each time; the combined organic solutions are dried over magnesium sulfate and evaporated under reduced pressure. 0.085 g of the residue in methylene chloride is chromatographed on 5 g of silica gel (contains 7% water; column).



  The 3-isopropyl-4-thia-2,6-diazabicyclo [3.2.0] heptan-7-one, m.p. 151-155 after recrystallization from a mixture of methylene chloride and hexane, is with methylene chloride containing about 10 % to about 20% methyl acetate, eluted. The 4,4-dimethyl-5-thia-2,7-diaza-cyclo [4.2.0] oct-2-en-8-one also formed, mp 152-153 after crystallization from a mixture of tetrahydrofuran and Diethyl ether is washed out with methylene chloride containing about 50% methyl acetate.



   The starting material can be made as follows:
The yellow solution of 23 g of crude 3-isocyanato-2,2-dimethyl-6- (N-phenylacetyl) prepared by heating 2,2-dimethyl-6- (N-phenylacetyl-amino) -penam-3-carboxylic acid azide -amino) -penam in 230 ml of benzene is mixed with 4.9 ml of 2-bromoethanol and 0.1 ml of bis-tri-n-butyltin oxide and left to stand for 2 hours at room temperature, then evaporated. The residue is taken up in methylene chloride and chromatographed on 350 g of silica gel (column). The 3- (N-2-bromoethyloxycarbonyl-amino) -2,2-dimethyl-6- (N-phenylacetyl-amino) -penam is eluted with a 9: 1 mixture of methylene chloride and ethyl acetate.



  After recrystallization from a mixture of methylene chloride and cyclohexane or acetone and cyclohexane, the product melts at 149-150; [oc] D20 = + ggo + 1 (c = 1.008 in chloroform); Thin-layer chromatogram (silica gel): Rf = 0.51 (system toluene / ethyl acetate 1: 1), Rf = 0.32 (system toluene / acetone 4: 1) and Rf = 0.71 (system toluene / acetone 1: 1); Ultraviolet absorption spectrum (in ethanol): #max 252 m (# = 300), 258 m (# = 270) and 265 m (# = 180);

  Infrared absorption spectrum: characteristic bands at 2.91, 5.58, 5.77, 5.94, 6.62 (shoulder), 6.66, 8.21, 8.30, 8.48, 9.32 and 9, 64 (in methylene chloride) and at 2.93, 2.95, 3.01, 5.62, 5.79, 5.82 (shoulder), 5.91, 5.98, 6.53, 6.57, 6.68 and 7.36 (in mineral oil).



   A solution of 6.9 g of sodium iodide in 34.5 ml of purified acetone is poured over 5.265 g of 3- (N-2-bromoethyloxycarbonyl-amino) -2,2-dimethyl-6- (N-phenylacetyl-amino) penam and let stand for 16 hours at 30; After a few minutes, a dense precipitate of sodium bromide begins to precipitate. After the reaction has ended, the solvent is evaporated off under reduced pressure and the residue is taken up in 30 ml of water and 70 ml of ethyl acetate.

  The golden yellow organic phase becomes 0.1-n after adding a few drops. shaken aqueous sodium thiosulphate solution; the aqueous phase is separated off and washed twice with 50 ml of ethyl acetate each time. The combined organic solutions are washed twice with water each time and dried over magnesium sulfate and concentrated to a volume of 20-30 ml.

  It is diluted with 50 ml of methylene chloride and treated with 200 ml of hot cyclohexane, the mixture is cooled to room temperature and then left to stand at 4 for one hour. The colorless needles are filtered off and washed with a 4: 1 mixture of cyclohexane and ether.

  The 3- (N-2-Jodäthyloxycarbonyl-amino) -2,2-dimethyl-6- (N-phenylacetyl-amino) -penam is obtained, which after crystallization from ethyl acetate and cyclohexane melts at 153-154; [α] 20 D = +89 + 1 (c = 1.011 in chloroform); Thin-layer chromatogram (silica gel):

  Rf = 0.56 (toluene / ethyl acetate system 1: 1), Rf = 0.35 (toluene / acetone system 4: 1) and Rf = 0.74 (toluene / acetone 1: 1 system); Ultraviolet Absorption Spectrum (in ethanol): #max 252 m (# = 815), 258 m (# = 775), 264 m (# = 600) and 335 m (# = 45); Infrared absorption spectrum: characteristic bands at 2.90, 5.58, 5.76, 5.93, 6.63, 6.85, 8.18, 8.34, 8.47 and 9.37 (in methylene chloride) and at 2.97, (shoulder), 3.03, 5.62, 5.87, 6.58, 6.59, 6.67, 7.65, 8.01, 9.67 and 13.92 (in mineral oil ).



