AT353971B - PROCESS FOR THE PREPARATION OF NEW CEPHALOSPORINES CONTAINING A LOW ALKYLSULFONYLAMINO GROUP - Google Patents

Description

  

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   The invention relates to a process for the preparation of new 7ss- [D-2-amino-2- (lower alkylsulfonylamino-phenyl) -acetylamino] -3-R-3-cephem-4-carboxylic acids of the general formula
 EMI1.1
 in which R is lower alkoxy or chlorine, and in which lower alkyl and lower alkoxy contain up to 7 carbon atoms, and their salts.



   Lower alkyl in lower alkylsulfonylamino preferably contains up to 4 carbon atoms and means e.g. B. ethyl, n-propyl, isopropyl, n-butyl or isobutyl and primarily methyl, lower alkylsulfonylamino can be in any position of the phenyl radical, but takes first
Line up the 3 position.



   Lower alkoxy R preferably contains up to 4 carbon atoms and is z. B. ethoxy, n-propyloxy, isopropyloxy, n-butyloxy or isobutyloxy and primarily methoxy, while halogen represents fluorine or bromine, but primarily represents chlorine.



   Salts are in particular pharmaceutically usable, non-toxic salts, such as metal or
Ammonium salts, especially alkali metal and alkaline earth metal, e.g. B. sodium, potassium, magnesium or calcium salts, and ammonium salts with ammonia or suitable organic amines, with primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic and araliphatic primary, secondary or tertiary mono-, di- or polyamines, and heterocyclic Bases for the
Salt formation come into question, such as lower alkylamines, e.g. B. triethylamine, hydroxy lower alkylamines,
 EMI1.2
 



  The new compounds can also contain acid addition salts, e.g. B. with inorganic acids such as hydrochloric acid, sulfuric acid, or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, e.g. B. trifluoroacetic acid or 4-methylphenylsulfonic acid. Preferably the new compounds are in the form of their internal salts; H. in zwitterionic form.



   The new compounds of the invention have valuable pharmacological properties.



  They are in free form or in the form of their salts in vitro against cocci, such as Staphylococcus aureus, Streptococcus pyogenes, Streptococcus haemolyticus, Streptococcus faecalis, Diplococcus pneumoniae, Neisseria gonorrhoae and Neisseria meningitidis in a dose range of 0.05 to 100 g. ml, against enterobacteria such as Escherichia coli, Salmonella species, Shigella flexneri, Klebsiella pneumoniae, Proteus vulgaris, Proteus rettgeri, Proteus mirabilis in a dose range of 0.8 to 50 g / ml, as well as against other pathogens such as Haemophilus influenzae and Pasteurella multocida, in a dose range from 0.4 to 12.5! J. g / ml, effective. In the case of parenteral or, in particular, oral administration, those against microorganisms such as gram-positive bacteria, e.g. B.

   Staphylococcus aureus, Streptococcus pyogenes and Diplococcus pneumoniae, (e.g. in mice at doses of about 0.5 to about 100 mg / kg s. C. Or p. O.), And gram-negative bacteria, e.g. B. Escherichia coli, Salmonella typhimurium, Shigella flexneri, Klebsiella pneumoniae, Proteus vulgaris, Proteus rettgeri and Proteus mirabilis (for example, in mice in doses of about 3.0 to about 200 mg / kg sc or po), especially against Penicillin-resistant bacteria, effective with low toxicity.



   Compared to the 3-substituted 7ss-phenylglycylamino-3-cephem-4-carboxylic acids known from DE-OS 2331133 and 2408698, which do not contain any lower alkylsulfonylamino group in the phenyl nucleus, the compounds of the invention are characterized by a higher in vitro activity against many of the Enterobacteria strains. In vivo, on the mouse, they are these known preparations

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 EMI2.1
 increased in vitro and in vivo (mouse) activity, especially against strains of Enterobacteria. They also have a high solubility in water and urine, which makes the possibility of crystalluria appear to be low. The new connections can e.g.

   B. in the form of antibiotic preparations for the treatment of the specified infections are used.
 EMI2.2
 Represents chlorine, and their salts, in particular their pharmaceutically acceptable, non-toxic salts and in particular their internal salts.



   The new compounds are produced in a manner known per se.



   The new compounds (I) were obtained when a 7ss [D-2-amino-2- (lower alkylsulfonylaminophenyl) acetylamino] -3-R-2-cephem-4-carboxylic acid
 EMI2.3
 wherein 2-amino and / or caroxyl can optionally be present in protected and / or lower alkylsulfonylamino, if appropriate in N-acylated form, isomerized by oxidizing them in the 1 position with a peracid or an organic halite compound and the corresponding 3-cephem-l- oxide is reduced with a reducing agent and, if necessary or desired, a protected 2-amino group and / or an N-acylated lower alkylsulfonylamino group in a compound obtained in the free amino group or

   into the lower alkylsulfonylamino group, and / or the protected carboxyl group into the free carboxyl group, and, if desired, converts a salt obtained into the free compound or into another salt and / or a free compound into a salt.



