CH554895A - 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 thiadiazabicycloalkene compound, namely 4,4-dimethyl-5-thia-2, 7-diazabicyclo [4.2. ()] Oct-2-en-8 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 easily split off under acidic conditions, in which X1 is a group of the formula -O-ROd in which R ,, d is a methyl group which is released by an electron donor , Carbocyclic aryl group having substituents or by one having oxygen or sulfur atoms as ring members,

   heterocyclic group of aromatic character is monosubstituted, or then in an oxa or thiacycloaliphatic radical which represents the a position to the oxygen or sulfur atom and R represents hydrogen or an acyl radical Ac "of an organic acid which can be split off under the conditions of the process, with cleavage of the 5-membered ring, rearrangement and ring closure to the 6-membered nitrogen and sulfur-containing ring and simultaneous cleavage of the group -NH-C (= O) -X1 treated with an acidic agent.



   An acylamino group Ac -NH- which can be cleaved under the reaction conditions is in particular a group of the form -NH-C (= O) -O-R, d, in which ROd has the meanings given below, but can also represent any other acylamino group which can be cleaved under the reaction conditions.



   The cleavage of the -NH-C (= O) -X group depends on the nature of this group. 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, form esterified carboxyl groups which can be easily cleaved under acidic conditions.



   A group X1 represents the remainder of the Formef-O-ROd which, together with the carbonyl grouping, forms an esterified carboxyl group which can easily be cleaved under acidic conditions. Such a radical ROd is primarily a methyl group, which is monosubstituted by a carbocyclic aryl group having electron-donating substituents or by a heterocyclic group of aromatic character having oxygen or sulfur atoms as ring members, or then in an oxa- or thiacycloaliphatic group The remainder is the ring member representing the a-position to the oxygen or sulfur atom.



   A carbocyclic aryl group containing electron-donating substituents in the aryl radical is a bi- or polycyclic, in particular monocyclic, aryl, e.g. B. naphthyl and primarily phenyl. Electron-donating substituents, which are preferably in the p- and / or o-position of the aryl radical, are, for. B. free or preferably functionally modified, such as esterified and primarily etherified hydroxyl groups, such as lower alkoxy, e.g. Methoxy-. also ethoxy or isopropyloxy groups. as well as corresponding free or functionally modified mercapto groups, and also aliphatic groups. cycloaliphatic, aromatic or araliphatic, optionally suitably substituted hydrocarbon radicals, in particular lower alkyl, e.g. B. methyl or tert. Butyl groups, or aryl, e.g. B. phenyl groups.



   A heterocyclic group of aromatic character containing oxygen or sulfur atoms as ring members can be bi- or polycyclic, but is primarily monocyclic and is primarily a furyl, e.g. B. 2-furyl radical. or a thienyl, e.g. 2-thienyl radical.



   An oxa and thiacycloaliphatic radical linked in the a position is primarily a 2-oxa or 2-thiacycloalkyl and 2-oxa or 1-thiacycloalkenyl group in which the methyl group ROd is the one adjacent to the ring oxygen or ring sulfur atom, with the oxygen atom of the group of the formula -OR, d represents linked ring member, and which preferably contains W6 ring carbon atoms, primarily a 2-tetrahydrofuryl, 2-tetrahydropyranyl or 2,3 dihydro-2-pyranyl radical or a corresponding sulfur analog.



   Preferred radicals Rnd are 4-methoxybenzyl and 3.4 dimethoxybenzyl radicals, as well as 2-tetrahydrofuryl, 7-tetrahydropyranyl or 2,3-dihydro-2-pyranyl groups.



   In a starting material of the formula 1, in which X1 is a group of the formula -OR, d, the grouping of the formula -C (= O) -O-ROd can be obtained by treating with an acidic agent, in particular with an acid such as a strong organic Carboxylic acid, e.g. an optionally substituted lower alkanecarboxylic acid, preferably containing halogen atoms, such as acetic acid or trifluoroacetic acid, furthermore with formic acid or a strong organic sulfonic acid, e.g. p-toluenesulfonic acid.



  Usually, an excess of an acidic reagent which is liquid under the reaction conditions is used as a diluent and the reaction is carried out at room temperature or with cooling, e.g. B. to about - 20 "C to about + 10.



   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 by known separation methods, e.g. isolated by fractional crystallization, adsorption chromatography (column or thin layer chromatography) or other suitable separation processes and 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 embodiments according to which compounds obtained as 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, for. B. be prepared by adding a penam-3-carboxylic acid compound purple with the formula
EMI2.1
 in which Aca represents the acyl radical of an organic carboxylic acid, in which free functional groups such as hydroxyl, mercapto and, in particular, amino and carboxyl groups, optionally, e.g.

  B. are protected by acyl groups or in the form of ester groups, and Ro stands for a carboxyl group -C (= O) -OH (compound purple), or a salt thereof into the corresponding acid azide compound with the formula III, where Ro is the azidocarbonyl radical C ( = O) -N3 (compound IIlb), converts 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), and converts it simultaneously or subsequently with a compound the formula H-X1 (IV) treated,

   and in a compound obtained, an acyl radical Aca which cannot be split off 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 individual isomers separates.



   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 one in naturally occurring or biosynthetically produced N-acyl derivatives of 6-aminopenam-3-carboxylic acid or 6-amino-ceph - Acyl radical containing 3-emcarboxylic acid compounds, such as a monocyclic arylacetyl or aryloxyacetyl, also an optionally substituted lower alkanoyl or lower alkenoyl, eg the 4-hydroxy-phenylacetyl, hexanoyl, octanoyl, 3-hexenoyl, 5-amino-5-carboxy-valeroyl, n-butyl mercapto-acetyl or allyl mercapto-acetyl, in particular the phenylacetyl or phenyloxy-acetyl radical, or preferably one under acidic conditions, easily cleavable acyl residue,

   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. B. by treating with trifluoroacetic acid, easily cleavable lower alkoxycarbonyl, z. B. tert-Butyloxycarbonyl- or tert-Pentyloxycarbonylrest, Cycloalkoxycarbonyl-, z. B. Adamantyloxycarbonylrest, Phenyl-lower alkoxycarbonyl, z. B. Diphenylmethoxycarbonyl, and a-4-biphenylyl-ot-methyl-ethoxycarbonyl, or furyl-lower alkoxycarbonyl, z. B. furfuryloxycarbonyl radical.