   A solution of 5.03 g of 3- (N-2-Jodäthyloxycarbonyl-amino) -2,2-dimethyl-6- (N-phenylacetyl-amino) -penam in 105 ml of absolute methylene chloride and 11 ml of absolute pyridine is under a nitrogen atmosphere Cooled to about -10 and mixed with 91 ml of a solid solution of phosphorus pentachloride in absolute methylene chloride.

  The reaction mixture is stirred for 30 minutes at 0, then cooled again to 10 and treated with 50 ml of absolute ethanol. After 105 minutes at 0 the reaction mixture is diluted with 36 ml of water, the pH of the two-phase solution by adding about 12 ml of a 2-n.



  aqueous sodium hydroxide solution from 2.1 to 3.3 and stirred for 30 minutes at 0, then for 45 minutes at room temperature. The reaction mixture is poured into 120 ml of an imolar aqueous dipotassium phosphate solution and the pH is adjusted to 7.0 by adding 50% aqueous tripotassium phosphate solution. The organic phase is separated off and washed twice with 40 ml of a saturated aqueous sodium chloride solution each time.



  The aqueous solutions are back-extracted twice with 100 ml of methylene chloride each time and the combined organic solutions are dried over anhydrous magnesium sulfate, evaporated under reduced pressure and gentle conditions (low temperature) and the residue is briefly dried under reduced pressure.



   The amorphous, honey-like colored residue in methylene chloride is chromatographed on 100 g of silica gel (column), with non-polar by-products being washed out with methylene chloride and methylene chloride containing 3% methyl acetate.

  The 6-amino-3- (N-2-iodäthyloxycarbonyl- aminio) -2,2-dimethyl-penam is eluted with methylene chloride containing 5-20% methyl acetate and, after repeated chromatography, melts at 131-134; [α] 20 D = +86 # 1 (c = 0.974 in chloroform); Thin-layer chromatography: Rf = 0.18 (system 1: 1 mixture toluene: liquefied-> BR <acid ethyl ester), Rf = 0.30 (system 4: 1 mixture chloro form:

  Acetone) and Rf = 0.58 (system 1: 1 mixture toluene: acetone); Infrared absorption spectrum: characteristic bands in methylene chloride at 2.90 u, 5.60, 5.77 u, 6.18 {, 6.64, 6.85, 8.17 a, 8.34 a, 8.47 u, 9 , 25 p, 9.37 and 9.66, and in mineral oil at 2.89, 5.71, 5.79, 6.50, 7.61, 8.04, 8.39, 9.18, 9, 27, 10.65 and 11.54,
The 4,4-dimethyl-5-thia-2,7-diazacyclo [4,2.0] oct-2-en-8-one obtainable according to the invention can e.g. processed as follows.



   Example 3
0.051 g of 4,4-dimethyl-5-thia-2.7-diazabicyclo [4.2.0] oct-2-en-8-one and 0.1 g of zinc dust are in a mixture of 0.5 ml of water, 1 ml of acetone and 0.2 ml of glacial acetic acid were added and shaken at 22 for one hour. After filtering, the solution is between 20 ml of ethyl acetate and 10 ml of l-m. aqueous dipotassium hydrogen phosphate solution distributed; the aqueous phase is extracted with 20 ml of ethyl acetate.

  The combined organic solutions are l-m with 10 ml. washed aqueous dipotassium hydrogen phosphate solution and dried over sodium sulfate and evaporated; so that 3-isopropyl-4-thia-2,6-diazabicyclo [3.2.0] heptan-7-one, the It. thin-layer chromatogram (silica gel; systems toluene / acetone 6: 4 and 8: 2) is uniform and, after recrystallization from a mixture of methylene chloride and hexane, melts at 151-155; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.98, 3.32, 3.40 u, 5.65 R ", 7.07 y, 8.90, 10.51 l and 11.17 q.