   In the above starting material, the carboxyl group is present in protected form and the amino group is usually present in protected form, the radicals used in penicillin or cephalosporin chemistry and in peptide chemistry in particular being suitable as protective groups.



   The carboxyl group is usually protected in esterified form, such an ester grouping being easily cleavable under mild conditions. Particularly suitable protected carboxyl groups are lower alkoxycarbonyl, in particular tert-lower alkoxycarbonyl, e.g. B. tert-butyloxycarbonyl, polycycloalkoxycarbonyl, e.g. B. Adamantyloxycarbonyl, Arylmethoxycarbonyl,
 EMI2.4
 and / or nitro, mono- or polysubstituted phenyl radicals, such as optionally, z. B. substituted benzyloxycarbonyl as mentioned above, e.g. B. 4-nitro-benzyloxycarbonyl, or e.g. B. as mentioned above substituted diphenylmethoxycarbonyl, z. B.

   Benzhydryloxycarbonyl or di- (4-methoxyphenyD-methoxycarbonyl, or 2-halo-lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl or 2-bromo- or 2-iodoethoxycarbonyl, or acylmethoxycarbonyl, in particular aroylmethoxycarbonyl, in which the aroyl group preferably optionally benzoyl substituted, for example by halogen, such as bromine, for example phenacyloxycarbonyl, in question. Esterified carboxyl groups are likewise corresponding silyloxycarbonyl, especially organic silyloxycarbonyl groups. In these, the silicon atom preferably contains lower alkyl, especially methyl, and also lower alkoxy , for example methoxy, and / or halogen, for example chlorine, as substituents.

   Suitable silyl protective groups are primarily tri-lower alkylsilyl, in particular trimethylsilyl, and also dimethyl-tert.-

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 butyl-silyl, lower alkoxy-lower alkyl-halosilyl, e.g. B. methoxy-methyl-chlorosilyl, or di-lower alkyl-halosilyl, z. B. dimethyl-chloro-silyl. Silyl protective groups, in particular those which have a halogen atom as a substituent, can protect the carboxyl groups in two different molecules of the starting material at the same time; d. H. there is one in such groups
Halogen atom exchanged for the carbonyl group of another starting material molecule.



   A preferred protected carboxyl group is, in particular, where appropriate, e.g. B. as mentioned substituted benzyloxycarbonyl, z. B. 4-nitrobenzyloxycarbonyl, or diphenylmethoxycarbonyl, e.g. B. benzhydroyloxycarbonyl.



   A protected 2-amino group can e.g. B. in the form of an easily cleavable acylamino, triarylmethylamine, etherified mercaptoamino, l-acyl-2-lower alkylideneamino or silylamino group or as an azido group.



   In a corresponding acylamino group, as well as in an N-acyl-lower alkylsulfonylamino group, acyl is preferably the acyl radical of a carbonic acid half-ester, such as lower alkoxycarbonyl,
 EMI3.1
 oxy such as methoxy, hydroxy, halogen, e.g. B. chlorine, and / or nitro, mono- or polysubstituted
Represents phenyl radicals, such as, where appropriate, e.g. B. as mentioned above, substituted benzyloxycarbonyl, e.g. B. 4-nitro-benzyloxycarbonyl, or e.g. B. as mentioned above substituted diphenylmethoxycarbonyl, z. B.

   Benzhydryloxycarbonyl or di- (4-methoxyphenyl) methoxycarbonyl, or 2-halo-lower alkoxycarbonyl, e.g. B. 2, 2, 2-Trichloräthoxycarbonyl, 2-Bromoäthoxycarbonyl or 2-Iodäthoxycarbonyl, or acylmethoxycarbonyl, especially aroylmethoxycarbonyl, wherein the aroyl group preferably optionally, z. B. is benzoyl substituted by halogen such as bromine, e.g. B. phenacyloxycarbonyl. Acyl in an acylamino group or in an N-acyl-lower alkylsulphonylamino group can also represent the corresponding radical of an organic sulphonic acid; such a radical is in particular arylsulfonyl, wherein aryl is an optionally, z. B. by lower alkyl, such as methyl, halogen, such as bromine, or nitro, substituted phenyl, z. B. 4-methylphenylsulfonyl.



   In a triarylmethylamino group, the aryl radicals are in particular optionally substituted phenyl radicals; a corresponding group is primarily trityl.



   An etherified mercapto group in an amino group protected by such a radical is primarily arylthio or aryl-lower alkylthio, in which aryl is in particular optionally, e.g. B. by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and / or nitro-substituted phenyl. A corresponding amino protecting group is e.g. B.



    4-nitrophenylthio.