   The conversion of an acid compound IIIa or a suitable salt, especially an ammonium salt, into the corresponding acid azide IIIb can e.g. by converting into a mixed anhydride (for example by treating with a haloformic acid lower alkyl ester, 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. . B. benzyltrimethylammonium azide.

  The acid azide compound IIIb thus obtainable can be used in the presence 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 formula IV, i. H. with an alcohol of the formula R0dOH, e.g. B. 4-methoxybenzyl alcohol, is optionally in an inert solvent, e.g. B. in a halogenated hydrocarbon such as carbon tetrachloride, chloroform or methylene chloride, or in an aromatic solvent such as benzene, toluene or chlorobenzene, preferably carried out with heating.



   Protected functional groups in the acyl radical Aca can, if desired, in a conventional manner, e.g. hydrolytically, reductively or by treatment with acid. Furthermore, an acyl radical Ac can be cleaved in a manner known per se, e.g. B. by treatment with a suitable halogenating agent such as phosphorus pentachloride, reacting the imide chloride with an alcohol such as lower alkanol and cleaving the imino ether, preferably under acidic conditions. The acyl radical of a suitable half ester of carbonic acid, such as a carbo-lower alkoxy which can be cleaved under acidic conditions, e.g. B. the carbo-tert-butyloxy, as well as carbo-tert.pentyloxy, carbo-adamantyloxy 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.



   In addition, in starting materials of the formula II in which R "denotes 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, incl.



  mixed, especially with haloformic acid esters, e.g. B.



  Ethyl chloroformate, producible anhydrides, 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. B. 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 R "is a halocarbonyl group, with a suitable alcohol, for example an optionally substituted lower alkanol, such as tert .-Butanol, 2,2,2-trichloroethanol, or phenacyl alcohol.

 

   The compound of formula I is a valuable intermediate that can be easily converted into starting materials that are particularly useful for the preparation of pharmacologically valuable compounds, e.g. B. of the 7-N-acylamino cephalosporanic acid type, with effects against microorganisms, such as gram-positive and gram-negative bacteria, can be transferred.



   Thus, the compound of the formula I can be converted into the 3-isopropyl-4-thia-2,6diazabicyclo [3.2.0] heptan-7-one of the formula by reducing the -N = CH double bond
EMI3.1
   wherein R, stands for hydrogen. convert, and in this the hydrogen R, through an acyl radical Ac. primarily an acyl radical Ac 'which can be easily split off, especially under acidic conditions. -ie the tert-butyloxycarbonyl radical.

   If you replace a compound of the formula IV, wherein R, an acyl radical Ac. in particular represents an acyl radical Ac ', usually in the absence of a condensing agent, with a 3,3-diformyl-acrylic acid-R2A ester of the formula
EMI3.2
 wherein R 'represents an organic radical which, together with the carboxyl group, forms an easily cleavable esterified carboxyl group. or a tautomer thereof and treats a obtained 2- (2-Ac-3-isopropyl-7-oxo-2,6diaza-4-thia-6-bicyclo [3.2.0] heptyl-3,3-diformyl-propionic acid- R2A ester of the formula
EMI3.3
 with an acidic agent, a 7-amino-3-formyl-ceph-2-em-4-carboxylic acid RA2 ester of the formula is obtained
EMI3.4
 This can e.g.

  B. according to the Austrian patent no.



  264 537 method described. can be converted into 7-amino-cephalosporic acid and its N-acyl derivatives.



   In a compound of the formula the -N = CH double bond becomes through exhaustive reduction. z. By treating with an excess of a chemical reducing agent such as a reducing metal. or a reducing metal compound. z. B. metal alloy or amalgam, preferably a presence of a hydrogen donating agent such as one of the reducing agents described above. especially zinc in the presence of acetic acid, preferably aqueous acetic acid. reduced.



   A hydrogen atom R in a compound of the formula IV is used in a manner known per se, for. B. after the acylation reaction described above. replaced by an acyl group Ac.



  A tert-butyloxycarhonyl group can e.g. B. by treatment with fluoroformic acid tert-butyl ester. or then by treating with phosgene and reacting a compound of the formula IV. in which R 1 represents the chlorocarbonyl group. be introduced 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. R3 stands in particular for one of the radicals Roa, R (, b, Roc, Rz, d and R0 with the meanings given above, in particular for the 2,2,2-trichloroethyl, 2-iodoethyl, phenacyl or tert. -Butyl group, also for one with the carboxyl group a hydrolic group.



  optionally under weakly acidic or weakly basic conditions, easily cleavable esterified carboxyl group-forming organic radical red, such as a hydrocarbon radical, in particular aliphatic, aromatic or araliphatic hydrocarbon radical, substituted by electron-withdrawing groups, where electron-withdrawing groups e.g. Nitro groups, optionally functionally modified carboxyl or sulfo groups, such as cyano or sulfamoyl groups, halogen atoms or acylamino groups. such as

  B. the 4-nitrophenyl, 2,4-dinitrophenyl. 4-nitrobenzyl-. 2.5.6 Trichlorophenyl, 2,3,4,5,6-pentachlorophenyl, phthaliminomethyl or succinimomethyl group. or for an organic radical Rog which together with the carboxyl group forms an esterified carboxyl group which can be cleaved under physiological conditions, such as an acyloxy group. z. B. a lower alkanoyloxy, especially acetyloxy, substituted methyl radical.