   A solution of 1.64 g of 3-isopropyl-4-thia-2,6-diazabicyclo [3.2.0] heptan-7-one in 33 ml of a 1: 1 mixture of acetic acid and water is made within 10 minutes with 71.7 ml of a 0.5 n. Solution of iodine in ethanol are added, the mixture is left to stand at room temperature for one hour and then concentrated under reduced pressure. The residue, dried under a high vacuum, is suspended in 90 ml of acetonitrile, and 4.5 ml of pyridine and 4.5 ml of phenylacetic acid chloride are added at 0. It is left to stand for 15 minutes at 0 and for one hour at room temperature and then evaporated under reduced pressure.

  It is triturated for 30 minutes with 10 ml of a 1: 1 mixture of dioxane and water and the residue is taken up in ethyl acetate; the solution is washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried and evaporated.

  The oily residue is chromatographed on 100 g of pure silica gel; the oily bis- [2-oxo-3lS- (N-phenylacetyl-amino) -azetidin-4ss-yl] -disulfide is eluted with a 19: mixture of ethyl acetate and acetone and converted into a finely powdered amorphous form by lyophilization; Thin-layer chromatogram (silica gel): Rf ¯ 0.36 (system: ethyl acetate / acetone 1: 1); Infrared absorption spectrum (in potassium bromide): characteristic bands at 3.08 u, 5.62 a, 5.97 and 6.51.



   A solution of 0.35 g of bis [2-oxo-3ss- (N-phenylacetyl-amino) -48-azetidinyl disuffles in 16 ml of a 9: 1 mixture of acetic acid and water is mixed at about 5 with about 3.2 g of ethylene oxide, then mixed with 3.5 g zinc dust. The reaction mixture is stirred for 15 minutes at about 5 and for 30 minutes at room temperature, then filtered. The filter residue is washed with acetone and the filtrate is evaporated. The residue is taken up in about 150 ml of ethyl acetate and the solution is washed with 50 ml of a saturated aqueous sodium hydrogen carbonate solution and with 100 ml of a saturated aqueous sodium chloride solution, dried and evaporated.

  The residue is chromatographed on 50 g of silica gel together with a crude product obtained in an analogous manner from 0.58 g of bis (2- -oxo-3ss- (N-phenylacetyl-amino) -4ss-azetidinyl] disulfide a 19: 1 mixture of 4p- (2-Hydroxyäthyl- mercapto) -3ss- (N-phenylacetyl-amino) -azetidin-2-one as a uniform product, which after crystallization from a mixture of acetone and diethyl ether at 141-142 Melts; [α] D20 = +44 # 2 (c = 0.571 in ethanol); thin layer chromatography (silica gel; developing with iodine); Rf 0.45 (system:

  Ethyl acetate / acetone 1: 1); Infrared absorption spectrum (in mineral oil): characteristic bands at 3.01 (, 5.68, 6.01, 6.43 and 6.52.



   A solution of 0.61 g of 4p- (2-Hydroxyäthylmercapto) -3p- - (N-phenylacetyl-amino) -azetidin-2-one in 10 ml of tetrahydrofuran is added dropwise at 0 with 1.38 g of chloroformic acid -2.2, 2-trichloroethyl ester in 5 ml of tetrahydrofuran, then mixed with 1.06 g of pyridine in 5 ml of tetrahydrofuran. The reaction mixture is stirred under a nitrogen atmosphere for 15 minutes at 0 and for 2 hours at room temperature, then taken up in 150 ml of methylene chloride. It is washed with a saturated aqueous sodium chloride solution, dried and evaporated.

  The residue is chromatographed on 50 times the amount of silica gel; the 3ss- (N-phenylacetyl-amino) -4ss- [2- (2,2,2-trichloroethoxycarbonyl) -ethylmercapto] -azedizin-2-one is eluted with a 1: 1 mixture of methylene chloride and ethyl acetate.

  After crystallization and single recrystallization from diethyl ether, the product is obtained in the form of colorless needles, mp 99-1010; Thin-layer chromatogram (silica gel): Rf ¯ 0.46 (system: ethyl acetate; development with iodine); [α] 20 D = +3 # 2 (c = 0.518 in chloroform);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.88, 5.58, 5.64, 5.9211 and 6.6211
A mixture of 1.0 g of 3ss- (N-phenylacetyl-amino) -4ss- - [2- (2,2,2-trichloräthoxycarbonyloxy) -äthylmercapto] -azeditin -2-one and 3.0 g of glyoxy acid tert. Butyl ester hydrate in 50 ml of benzene is refluxed for 16 hours with separation of water, then cooled and washed twice with 25 ml of distilled water each time, dried over sodium sulfate and evaporated.