   In a l-acyl-2-lower alkylidene radical which can be used as an amino protecting group, acyl is preferably the corresponding radical of a lower alkanecarboxylic acid, an optionally, e.g. B. by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and / or nitro-substituted benzoic acid or a carbonic acid half-ester, such as a carbonic acid-lower alkyl half-ester. Corresponding protecting groups are primarily 1-lower alkanoyl-2-propylidene, e.g. B. l-acetyl-2-propylidene, or l-lower alkoxycarbonyl-2-propylidene, e.g. B. 1-ethoxycarbonyl-2-propylidene.



   A silylamino group is primarily an organic silylamino group in which the silicon atom is preferably lower alkyl, in particular methyl, furthermore lower alkoxy, e.g. Methoxy, and / or halogen, e.g. B. chlorine, contains as a substituent. Corresponding silyl groups are primarily tri-lower alkylsilyl, in particular trimethylsilyl, also dimethyl-tert-butyl-silyl, lower alkoxy-lower alkyl-halosilyl, e.g. B. methoxy-methyl-chlorosilyl, or di-lower alkyl-halosilyl, z. B. dimethyl-chloro-silyl. Silyl protective groups, in particular those which have a halogen atom as a substituent, can simultaneously protect the amino group in two different molecules of the starting material; d. that is, in such groups the halogen atom is replaced by the amino group of another starting material molecule.



   The 2-amino group in the starting material can also be protected in protonated form; as anions come primarily those of strong inorganic acids, such as halo-

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   hydrogen acids, e.g. B. the chlorine or bromine ion in question.



  Preferred amino protective groups are the acyl radicals of carbonic acid half-esters, in particular tert-lower alkoxycarbonyl, optionally, e.g. B. substituted benzyloxycarbonyl or diphenylmethoxycarbonyl as indicated, or 2-halo-lower alkoxycarbonyl.



  The above-mentioned isomerization of 2-cephem compounds (VIII) can be carried out in a manner known per se by oxidizing them in the 1-position, with rearrangement of the 2-cephem compound into a 3-cephem compound taking place, if desired, an available isomer mixture of Separates 1-oxides from 3-cephem compounds, and reduces the 1-oxides of the corresponding 3-cephem compounds thus obtainable.



  Suitable oxidizing agents for the 1-position oxidation of 2-cephem compounds (VIII) are suitable inorganic or organic peracids or mixtures of hydrogen peroxide and acids, in particular organic carboxylic acids with a dissociation constant of at least 10-5. Suitable inorganic peracids are periodic and persulfuric acid.



  Organic peracids are corresponding percarboxylic and persulfonic acids, which can be added as such or formed in situ by using at least one equivalent of hydrogen peroxide and one carboxylic acid. It is advantageous to use a large excess of the carboxylic acid if, for. B. acetic acid is used as the solvent. Suitable peracids are e.g. B. performic acid, peracetic acid, petrifluoroacetic acid, permaleic acid, perbenzoic acid, monoperphthalic acid or p-toluene persulfonic acid. The oxidation can also be carried out using hydrogen peroxide with catalytic amounts of an acid with a dissociation constant of at least 10-5, such as acetic acid, perchloric acid or trifluoroacetic acid.



  The above oxidation is carried out in a manner known per se, if necessary, in the presence of catalysts and under mild conditions, e.g. B. at temperatures from about -50 to about +100 C, preferably from about -10 to about +40 C carried out.



  The oxidation of 2-cephem compounds to the 1-oxides of the corresponding 3-cephem compounds
 EMI4.1
 such as optionally halogenated hydrocarbons, e.g. B. methylene chloride, and used at temperatures from about -10 to about +30 C, with periodate compounds such as alkali metal periodates, e.g. B. potassium periodate, which is preferably used in an aqueous medium at a p-value of about 6 and at temperatures of about -10 to about +30 C, with iodobenzene dichloride, which is used in an aqueous medium, preferably in the presence of an organic base, z. B.



  Pyridine, and with cooling, e.g. B. at temperatures of about -20 to about OOC, or carried out with any other oxidizing agent which is suitable for converting a thio group into a sulfoxide group.



   An optionally obtained mixture of isomeric -undss-l-oxides can, for. B. chromatographically separated.



   The reduction of the 1-oxides of 3-cephem compounds can be carried out in a manner known per se by treatment with a reducing agent, if necessary in the presence of an activating agent. Possible reducing agents are: catalytically activated hydrogen; reducing tin, iron, copper or manganese cations, which in the form of corresponding compounds or complexes of inorganic or organic nature, e.g. B. as tin (II) chloride, copper (I) chloride or manganese (II) chloride, or as complexes, e.g.

   B. with ethylenediaminetetraacetic acid or nitrilotriacetic acid can be used; reducing dithionite, iodine or iron-11-cyanide anions, which are used in the form of corresponding inorganic or organic salts, such as alkali metal dithionite, iodide or iron-II-cyanide, or in the form of the corresponding acids; reducing trivalent inorganic or organic phosphorus compounds, such as phosphines, also esters, amides and halides of phosphinous, phosphonous or phosphorous acid, and phosphorus-sulfur compounds corresponding to these phosphorus-oxygen compounds, in which organic radicals are primarily lower alkyl or phenyl, e.g. B.