   The reaction of a compound of the formula IV, in which R1 is an acyl radical Ac, in particular an acyl radical Ac 'which can easily be split off under acidic conditions, with a diformyl acrylic acid R2 ester of the formula V is carried out in a manner known per se, e.g. B. by heating the reaction mixture to temperatures at which decomposition of the olefin of the formula V. also occurs in hydrated form, d. H. as 3,3-diformyl lactic acid RA ester of the formula
EMI3.5
 can be used and loses water under the reaction conditions is largely avoided, d. H. at about 50 to about 120 ° C., usually in the presence of a solvent such as a suitable, optionally halogenated, aliphatic or aromatic hydrocarbon, e.g.

  B. n-octane or xylene, or a suitable ether, e.g. 13.



  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 5-membered ring and the ring closure to the 6-membered sulfur-nitrogen 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 oxygen-containing acids are e.g. Sulfuric acid, phosphoric acid or perchloric acid, while strong organic oxygen-containing 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, d. H. 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 (certain acidic agents, such as trifluoroacetic acid, can also serve as solvents). under cooling. at room temperature or with warming, if necessary, in a nitrogen atmosphere and / or in a closed vessel.



   In this case, an acyl group Ac 'which can easily be split off under acidic conditions, e.g. B. the tert-butyloxycarbonyl radical, usually also split off under the reaction conditions.



   In contrast to the known. 2-R <-4-thia-2, 6-diazabicyclo [3.2, ()] heptan-7-one compounds, the carbon atom of which is in the 4 position, for example, in the above reaction sequence for the preparation of compounds of the formula VII. B. by lower alkyl, especially methyl groups.



   Is disubstituted, the compounds of the formula I can be obtained in a simple manner from readily available starting materials of the 6-N
Acylamino-penicillanic acid series produce, whereby the synthetic access to compounds of the 7-N-acylaminocephalosporanic acid type is significantly simplified.



   A compound of the formula IV, where R1 is 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 formula IV is oxidized. Wherein R <for
Hydrogen is, with a mercaptan disulfide oxidizing agent, so you get. possibly after treatment with
Water, to a disulfide compound of the formula
EMI4.1
 wherein R, a and R, b represent hydrogen or together represent a 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, a 1-isobutylidene group formed by the radicals R, a and R, b, optionally in modified form, being split off simultaneously or subsequently.

  A compound of the formula VIII obtainable in this way, wherein R, a is a
Acyl radical Ac and R, b represents hydrogen, is reacted with ethylene oxide with simultaneous treatment with a reducing agent, and thus a compound of
formula
EMI4.2
 in which the primary hydroxyl group is converted into a hydroxyl group esterified by the acyl radical of the formula -C (= O) -X2. Here, X stands for an etherified hydroxyl or mercapto group which, together with the carboxyl group, forms an esterified carboxyl group which can be cleaved under mild conditions.

 

   The thus obtainable compound of the formula
EMI4.3
 is made with a compound of the formula
EMI4.4
 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
EMI4.5
 the secondary hydroxyl group is converted into a reactive esterified hydroxyl group.

  The reactive ester of the formula
EMI4.6
 wherein Z is a reactive esterified hydroxyl group, primarily a halogen, in particular chlorine or bromine atom, and an organic sulfonyloxy. e.g. 4-Methylphe nylsulfonyloxy- or Methylsulfonyloxygruppe, is set with a phosphine compound of the formula
EMI5.1
 wherein each of the radicals Ra, Rb and Rc is an optionally substituted hydrocarbon radical, and thus, if necessary, after cleavage of the elements of an acid, obtains the
Formula H-Z (XVb) from one available as an intermediate
Phosphonium salt compound of the formula
EMI5.2
 the phosphoranylidene compound of the formula
EMI5.3
 in which the esterified carboxyl group -C (= O) -x2 is cleaved.

  Is oxidized in such a obtainable compound of the formula
EMI5.4
 the carbinol group of the formula XH2 {) H to a formyl group of the formula -CHO is obtained, with simultaneous ring closure, an aldehyde compound of the formula formed as an intermediate product
EMI5.5
 the ceph-3-em compounds of the formula
EMI6.1
 where R 1 stands for an acyl radical Ac and R2 represents the organic radical R20r of an alcohol, where. if wanted.

   the acyl groupAc 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-R2n 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-R2, and / or a compound obtained with a salt-forming group in a salt or a salt obtained in the free compound or in another salt converted and / or an isomer mixture obtained can be separated into the individual isomers.



   The compounds of the formula XVIII have valuable pharmacological properties or can be used as intermediates for the preparation of such.



  Compounds of the formula XVIII, wherein R <is an acyl radical occurring in pharmacologically active N-acyl derivatives of 6-amino penam-3-carboxylic acid or 7-aminoceph-3-em-4-carboxylic acid compounds and R2 is hydrogen or a physiological one Conditions easily split off organic residue of an alcohol 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. B. in dilutions up to 0.0001 y / ml, and against gram-negative bacteria, e.g. B.



  Escherichia coli, effective.



   An acyl radical contained in pharmacologically active N-acyl derivatives of 6-aminopenicillanic acid or 7-aminocephalosporanic acid is primarily 2,6-dimethoxybenzoyl, tetrahydronaphthoyl, 2-methoxynaphthoyl, 2 ethoxynaphthoyl, cyclopentylcarbonyl , n-Amino cyclopentylcarbonyl or z-Amino cyclohexyl carbonyl (optionally with substituted amino, z.