  The α-hydroxy-a-(2-oxo-3 B- (N-phenylacetyl-amino) -4p- [2- (2,2,2-trichloro-ethoxycarbonyloxy) -ethylmercapto] -1- is obtained in this way. azetidinyl} -acetic acid tert-butyl ester, which is further processed without purification.



   The crude α-hydroxy-α- (2-oxo-3ss- (N-phenylacetyl-amino) -4ss- [2- (2,2,2- -trichloroethoxycarbonyloxy) -ethylmercapto] -1 obtainable by the above process -azetidinyl} -acetic acid tert-butyl ester is dissolved in 20 ml of a 1: 1 mixture of dioxane and tetrahydrofuran and at -10 dropwise with 0.54 ml of pyridine in 2 ml of dioxane and 0.48 ml of thionyl chloride in 10 ml of a 1: 1 mixture of dioxane and tetrahydrofuran was added.

  The reaction mixture is stirred for 30 minutes at 100 to -5 and for one hour under a nitrogen atmosphere, the precipitate is filtered off and the filtrate is treated with the? -Chloro-? - {2- -oxo-3sss- (N-phenylacetyl-amino ) -4ss-t2- (2,2,2-trichlorethoxy-carbonyloxy) -ethylmercapto] -azetidinyl} -acetic acid tert-butyl ester evaporated; the product is processed further in its raw state.

 

   A solution of the crude α-chloro-α - {2-oxo-3ss- (N-phenylacetyl-amino) -4ss- [2- (2,2,2-trichoroethoxycarbonyloxy) -ethylmercapto] obtainable by the above process -1-azetidi nyl) -acetic acid tert-butyl ester in 30 ml of a 1: 1 mixture of dioxane and tetrahydrofuran is mixed with 1.15 g of triphenylphosphine and 0.35 ml of pyridine and heated for 2 hours at 50, then to Evaporated to dryness.

  The residue is chromatographed on 30 g of pure silica gel, using a 1: 1 mixture of toluene and ethyl acetate to obtain the α - {2-oxo-3ss- (N-phenylacetylamino) -4ss - [2- (2, 2,2-trichlorethoxycarbonyloxy) -äthylmeracapto] -1-azeti dinyl} -α-triphenylphosphoranylidene-acetic acid tert-butyl ester eluted, which is contaminated with a little triphenylphosphine oxide and can be purified by means of preparative thin-layer chromatography (silica gel; development with iodine) Rf ¯ 0.57 (system: toluene / acetone 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00, 3.42 y, 5.68 a, 5.97, 6.10 L and 6.65 4 ,.



   A mixture of 0.225 g of α - {2-oxo-3ss- (N-phenylacetylamino) -4ss- [2,2,2-trichloroethoxycarbonyloxy) ethyl mercapto] -1-acetidinyl} -a-triphenylphospheranylidene-acetic acid-tert .- butyl ester in 10 ml of a 9: 1 mixture of acetic acid and water is mixed with 3.0 g of zinc dust and stirred for 45 minutes at 15. It is filtered and the filtrate is evaporated; the residue is taken up in 50 ml of ethyl acetate and the solution is washed with 25 ml of a saturated aqueous sodium hydrogen carbonate solution and twice with 25 ml each of a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated.

  The α- [4ss- (2-hydroxyethylmercapto) -2-oxo-3ss- (N- -phenylacetyl-amino) -1-azetidinyl] -α-triphenylphosphoranyldene-acetic acid tert-butyl ester is obtained in this way; Thin-layer chromatogram (silica gel; development with iodine): Rf ¯ 0.24 (system: toluene / acetone 1: 1).



   A mixture of 0.221 g of the crude α- [4ss- (2-hydroxy-ethylmercapto) -2-oxo-3ss- (N-phenylacetylamino) -1-azetidinyl] a-triphenylphosphoranylidene-acetic acid tert-butyl ester in 5 ml Dimethyl sulfoxide and 5 ml of acetic anhydride are left to stand for 16 hours at room temperature and then concentrated under reduced pressure. The residue is taken up in 100 ml of toluene; the organic solution is washed three times with 50 ml of distilled water each time, dried over sodium sulfate and evaporated.