   Triphenylphosphine, methyl diphenylphosphinate, diphenylchlorophosphine, dimethyl benzene phosphonate, trimethyl phosphate, phosphorus trichloride or phosphorus tribromide, etc .; reducing halosilane compounds which have at least one water bonded to the silicon atom

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 have substance atom and the except halogen, z. B. chlorine, organic radicals such as lower alkyl or phenyl, such as chlorosilane, di- or trichlorosilane, diphenylchlorosilane, etc .; reducing quaternary chloromethyleneiminium halides, in which the iminium group is substituted by one divalent or two monovalent organic radicals, such as lower alkylene or lower alkyl, such as N-chloromethylene-N, N-diethyliminium chloride or N-chloromethylene pyrrolidinium chloride; and complex metal hydrides such as sodium borohydride, e.g.

   B. in the presence of suitable activating agents such as cobalt-III-chloride; and borane dichloride.



   As activating agents, which together with those of the above-mentioned reducing agents
 EMI5.1
 Phosphorus reducing agents or used in catalytic reduction are, in particular, organic carbonic and sulfonic acid halides, and also sulfur, phosphorus or silicon halides with the same or greater hydrolysis constant of the second order than benzoyl chloride, e.g. B.



  Phosgene, oxalyl chloride, acetic acid chloride, 4-toluenesulphonic acid chloride, methanesulphonic acid chloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, dimethylchlorosilane or trichlorosilane, furthermore suitable acid anhydrides, such as trifluoroacetic anhydride, or cyclic sultone, 1-butane or 1-butane sultone, 1-4-sultone, 3-hexanesultone, to be mentioned.



   The reduction is preferably carried out in the presence of solvents or mixtures thereof, the selection of which is primarily determined by the solubility of the starting materials and the choice of reducing agent, e.g. B. lower alkanecarboxylic acids or esters thereof in the catalytic reduction, and z. B. optionally substituted, such as halogenated or nitrated aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbons, e.g. B. methylene chloride, lower alkanecarboxylic acid esters or nitriles, e.g. B. ethyl acetate or acetonitrile, or amides of inorganic or organic acids, e.g. B. dimethylformamide or hexamethylphosphoramide, or ether, e.g. B. diethyl ether, tetrahydrofuran or dioxane, ketones, z. Acetone, etc., these solvents preferably not containing water.

   The work is usually carried out at temperatures from about -20 to about 100 ° C., it being possible to carry out the reaction at lower temperatures when using very reactive activating agents.
 EMI5.2
 
Starting materials (VIII) alkylsulfonylamino-phenyl) -acetyl (optionally with protected 2-amino and N-acylated lower alkylsulfonylamino) represents different, cleavable acyl radical, and carboxyl and / or functional groups present in the acyl radical are optionally present in protected form, to the corresponding 2-cephem compound isomerized (e.g. by treatment with a suitable base), and in this the acyl radical, e.g. B. by treatment with phosphorus pentachloride in the presence of pyridine, followed by methanol and optionally water, split off.

   The free amino group is then treated with D-2-amino-2- (lower alkylsulfonylaminophenyl) acetic acid (VII), in which 2-amino is preferably in protected and / or lower alkylsulfonylamino, optionally in N-acylated form, or with a reactive derivative, In particular one, preferably mixed anhydride thereof, such as a corresponding acid chloride or anhydride with a formic acid lower alkyl ester, with the D-2-amino-2- (lower alkylsulfonylaminophenyl) acetyl radical (preferably with a protected 2-amino group and / or optionally N-acylated lower alkylsulfonylamino group ) acylated.



   The starting materials (VIII) in which R is lower alkoxy and in which carboxyl and 2-amino are preferably in protected and lower alkylsulfonylamino, if appropriate in N-acylated form
 EMI5.3
 acid (X), in which the carboxyl group and the 2-amino group are preferably in protected form and the lower alkylsulfonylamino group is optionally in N-acylated form.



   In a starting material (X), the lower alkoxy group R can be in the trans (crotonic acid configuration) or in the cis position (isocrotonic acid configuration) to the carboxyl group.



   In a starting material (X) in which the carboxyl and amino groups in a manner known per se, e.g. B. as described above, protected and the lower alkylsulfonylamino group against

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 EMI6.1
 cyclic radical of aromatic character which has at least one ring nitrogen atom and optionally a further ring heteroatom, such as oxygen or sulfur, and which is bonded to the thiosulfur with one of its ring carbon atoms, which is linked to a ring nitrogen atom by a double bond. Such residues can optionally, for. B. by lower alkyl such as methyl or ethyl, lower alkoxy such as methoxy or ethoxy, halogen, such as.