  B. 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 -Dichlorphenyl) -5-methyl-4isoxazolylcarbonyl-, phenylacetyl-, phenacylcarbonyl-, phenyloxyacetyl-, phenylthioacetyl-, bromophenylthioacetyl-, 2-phenyloxypropionyl-, a-phenyloxy-phenylacetyl-, phenyloxy-phenylacetyl-, a-methoxyphenylethyl-, -Methoxy-3, 4dichlorophenylacetyl-, a-cyano-phenylacetyl-, phenylglycyl (optionally with substituted amino, such as one.

   optionally present in salt form, sulfoamino group), benzylthioacetyl, benzylthiopropionyl, α-carboxyphenylacetyl (optionally with functionally modified, e.g. present in salt form, carboxyl group), 2-pyridylacetyl, 4 aminopyridiniumacetyl, 2-thienylacetyl, ov- Carboxy-2-thienylacetyl- or α-carboxy-3-thienylacetyl (optionally with a functionally modified carboxyl group, for example in salt form), oc-cyano-2-thienylacetyl, α-amino-2-thienylacetyl or α-amino -3-thienylacetyl- (optionally with substituted amino, e.g.

  B., optionally present in salt form, sulfoamino group), 3-thienylacetyl, 2 furylacetyl, 1-imidazolylacetyl, 1-methyl-5-tetrazolylacetyl, 3-methyl-2-imidazolylthioacetyl, 1, 2,4-triazole -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), anzidoacetyl , Carboxyacetyl, methoxycarbonylacetyl, ethoxy carbonylacetyl, bismethoxycarbonylacetyl, N-phenylcarbamoylacetyl, cyanoacetyl, n-cyanopropionyl, 2-cyano-3-dimethylacrylyl or N-2-chloroethylcarbamoyl radical.



   Compounds of the formula XVIII in which both radicals R1 and R2 are hydrogen, or in which R is hydrogen or an acyl radical Ac and R2 is a preferably easily cleavable, esterified carboxyl group together with the -C (= O) -O group organic residue of an alcohol R2A represents, are valuable intermediates, which in a simple manner. z. B. 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 commonly used to prepare disulfide compounds, such as oxygen or hydrogen peroxide (preferably in the presence of heavy metal salts such as copper (II) 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. B. lead tetraacetate, usually in the presence of a suitable diluent such as benzene, ethanol, acetone or acetic acid, and optionally water.



   The disulfide obtained is usually 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 at the same time in the treatment of a disulfide compound of the formula VIII with ethylene oxide, e.g. the above 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 hydroxy group is converted in a manner known per se into the acyloxy group of the formula -OC (= O) -X2, in particular into one of the groups of the formulas -OC (= O) -O-R0a, = OO) -O-R0b, -OC (= O) -OR, C, -OC (= O) OR0d, -OC (= O) -O-R0e or -OC (= O) -OR, ', in which R0a, R0b, RoC, Rod, ROe and Rof have the meanings given above, and primarily for the 2,2,2-trichloroethyl, 2-bromoethyl, 2-iodoethyl, phenacyl, 4,5- Dimethoxy2-nitro-benzyl, 4-methoxy-benzyl or tert-butyl radical.

 

   The above acylation reaction is carried out e.g. B. carried out as described above. A In a compound of the formula XI, an R # radical stands primarily for one of the groups R0a, Rob, RoC, Rod, R0, Rof or Rogs, such as one of the above-mentioned groups of this type and in particular for 2,2,2-trichloro ethyl, 2-iodoethyl (or the 2-bromoethyl which can be converted into these), phenacyl, 4,5 dimethoxy-2-nitrobenzyl, 4-methoxybenzyl or tert. Butyl radical.



   The addition of the glyoxylic acid 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 150 ° C., in the absence of a condensing agent and / or without the formation of a salt. Instead of the free
Glyoxylic acid ester compound also a reactive one
Oxoderivat thereof, primarily a hydrate, can be used, with one resulting from using the hydrate
Water, if necessary, by distillation, e.g. azeotropic, can remove.



   It is preferable to work in the presence of a suitable one
Solvent, e.g. Dioxane or toluene, or solvent mixtures. 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 z. B. suitable halogenating agents such as a thionyl 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 being carried out in the presence of a basic, primarily an organic basic agent such as an aliphatic tertiary amine, e.g.

  Triethylamine or diisopropyl ether laminate, 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. 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, with a bromine or iodine reagent.



  Replace iodine atom.



   In a phosphine compound of the formula XIV, each of the groups R 1 denotes. Rb and Re primarily an optional, 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. by aliphatic hydrocarbon radicals, such as lower alkyl groups, or etherified or esterified hydroxy groups, such as lower alkoxy groups or halogen atoms, or nitro groups, substituted phenyl radical.



   The reaction of a compound of formula XIII with the phosphine compound of formula XIV wherein each of the groups Ra. Rb and Re primarily for phenyl, as well as a lower alkyl. in particular the n-butyl radical is preferably 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 nitrogen.



   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. can remove the phosphonium salt compound by treating with a weak base such as an organic base. z. B. diisopropyl ethylamine 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. For example, a group of the formula -C (= O) -X2, in which X2 represents the group of the formula -OR "a and -O-ROb, can be converted into a group of the formula -C (= O) by treatment with a chemical reducing agent. -X2.



  wherein X2 represents the group of the formula -O-R, E, by irradiation, and a grouping of the formula -C (= 0) -X2.



  wherein X2 represents the group of the formula -O-R ,, d or R0 cleavage by treatment with an acid. These reactions can e.g. can be carried out as described above. it is also possible to work in the absence of water. An esterified carboxyl group of the formula -C (= O) -O-R, <can under weakly basic conditions, e.g. B. at a pH of about 7 to about 9, e.g. B. by treating 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 (= 0) -X2 and -C (= O) -O-RA preferably differ from one another in this way. that under the conditions of cleavage of the esterified carboxyl group of the formula -C (=) -X2, the esterified carboxyl group of the formula -C (= O) -O-R2A remains intact. Provides z.