  The oily residue is chromatographed on 10 g of silica gel: the desired tert-butyl 7- (N-phenylacetylamino) -ceph-3-em-4-carboxylate, which is obtained by ring closure from the unisolated α- [ 4ss-Formylmethylmer-capto-2-oxo-3ss- (N-phenylacetyl-amino) -1-azetidinyl] -α-triphenylphosphoranylidene acetic acid tert-butyl ester is formed with a 4: 1 mixture of toluene and ethyl acetate eluted; Thin-layer chromatogram (silica gel): Rf ¯ 0.48 (system:

  Toluene / ethyl acetate 1: 1); Ultraviolet absorption spectrum (in pure ethanol): #max 258 my; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00, 3.48, 5.62'L, 5.81 y, 5.93, 6.10, 6.67, 7.15, 7.31 1 7, 70, 8.6515 and 9.03,
A mixture of 0.03 g of 7- (N-phenylacetyl-amino) -ceph -3-em-4-carboxylic acid tert-butyl ester and 0.5 ml of trifluoroacetic acid is left to stand at room temperature for one hour. The trifluoroacetic acid is then removed under reduced pressure and the residue is taken to dryness twice with 5 ml each of a mixture of benzene and chloroform.

  The residue is chromatographed on 5 g of silica gel and the 7- (N-phenylacetyl-amino) -ceph-3-em-4-carboxylic acid is eluted with methylene chloride containing 5% acetone; Thin-layer chromatogram (silica gel: development with iodine) Rf ¯ 0.49 (system: n-butanol / pyridine / acetic acid / water 40: 24: 6: 30).

 

Claims (1)

PATENT CLAIM Process for the preparation of 4,4-dimethyl-5-thia-2,7-diazabicyclo [4.2.0] oct-2-en-8-one of the formula EMI14.1 characterized in that there is a penam compound of the formula EMI14.2 wherein the group -NH-C (= O) -Xt represents an esterified hydroxycarbonylamito group which can be cleaved off on treatment with a reducing agent under neutral or acidic conditions, wherein X1 represents a group -O-Ros or -O-Rob, wherein ROa is a 2 -Hallo-lower alkyl radical and Rob represents an optionally substituted arylcarbonylmethyl group, and Ro represents hydrogen or an acyl radical Aco of an organic acid which can be split off under the conditions of the process, a reducing agent, treated under neutral or acidic conditions and simultaneously or subsequently with at least an equimolar amount of water. SUBCLAIMS 1. The method according to claim, characterized in that an acyl group Aco in the starting material of the formula II is a group of the formula -C (= O) -Xt, in which X has the meaning given in the claim. 2. The method according to claim, characterized in that Ro is hydrogen. 3. The method according to claim or dependent claim 1 or 2, characterized in that RO represents the 2,2,2-trichloroethyl or 2-iodoethyl radical 4. The method according to claim or dependent claim 1 or 2, characterized in that Rob is a phenacyl radical substituted in the aromatic part or in the methyl part. 5. The method according to claim or dependent claim 1 or 2, characterized in that Rob is the unsubstituted phenacyl radical. Process according to claim, characterized in that reducing metals or metal compounds are used as reducing agents. 7. The method according to claim, characterized in that zinc, zinc alloys or zinc amalgam, in the presence of acids, acidic agents or alcohols, in particular zinc and acetic acid, with the addition of water, is used as the reducing agent. 8. The method according to claim, characterized in that alkali metal amalgams or aluminum amalgams, preferably in the presence of moist solvents, are used as reducing agents. 9. The method according to claim, characterized in that one uses chromium (II) compounds, such as chromium (II) chloride or chromium (II) acetate, in the presence of aqueous media as reducing agents. Process according to claim, characterized in that the 4,4-dimethyl-5-thia-2,7-diazabicyclo [4,2,0] oct-2- -en-8-one formed from 3-isopropyl-4- thia-2,6-diazabicyclo- [3,2,01heptan-7-one separated by means of fractional crystallization or by means of adsorption chromatography. 11. The method according to claim, characterized in that starting materials are used in the form of raw reaction mixtures obtainable under the reaction conditions.