   Fluorine or chlorine, or aryl, such as phenyl, may be substituted.
 EMI6.2
 oxadiazacyclic or oxatriazacyclic radicals of aromatic character, but in particular monocyclic five-membered diazacyclic, oxazacyclic and thiazacyclic radicals of aromatic character, or primarily the corresponding benzdiazacyclic, benzoxazacyclic or benzthiazacyclic radicals, in which the heterocyclic part has a five-membered substituent, where the heterocyclic part is substituted in five-membered radicals Ring nitrogen atom optionally, e.g. B. may be substituted by lower alkyl, such as methyl. Representative for such groups are 1-methyl-2-imidazolyl, 2-thiazolyl, 1, 3, 4-thiadiazol-2-yl, 1, 3, 4, 5-thiatriazol-2-yl, 2-oxazolyl,
 EMI6.3
 
 EMI6.4
 be aromatic or heterocyclic acyl or thioacyl radical.

   Such radicals include lower alkanoyl, e.g. B. acetyl or propionyl, lower thioalkanoyl, e.g. B. thioacetyl or thiopropionyl, cycloalkylcarbonyl, e.g. Cyclohexylcarbonyl, cycloalkylthiocarbonyl, e.g. Cyclohexylthiocarbonyl, benzoyl, thiobenzyol, naphthoyl, naphthylthiocarbonyl, pyridoyl, e.g. 2-, 3- or 4-pyridoyl, thenoyl, e.g. E.g. 2- or 3-thenoyl, furoyl, e.g. B. 2- or 3-furoyl, or pyridylthiocarbonyl, e.g. B.



  2-, 3- or 4-pyridylthiocarbonyl, or corresponding substituted, e.g. B. by lower alkyl, such as methyl, halogen, such as fluorine or chlorine, lower alkoxy, such as methoxy, aryl, such as phenyl, or aryl
 EMI6.5
 Methoxy, halogen, e.g. B. fluorine, chlorine or bromine, aryl, e.g. Phenyl, or aryloxy, e.g. B. phenyloxy, mono- or polysubstituted alkyl, especially lower alkyl, such as methyl, ethyl or butyl, Al-
 EMI6.6
 or polysubstituted naphthyl or in particular phenyl, such as phenyl, 2-, 3- or preferably 4-tolyl, 2-, 3- or preferably 4-methoxyphenyl, 2-, 3- or 4-chlorophenyl, 4-biphenylyl, 4-phenyloxyphenyl, 4-nitrophenyl or 1- or 2-naphthyl.



   Bases suitable for the ring closure reaction are in particular strong organic or inorganic
 EMI6.7
 substituted, e.g. B. by lower alkyl such as methyl, polysubstituted guanidines such as tetramethylguanidine, and metal bases such as alkali metal, z. B. lithium, sodium or potassium hydrides, - amides or alcoholates, especially lower alkoxides, z. B. sodium hydride, lithium di-lower alkylamides, such as lithium diisopropylamide, or potassium lower alkanolates, such as potassium tert-butoxide, starting materials (X) in which the carboxyl group is in the form of a halogenocarbonyl, e.g. B. chlorocarbonyl group, can also be obtained by treatment with a tertiary organic nitrogen base, e.g. B. a tri-lower alkylamine, such as triethylamine, cyclized, in the presence of an alcohol such as a suitable lower alkanol z.

   B. tert-butanol, the corresponding ester of a compound (I) can be obtained.

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   The reaction is carried out in the presence of a suitable inert solvent, for example in an optionally halogenated, e.g. B. chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon such as hexane, cyclohexane, benzene, toluene or methylene chloride, an ether such as a di-lower alkyl ether, e.g. B. diethyl ether, a Diniederalkoxyniederalkan such as dimethoxy ethane, or a cyclic ether such as dioxane or tetrahydrofuran, or a lower alkanol, z. B. methanol, ethanol or tert-butanol, or in a mixture thereof, at room temperature or, if necessary, with gentle heating, e.g. B. carried out to about 50 C, and if desired in an inert gas, such as nitrogen atmosphere.
 EMI7.1
 (X) where R is a group -S-Ra, e.g. B. the. Yield can be increased.



   In the ring closure reaction, depending on the starting material and reaction conditions, a uniform 3-cephem compound or a mixture thereof with the corresponding 2-cephem compound can be obtained. Mixtures obtained can in a manner known per se with the aid of separation processes, for. B. by adsorption and fractional elution, including chromatography (column, paper or plate chromatography) using suitable adsorbents, such as silica gel or aluminum oxide, and eluents, further separated by fractional crystallization, solvent distribution, etc. The starting materials (X) can, for.

   B. obtained by adding a 6-acylamino-2, 2-dimethyl-penam-3-carboxylic acid (XI), wherein acyl is a D-2-amino-2- (lower alkylsulfonylamino) acetyl radical, the 2-amino group being preferred is in protected form and the lower alkylsulfonylamino group can be N-acylated, or represents any other cleavable acyl radical of an organic carboxylic acid, functional groups that may be present in such a group preferably being in protected form, and in which the carboxyl group is in protected form
Form is present in a manner known per se, for. B. by treatment with a percarboxylic acid, such as 3-chloroperbenzoic acid, converted into the corresponding 1-oxide. By implementing with a
 EMI7.2
 (XIII) heavy metal thiosulfinate converts, wherein as heavy metals z.