  B. the esterified carboxyl group of the formula -C (= O) -X2 one of the treatment with a chemical reducing agent. like zinc in the presence of aqueous acetic acid. cleavable esterified carboxyl group, e.g. 13. a grouping of the formula -C (= O) - -OR, a or -C (= O) -OR, b. Wherein ROa is preferably 2,2,2-trichloroethyl or 2-iodoethyl or the 2-bromoethyl radical, which can easily be converted into the latter, and ROh primarily represent the phenacyl group. so is the esterified carboxyl group of the formula -C (= O) -O-R2A. z. B 13.



  for one of the treatment with a suitable acid. such as trifluoroacetic acid, cleavable esterified carboxyl groups -C (= 0) -0-R2 z. B. for a grouping of the formula -C (= O) -O-R, e, in which R0 preferably represents 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. Aliphatic sulfoxide compounds, such as di-lower alkyl sulfoxides, are primarily suitable as oxidizing sulfoxide compounds. primarily dimethyl sulfoxide, or lower alkylene sulfoxides. z. B. 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, especially acetic anhydride.

 

  also propionic anhydride. or benzoic anhydride.



  and anhydrides of inorganic acids, in particular of phosphoric acids, such as phosphorus pentoxide. The above anhydrides, primarily of organic carboxylic acids, e.g. B.



  Acetic anhydride, are preferably used in an approximately 1: 1 mixture with the sulfoxide oxidizing agent. Other dehydrating or absorbing agents are carbodiimides, primarily dicyclohexylcarbodiimide, also diisopropylcarbodiimide, or ketenimines. z. B. Diphenyl-N-p-tolylke tenimin; 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 or dehydrating agent, usually in the form of a complex, e.g. B. with pyridine brings to use.



   The sulfoxide oxidizing agent is usually used in excess. Liquid sulfoxide compounds under the reaction conditions, especially dimethyl sulfoxide, can, for. B. serve as a solvent at the same time; inert diluents such as benzene or mixtures of solvents could additionally be used as solvents.



   The above oxidation reaction is carried out if desired. with cooling, but usually at room temperature or slightly elevated temperature.



   In a compound of the formula XVIII, an acyl group Ac, in particular an easily cleavable acyl group, in a manner known per se, a tert-butyloxycarbonyl group, for. B. by treatment with trifluoroacetic acid, a 2,2,2-Trichloräthoxycarbonylgruppe by treatment with a suitable metal or a metal compound, for. B. zinc, or a chromium (II) compound, such as chloride or acetate, advantageously in the presence of a hydrogen generating nascent together with the metal or the metal compound. Hydrogen-releasing agent, preferably from hydrous acetic acid, are split off.

  Furthermore, in a compound of the formula XVIII in which a carboxyl group of the formula -C (= O) -O-R2 is preferably a e.g. by esterification, including by silylation or stannylation, e.g. with a suitable organic halosilicon or halotin-IV compound, such as trimethylchlorosilane, is a protected carboxyl group, 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 resulting imide halide 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 the formula XVIII thus obtained, the unsubstituted amino group can by acylation methods known per se, eg. B. as described above, be acylated, it being possible to introduce an acyl group in stages. Thus, in the free amino group of a compound of formula XVIII, a halo-lower alkanoyl, e.g. Bromoacetyl group, and a thus obtainable N halo-lower alkanoylamino compound with suitable exchange reagents, such as basic compounds, e.g. B. tetrazole, thio compounds, e.g. B. 2-mercapto-1-methyl-imidazole, or metal salts, e.g. B. sodium azide, react; in this way substituted lower alkanoylamino compounds are obtained.



   In a compound of formula XVIII with an esterified carboxyl group, the latter z. B. represents an esterified carboxyl group of the formula-C (= O) -O-R2 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 nature of the esterifying radical R2A can be converted into the free carboxyl group, a grouping of the formula -C (= O) -O-ROa or -Ct = O) -O-ROb z. B.



  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) -OR, 'e.g. B. by irradiation, preferably with ultraviolet light, with shorter-wave ultraviolet light, e.g. B. below 290 mu, works when R0 z. B. one optionally in the 3-, 4- and / or 5-position, z.

  B. is substituted by lower alkoxy and / or nitro groups arylmethyl radical, or with longer-wave ultraviolet light, z. B. over 290 m, u, if RoC z. B. is an arylmethyl radical substituted in the 2-position by a nitro group, a grouping of the formula -C (= O) -O-R, d or -C (= O) -O-R ,, 'z. B. by treatment with an acidic agent such as formic acid or trifluoroacetic acid, and a group of the formula -C (= o) -O-ROf 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-R2hx can be converted into another of this formula, 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-iodoethoxy carbonyl group.



   A z. B. protected by silylation carboxyl group can in a conventional manner, for. B. by treatment with water or an alcohol, are released.



   In a compound of the formula XVIII with a group of the formula -C (= O) -O-R2, in which R2 is hydrogen, the free carboxyl group can be used in a manner known per se, e.g. B.



  by treating with a diazo compound such as a diazo lower alkane, e.g. B. diazomethane or diazoethane. or a phenyl diazo lower alkane. z. 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. be esterified.



  Furthermore, acid halides, such as chlorides (manufactured e.g.



  by treatment with oxalyl chloride), or activated esters, e.g.



  those with N-hydroxy nitrogen compounds, or z. B. with halomiesic acid lower alkyl esters, such as ethyl chloroformate, or with haloacetic acid halides, such as trichloroacetic acid chloride, mixed anhydrides formed by reaction with alcohols, optionally in the presence of a base such as pyridine, converted into esters.



   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, whereby primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic and aliphatic primary, secondary or tertiary mono-, di- or polyamines are possible for the salt formation, such as lower alkylamines, e.g.

  Triethylamine, zydroxy 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. 13. 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, e.g. B. with inorganic acids such as hydrochloric acid.