   B. mono- or divalent cations of copper, mercury, silver or tin are preferred. These heavy metal salt reagents can optionally be formed in situ from the corresponding sulfinic or thiosulfonic acid or readily soluble salts thereof by reaction with a suitable heavy metal salt such as copper (II) sulfate, mercury (II) diacetate, silver nitrate or tin (II) chloride.



   In a 3-butenoic acid compound (XVI) in which the carboxyl group is in protected form, the terminal vinylene group is converted oxidatively, preferably by treatment with ozone, into the corresponding ozonide, and this is carried out simultaneously or subsequently
 EMI7.3
 has given meaning. The hydroxy group can now in a known manner, for. B. as described above, for example by treatment with a diazo lower alkane, a suitable reactive ester of a lower alkanol; such as a corresponding sulfate, halogen sulfate or sulfonate, with a tri-lower alkyl-oxonium, di-lower alkylcarbenium or di-lower alkylhalonium salt, such as
 EMI7.4
 

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   If necessary, at any suitable stage in the preparation of a starting material (X), an acyl group other than D-2-amino-2- (lower alkylsulfonylaminophenyl) acetyl, e.g. B. by treatment with phosphorus pentachloride in the presence of pyridine, followed by methanol and optionally water, cleaved and the free amino group of an intermediate product obtainable in this way by treatment with the corresponding acid or a reactive derivative, such as a preferably mixed anhydride, e.g. B. the chloride, of which with the D-2-amino-2- (lower alkylsulfonylamino-phenyl) -acetyl radical, in which 2-amino is preferably in protected and lower alkylsulfonylamino optionally in N-acylated form, are acylated.

   Furthermore, at the appropriate stages, one radical Ro can be converted into another radical Ro and / or a group present in free or protected form can be converted into a protected or free or other protected form.



   In the compounds obtainable according to the invention are protected carboxyl and / or
Amino groups and / or N-acylated lower alkylsulfonylamino groups are released in a manner known per se, such as by means of solvolysis, including hydrolysis, alcoholysis or acidolysis, or by means of reduction, including hydrogenolysis or chemical reduction, optionally simultaneously.



   So you can z. B. a tert-lower alkoxycarbonyl, polycycloalkoxycarbonyl or diphenylmethoxycarbonyl group by treatment with a suitable acidic agent such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound such as phenol or anisole, converted into the free carboxyl group. An optionally substituted benzyloxycarbonyl group can, for. B. by means of hydrogenolysis by treatment with hydrogen in the presence of a hydrogenation catalyst, such as a palladium catalyst. In addition, certain substituted benzyloxycarbonyl groups, such as 4-nitrobenzyloxycarbonyl, can also be used by chemical reduction, e.g. B. by treating with an alkali metal, e.g. B. sodium dithionite, or with a reducing metal, e.g. B. zinc, or metal salt, such as a chromium-II salt, e.g. B.

   Chromium 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 and formic acid, or an alcohol, preferably adding water, is converted into the free carboxyl group . By treating with a reducing metal or metal salt, as described above, one can also convert a 2-halo-lower alkoxycarbonyl group (optionally after converting a 2-bromo-lower alkoxycarbonyl group into a 2-iodo-lower alkoxycarbonyl group) or an acylmethoxycarbonyl group into the free carboxyl group, with an aroylmethoxycarbonyl group can also be cleaved by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide. A z.

   B. protected by silylation carboxyl group can in a conventional manner, for. B. by treatment with water or an alcohol, are released. Similarly, a carboxyl group protected by reaction with an organic phosphorus halide compound can also be released by hydrolysis or alcoholysis.



   A protected amino group is known per se and, depending on the type of protective group, in various ways, e.g. B. by means of solvolysis or reduction, released. A 2-halo-lower alkoxycarbonylamino group (optionally after conversion of a 2-bromo-lower alkoxycarbonyl group into a 2-iodo-lower alkoxycarbonyl group), an acylmethoxycarbonylamino group or z. B. a 4-nitrobenzyloxycarbonylamino group can e.g. B. by treating with a suitable chemical reducing agent such as zinc in the presence of aqueous acetic acid, an aroylmethoxycarbonylamino group also by treatment with a nucleophilic, preferably salt-forming reagent such as sodium thiophenolate, and a 4-nitro-benzyloxycarbonylamino group also by treating with an alkali metal, e.g. . B.

   Sodium dithionite, a diphenylmethoxycarbonylamino, tert-lower alkoxycarbonylamino or polycycloalkoxycarbonylamino group by treating e.g. B. with formic or trifluoroacetic acid, an optionally substituted benzyloxycarbonylamino group z. B. by means of hydrogenolysis by treatment with hydrogen in the presence of a hydrogenation catalyst such as a palladium catalyst, an aryl or aryl lower alkylthioamino group z. B. by treating with a nucleophilic reagent such as sulfurous acid, an arylsulfonylamino group e.g. B. by means of electrolytic reduction, an l-acyl-2-lower alkylideneamino group or a triarylmethyl group z. B. by treating with aqueous mineral acid, and one with a

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 organic silyl group protected amino group e.g.

   B. released by hydrolysis or alcoholysis.



   An amino group protected in the form of an azido group is converted into the free amino group in a manner known per se by reduction, for example by catalytic hydrogenation with hydrogen and a hydrogenation catalyst such as platinum oxide, palladium or Raney nickel, or also with zinc and acid such as acetic acid. The catalytic hydrogenation is preferably carried out in an inert solvent such as a halogenated hydrocarbon, e.g. B. methylene chloride, or in water or a mixture of water and an organic solvent, such as an alcohol or dioxane, at about 20 to 25OC, or at a reduced or elevated temperature.



   An N-acylated lower alkylsulfonylamino group is also used in a manner known per se, e.g. B. solvolytically or reductively, converted into a lower alkylsulfonylamino group. To split off these N-acyl groups, the same methods can be used which are used for the split off of acyl groups, for example 2-halo-lower alkoxycarbonyl, acylmethoxycarbonyl, 4-nitrobenzyloxycarbonyl, aroylmethoxycarbonyl, diphenylmethoxycarbonyl, tert.-lower alkoxycarbonyl, polycycloalkoxycarbonyl, or benzyloxycarbonyl, polycycloalkoxycarbonyl, are given from corresponding acylamino groups.



   Salts of the new compounds (I) can be prepared in a manner known per se.



  So you can use salts z. By treating with metal compounds such as alkali metal salts of suitable carboxylic acids, e.g. B. the sodium salt dera-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 obtained in
 EMI9.1
 
B. ion exchangers are formed.



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



   The process also includes those embodiments according to which compounds obtained as intermediates 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.



   Such starting materials are preferably used and the reaction conditions are selected such that the compounds listed at the beginning as being particularly preferred are obtained.



   The new compounds of the invention can e.g. B. be used for the production of pharmaceutical preparations which contain an effective amount of the active substance together or in a mixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers which are suitable for enteral or parenteral administration. So you use tablets or gelatin capsules, which the active ingredient together with diluents, eg. B. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and lubricants, e.g. B. silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol; Tablets also contain binders, e.g. B.

   Magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, e.g. B. starch, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures, or adsorbents, colorants, flavorings and sweeteners. Furthermore, you can the new pharmacologically active compounds in the form of injectable, z. 13. Use intravenous preparations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, these e.g. B. from lyophilized preparations which contain the active ingredient alone or together with a carrier material, e.g. B.



  Mannitol, contained, can be prepared before use. The pharmaceutical preparations can

 <Desc / Clms Page number 10>

 NEN be sterilized and / or auxiliary materials, e.g. B. preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers.



   The present pharmaceutical preparations, which, if desired, may contain other pharmacologically valuable substances, are made in a manner known per se, for. B. by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes, and contain from about 0.1 to 100%, especially from about 1 to about 50%, lyophilisates up to 100% of the active ingredient. The single dose for a warm-blooded animal weighing about 70 kg is between 0.1 and 0.75 g, the daily dose between 0.2 and 1.0 g.



   In connection with the description, organic radicals denoted by "lower" contain up to 7, preferably up to 4, carbon atoms, unless expressly defined otherwise.



   The following examples serve to illustrate the invention; Temperatures are given in degrees Celsius.
 EMI10.1
    : cyclo 5. 4. 0] undec-5-ene stirred for 30 min at room temperature, then treated with ethyl acetate and washed with water and 2N hydrochloric acid until acidic and with saturated aqueous sodium chloride solution until neutral. The organic phase is dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel thick-layer plates using toluene / acetone 4: 1 as the mobile phase.

   The 7ss- [D-2-tert-butyl-
 EMI10.2
 Spectrum (in methylene chloride): characteristic bands at 3400.1780, 1730.1700, 1620.1490, 1335.1160 cm "'; and the 7 ss- [D-2-tert-butyloxycarbonylamino-2- (3-methylsulfonylamino- phenyl) - acetylamino] -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester from melting point 127 to 1320C (decomposition); thin-layer chromatogram: Rf value 0.22 (silica gel; toluene / acetone 3: 1); UV- Spectrum (in ethanol) x = 265 nm (s = 7000); IR spectrum (in methylene chloride): 3420 (broad), 1785.1725, 1705.1492, 1340 and 1160 cri 1.



   The starting material can be prepared as follows: b) A solution, cooled to -15 ° C., of 41.33 g (0.12 mol) of D-2-tert-butyloxycarbonylamino--2- (3-methylsulfonylamino-phenyl) -acetic acid and 16.7 ml (0.12 mmol) of triethylamine in 300 ml of tetrahydrofuran are mixed with 16.5 ml (0.12 mol) of isobutyl chloroformate and the pickle is stirred for 30 minutes. A solution of 21.6 g (0.11 mol) of 6-aminopenicillanic acid and 15.4 ml (0.11 mol) of triethylamine in 300 ml of tetrahydrofuran / water 2: 1 is then added. The reaction mixture is stirred for 1 h at 0 C and 2 h at room temperature, the p-value being kept constant at about 6.9 by adding triethylamine.