  Sulfuric acid or phosphoric acid. or with suitable organic carbonic or sulfonic acids. Compounds of formula XVIII in which R 2 is hydrogen and in which R 1 is hydrogen or which contain a basic group in an acyl radical R 1 could also be in the form of an inner salt, i. in second terionic form. exist.



   Salts of compounds of the formula XVIII could be prepared in a manner known per se. So you can salts of compounds of formula XVIII, wherein R2 is hydrogen, z. B. by treatment with metal compounds such as alkali metal salts of suitable carboxylic acids. z. B. the sodium salt of a-ethyl-caproic acid, or with ammonia or a suitable organic amine hilden, preferably using stichiometric amounts or only a small excess of the salt-forming agent. Acid addition salts are usually obtained, for. B. 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 z. B.



  by treatment with suitable acids, and acid addition salts e.g. B. 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 1 is used with a glyoxylic acid ester of the formula Xl or an aldehyde derivative, in particular the hydrate thereof, preferably at an elevated temperature and in the presence of an inert solvent. thus one obtains a compound of the formula
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
 wherein Z is a reactive esterified hydroxy 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 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
EMI9.4
 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 for the acyl radical Ac of an organic carboxylic acid, primarily for the in a pharmacologically active N-acyl derivative of the 6 amino penicillanic acid or 7-Amino-cephalosporanic acid or an acyl radical of a carbonic acid semi-derivative that can be split off easily, 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 R1 is an acyl radical of an organic carboxylic acid occurring in pharmacologically active N acyl derivatives of 6-amino-penicillanic acid and 7-aminocephalosporanic acid compounds, and R2 is hydrogen or an esterified one which can be physiologically cleaved together with the carboxyl group Carboxyl group-forming organic radical is, similar to the corresponding compounds of the formula XVIII, against microorganisms such as gram-positive bacteria, for example Staphylococcus aureus, in particular also against penicillin-resistant bacteria of this type, e.g.



  in dilutions up to 0.0001 y / ml, and against gram-negative bacteria, e.g. Escherichia coli, effective. Other compounds of formula XXIII, e.g. 1k those in which R1 represents hydrogen and / or R2 represents an organic radical which can easily be replaced 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 RA, 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 formula XIV, wherein each of the groups Ra, Rb and Rc is primarily an optionally substituted lower alkyl or phenyl, e.g. n-butyl or phenyl radical, are carried out according to the processes described above.



   The conversion of a phosphoranylidene 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. B. in an aqueous di-alkali metal hydrogen phosphate tri-alkali metal phosphate, such as an aqueous, z. B. 0.05 to 0.5 molar dipotassium 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 R 1 is an acyl radical and R 2 is an organic radical R 1, 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 nacylated intermediate is treated, usually without isolating it, with at least one mole, but not an excessively large excess, of water, with 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. in order to ensure the complete formation of the compound of the formula XXIII.

  In this, if desired, in the usual way, e.g. according to the process described above, the esterified carboxyl group and any protected functional groups present in the acyl radical Ac are released, an acyl group Ac is also replaced by hydrogen and a free amino group is acylated.



   The abovementioned acyl groups Ac, as well as Acta, 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-3em-4-carboxylic acid compounds, such as z. B. the acyl radicals mentioned above, also easily cleavable acyl radicals, such as 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. B. with trifluoroacetic acid, cleavable acyl residues of carbonic acid half-esters, wi such.

  B. dertert-Butyloxycar- bonyl-, tert-Pentyloxycarbonyl-, 2,2,2-Trichloräthoxycarbonyl- or 2-Jodäthoxycarbonylrest or a residue convertible in the latter, such as the 2-Bromoethoxycarbonyl, as well as the phenacyloxycarbonyl, adamantyloxycarbonyl, diphenylmethoxycarbonyl -, oc-4-biphenylyl- a-methyl- äthyloxycarbonyl- 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 to regulate the osmotic 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 1
A mixture of 0.005 g of 6-amino-3- (N-4-methoxybenzyloxycarbonyl-amino) -2,2-dimethyl-penam and 1 ml of trifluoroacetic acid is left to stand for 5 minutes at room temperature and then evaporated at 0.1 mm Hg. The residue is taken up in a mixture of pyridine and toluene and evaporated again. The residue contains 4,4-dimethyl-5-thia-2,7-diazabicyclo [4.2.0] oct-2-en-8-one, which in the thin layer chromatogram (silica gel) has an Rf value of 0.08 (system : Toluene-acetone 8: 2) and of 0.22 (system: toluene-acetone 6: 4); F. 152-153 "(corr.) After crystallization from a mixture of tetrahydrofuran and diethyl ether.

 

   If 1 ml of formic acid is used instead of 1 ml of trifluoroacetic acid and the mixture is left to stand for 30 minutes, 4,4-dimethyl-5-thia-2, 7-diaza [4.2.0] oct-2-en-8 is also obtained -on.



   The starting material can be obtained as follows:
A solution of 4.61 g of crude 3-isocyanato-2, 2-dimethyl6- (N-phenylacetyl-amino) -penam in 50 ml of benzene is mixed with 3.73 g of 4-methoxybenzyl alcohol and 0.2 ml of triethylamine and during 3 Left to stand for hours, then evaporated under reduced pressure.

  The residue is chromatographed on 25 () g of silica gel: the fractions eluted with a 9: 1 mixture of toluene and acetone contain the amorphous 3- (N-4-methoxy-benzyl-oxycarbonyl-amino) -2,2 dimethyl-6 - (N-phenylacetyl-amino) -penam. which in the thin-layer chromatogram (silica gel) in the toluene-acetone system (8: 2) has an Rf value of 0.27, and in the toluene-acetone system (6: 4) an Rf value of (1.59: infrared absorption spectrum (in methylene chloride) : characteristic bands at 2.88, 5.56, 5.76, 5.91, 6.16, 6.64, 8.48 and 9.67.



      A 1 solution of 3. () g of 3- (N-4-methoxybenzyloxycarbonyl-aminot -2,2-dimethyl-6- (N-phenylacetyl-amino) -penam in a mixture of 65 ml of anhydrous methylene chloride and 7.1 ml Pyridine is treated with 46 ml of a 10% solution of phosphorus pentachloride in methylene chloride under a nitrogen atmosphere at -10 and then stirred at 0 for 3 () minutes.

  Then, with vigorous cooling, 33 ml of absolute methanol are added and stirring is continued for 2 hours. 22 ml of water are added. sets the pH value (measured in samples diluted with water) with about 2 ml of a -n. aqueous sodium hydroxide solution to 3.3 and react for half an hour at () and for one hour at 20. It is then poured into 140 ml of a 1-m while stirring. aqueous dipotassium hydrogen phosphate buffer solution and adjusts the pH value to 7 () by adding 10.7 ml of a 50% aqueous tripotassium phosphate solution.

  The aqueous phase is separated off and washed three times with 140 ml of methylene chloride each time: the four organic solutions are washed twice with 200 ml of water each time, and are combined. dried over sodium sulfate and evaporated under reduced pressure.

  The amorphous residue is digested with hexane: the portion that is not soluble in hexane contains 6-amino-3- (N-4-methoxybenzyloxycarbonyl-amino) -2,2-dimethyl-penam. which in the thin-layer chromatogram in the toluene-acetone system (8: 2) has an Rf value of 0.13 and in the toluene-acetone system (6: 4) has an Rf value of 0.32; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00, 5.62, 5.81, 6.21, 6.70, 8.54 and 9.65!).



   I) as 4,4-dimethyl-5-thia-2, 7diazacyclo [4.2.0] oct-2-en-8-one obtainable according to the invention can, for. B. processed as follows.



   Example2 0.05 1 g of 4,4-dimethyl-5-thia-2,7-diazabicyclo [4.2.0] oct2-en-8-one and 0.1 g of zinc dust are dissolved in a mixture of 0.5 nil water, 1 ml acetone and (), 2 ml of glacial acetic acid added and shaken at 22 for one hour. After filtering, the solution is distributed between 20 ml of ethyl acetate and 1 ml of 1 ml of aqueous dipotassium hydrogen phosphate solution: the aqueous phase is extracted with 7 ml of ethyl acetate.

  The combined organic solutions are l-m with lt) ml. Washed aqueous dipotassium hydrogen phosphate solution and dried titer sodium sulfate and evaporated: this gives 3-izopropyl-4-thia-2,6-diazabicyclo [3.2.0 heptan-7-one, the lt.

  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, 5.65, 7.07, 8.90, 10.51 and 11.17
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 added within 10 minutes with 71.7 ml one (), 5-n. Solution of iodine in ethanol are added, left to stand for one hour at room temperature and then concentrated under reduced pressure.

  The residue, dried under high vacuum, is suspended in 90 ml of acentonitrile, and 4.5 ml of pyridine and 4.5 ml of phenylacetic acid chloride are added at 0. The mixture is left to stand for 15 minutes at room temperature and for one hour and then evaporated under reduced pressure. It is triturated for 3 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-3ss- (N-phenylacetyl-amino) -azetidin-4ss-yl] -disulfide is eluted with a 19: 1 mixture of ethyl acetate and acetone and converted into a finely powdered amorphous form by lyophilization: thin-layer chromatogram ( Silica gel): RfN, 0.36 (system: ethyl acetate / acetone 1: 1): Intra-red absorption spectrum (in potassium bromide): characteristic bands at 3.08, 5.62, 5.97 and 6.51.



   A solution of 0.35 g of bis [2-oxo-3fl- (N-phenylacetylamino) -4ss-azetidinylj disulfide in 16 ml of a 9: 1 mixture of acetic acid and water is about 3.2 g of ethylene oxide, then with 3.5 g zinc dust added. The reaction mixture is stirred for 15 minutes at about 5 ° C. and for 3 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 15 ml of ethyl acetate and the solution is washed with 5 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 5 () g of silica gel together with a crude product obtained in an analogous manner from () .58 g of bis- [2-oxo-3 / 3- (N-phenylacetyl-amino) -4ss-azetidinyl] disulfide.

  The 4ss- (2-hydroxyethylmercapto) 3ss- (N-phenylacetyl-amino) -azetidin-2-one is eluted with a 19: 1 mixture as a uniform product, which after crystallization from a mixture of acetone and diethyl ether at 141-142 melts; [a] 20 =
D +44 # 2 (c = 0.571 in ethanol): thin-layer chromatography (silica gel; developing with iodine): Rf (1.45 (system: ethyl acetate / acetone 1: 1): infrared absorption spectrum (in mineral oil): characteristic bands at 3.10, 5.68, 6.01, 6.43 and 6.52.



   A solution of 0.61 g of 4 / 3- (2-Hydroxyäthylmercapto) 3ss- (N-phenylacetyl-amino) -azetidin-2-one in 1 () 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 1.06 g of pyridine in 5 ml of tetrahydrofuran were added. The reaction mixture is stirred under a nitrogen atmosphere for 15 minutes at 00 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-phenylacetylamino) -4ss- [2 (2,2,2-trichlorethoxycarbonyloxy) ethyl mercapto] azetidin2-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, F.99-101; Thin-layer chromatogram (silica gel): Rf¯0.46 (system: ethyl acetate: development with iodine); [o'j 2D0 = +3 # 2 (c = 0.518 in
D.
Chloroform); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.88, 5.58, 5.64.

 

   5.92 and 6.62.



   A mixture of 1.0 g of 3ss- (N-phenylacetylamino) -4ss- [2- (2,2,2-trichlorethoxycarbonyloxy) -ethylmercapto] -azetidin2-one and 3.0 g of tert-butyl glyoxylate hydrant 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 a-hydroxy-a- (2-oco-3ss (N-phenylacetyl-amino) -4ss- [- (2,2,2-trichloroethoxycarbonyloxy) -ethylmereapton] -1-acetidinyl} -acetic acid tert-butyl ester is obtained in this way that is processed further without cleaning.



   The crude a-hydroxy-a- {2-oxo-3ss- (N-phenylacetyl-amino) -4ss- [2- (2,2,2-trichlorethoxycarbonyloxy) -äthylmereaptoj-1 -azetidinyl } -acetic acid-tert-butyl ester is dissolved in 20 ml of a 1: 1 mixture of dioxane and tetrahydrofuran and added dropwise at -10 with 0.54 ml of pyridine in 2 ml of dioxane and () .4X ml of thionyl chloride in | 1O ml of a 1:

  : 1 mixture of dioxane and tetrahydrofuran is added, the reaction mixture is stirred for 30 minutes at -10 to -5 and for one hour under a nitrogen atmosphere, the precipitate is filtered off and the filtrate is mixed with the? -Chloro-? - {2oxo- 3ss- (N-phenylacetyl-amino) -4ss- [2- (2,2,2-trichlorätho xyearbonyloxy) -äthylmercaptoj - 1 -azetidinyl} -acetic acid tert-butyl ester evaporated, the product is further processed in the crude state.



   A solution of the crude α-chloro-α - {2-oxo-3 /? - (N-phenylacetyl-amino) -4 /? - [2 (2,2,2-trichloroethoxycarbonyloxy) - äthylmercapto] -1-azetidinyl} -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 at 50 for 2 hours, then 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 give the x- {2-oxo-3ss- (N-phenylacetylamino) -4ss- [2 (2.2 , 2-trichloräthoxycarbonyloxy) -äthylmercapto] -1-azetidi nyl} -o-triphenylpposphoranyliden- 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) 0.57 (system: toluene / acetone 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00, 3.42, 5.68, 5.97, 6.10, 6.65.



   A mixture of 0.225 g of a- {2-oxo-3ss- (N-phenylacetylamino) -4ss- [2- (2,2,2-trichloroethoxycarbonyloxy) ethyl mercapto] - 1 -azetidinyl} - a-triphenylphosphoranylidene 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 at 15 for 45 minutes. 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 a- [4ss- (2-Hydroxyäthylmercapto) -2-oxo-3ss- (N-phenylacetyl-amino) -1 -azetidinyl] -a-triphenylphosphoranylidene 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-Hydroxyethylmercapto) -2-oxo-3ss- (N-phenylacetylamino] -1-azetidinyl] -a-triphenylphosphoranylidene-acetic acid tert-butyl ester in 5 ml of dimethyl sulfoxide and 5 ml of acetic anhydride are left to stand for 16 hours at room temperature, 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 7- (N-phenylacetylamino) -ceph-3-em-4-carboxylic acid tert-butyl ester, which is obtained by ring closure from the non-isolated z- [4 /? - formylmethylmer- capto-2-oxo- 3ss- (N-phenylacetyl-amino) -1-azetidinyl forms triphenylphosphoranylideneacetic acid tert-butyl ester, is eluted with a 4: 1 mixture of toluene and ethyl acetate; Thin-layer chromatogram (silica gel): Rf0.48 (system:

  Toluene / ethyl acetate 1: 1); Ultraviolet absorption spectrum (in pure ethanol):, (max 258 m; infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00, 3.48y, 5.62u, 5.81, 5.93u, 6, 10, 6.67, 7.15, 7.31, 7.70, 8.65 and 9.03.

 

   A mixture of 0.03 g of 7- (N-phenylacetylamino) -ceph3-em-4-carboxylic acid tert-butyl ester and 0.5 ml of trifluoroacetic acid is left to stand for one hour at room temperature. 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) -eeph-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-2,7diazabicyclo [4.2.0] oct-2-en-8-one of the formula EMI12.1 characterized in that there is a penam compound of the formula EMI12.2 in which the group -NH-C (= O) -X1 is an esterified hydroxycarbonylamino group which can be easily split off under acidic conditions, in which X1 is a group of the formula -O-ROd in which ROd is a methyl group which is substituted by an electron donating having carbocyclic aryl group or is monosubstituted by a heterocyclic group of aromatic character having oxygen or sulfur atoms as ring members, or then in an oxa- or thiacycloaliphatic radical which the a Position to the oxygen or sulfur atom Ring link means and R is hydrogen or one of them Conditions of the process represents cleavable acyl radical Ac of an organic acid, with cleavage of the 5-membered Ringes, rearrangement and ring closure to the 6-membered nitrogen and sulfur-containing ring and simultaneous cleavage of the group -NH-C (= O) -X1 treated with an acidic agent. 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) -O-R, d, wherein ROd has the meaning given in the claim. 2. The method according to claim, characterized in that R in the starting material of the formula II is hydrogen. 3. The method according to claim or dependent claim 1, characterized in that ROd represents the 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2-tetrahydrofuryl, 2-tetrahydropyranyl or 2,3-dihydro-2-pyranyl radical. 4. The method according to claim, characterized in that one treats with an acid. 5. The method according to claim or dependent claim 4. characterized in that one with a strong organic carboxylic or sulfonic acid. such as a lower alkanecarboxylic acid optionally containing halogen atoms. acts. 6. The method according to claim or one of the dependent claims 4 or 5, characterized in that the treatment is carried out with trifluoroacetic acid or formic acid. 7. The method according to claim, characterized in that the 4,4-dimethyl-5-thia-2, 7-diazabicyclo [4.2.0] oct-2-en-8-one from the 3-isopropyl-4 which may be formed -thia-2,6-diazabicyclo [3 .2.0] heptan-7-one separated by means of fractional crystallization or by means of adsorption chromatography. 8. The method according to claim, characterized in that starting materials are used in the form of a crude reaction mixture obtainable under the reaction conditions.