   The reaction mixture is adjusted to pH 2.0 at 5 C with phosphoric acid, saturated with sodium chloride and extracted three times with 500 ml of ethyl acetate each time, the organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The crude 6ss- [D-2-tert-butyloxycarbonylamino-2- (3-methylsulfonylaminophenyl) acetylamino] -2, 2-dimethyl-penam-4a-carboxylic acid obtained in the form of a light yellow foam has the Rf value in the thin-layer chromatogram 0.60.

   (Silica gel; ethyl acetate [n-butanol] pyridine / acetic acid / water 42: 21: 21: 6: 10). c) A solution of 67.84 g of crude 6ss [D-2-tert-butyloxycarbonylamino-2- (3-methylsulfonyl-aminophenyl-acetylamino] -2,2-dimethyl-penam-4α-carboxylic acid in 100 ml of glacial acetic acid) becomes 21.6 ml of 30% strength hydrogen peroxide (0.25 mol) were added over the course of 10 min and the mixture was stirred at room temperature for 2.5 h. The reaction mixture is then poured onto 2 l of ice water, which is in the form of a
 EMI10.3
 and dried in a vacuum. By extracting the filtrate with ethyl acetate, further amounts of crude 6% [D-2-tert-butyloxycarbonylamino-2- (3-methylsulfonylaminophenyl) acetylamino] -2,2-dimethyl-penam-4α-carboxylic acid-1- oxide can be obtained.

   Thin-layer chromatogram (silica gel: ethyl acetate / n-butanol / pyridine / acetic acid / water 42: 21: 21: 6: 10) Rf value -0, 30.

 <Desc / Clms Page number 11>

 d) A mixture of 87 g (about 0.12 mol) of crude 6ss- [[D-2-tert-butyloxycarbonylamino-2- (3-methylsulfonylaminophenyl) acetylamino] -2, 2-dimethyl-pneam-4a-carboxylic acid -I-oxide in 380 ml of dioxane is mixed with a solution of 32.9 g (0.18 mol) of diphenyldiazomethane in 130 ml of dioxane and stirred for 2.5 h at room temperature. After adding 5 ml of glacial acetic acid, it is evaporated in vacuo.

   The residue is digested with petroleum ether, the petroleum ether extract is discarded and the residue, 6 ss- [D-2-tert-butyloxycarbonylamino-2- (3-methylsulfonylaminophenyl) acetylamino] -2, 2-dimethyl-penam-4 a -carboxylic acid-diphenylmethylester-l-oxide, isolated as an amorphous powder; IR spectrum (methylene chloride): characteristic bands at 3450.3430, 1798.1750, 1725.1697, 1510.1390 and 1155 cm- '; Thin layer chromatogram:

   Rf value-0.22 (silica gel; toluene / ethyl acetate 3: 1). e) A mixture of 12.8 g (17.7 mol) 6ss- [D-2-tert-butyloxycarbonylamino-2- (3-methylsulfonyl-aminophenyl) -acetylamino] -2,2-dimethyl-pnean- Diphenylmethyl 4α-carboxylate 1-oxide and 3.26 g (19.5 mol) of mercaptobenzothiazole in 170 ml of toluene are boiled for 3 hours in a reflux apparatus with a water separator and then evaporated.

   The residue is chromatographed on silica gel with toluene / ethyl acetate 3: 1 as the eluent and gives the amorphous 2- {4- (benzothiazol-2-yldithio) -3- [a-tert-butyloxycarbonylamino-a- (3-methylsulfonylaminophenyD) -acetylami-
 EMI11.1
    -2-oxoazetidin-1-yl} -3-methylenebutyric acid diphenylmethyl ester, thin-layer chromatogram: Rf value 0.38 (silica gel; toluene / ethyl acetate 3: 1). f) A solution of 2.62 g (3.0 mmol) 2- {4- (Benzthiazol-2-yldithio) -3- [2-tert-butyloxycarbonylamino-2- (3-methylsulfonylaminophenyl) acetylamino] -2-oxoazetidin-1-yl) -3-methylen-butyric acid- (diphenylmethyl ester In 30 ml acetone / water 9:

   1, 0.868 g (3.46 mmol) of silver toluenesulfinate is added at OOC and the mixture is stirred in an ice bath for 1 h. The precipitate which has formed is filtered off.



   The filtrate is taken up in toluene and shaken out with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and, after a
 EMI11.2
 
2- {4- (p-Toluenesulfonylthio) -3- [2-tert-butyloxycarbonylamino-2- (3-methylsulforide): characteristic bands at 3440, 3430, 1785, 1752, 1722, 1620, 1510, 1390 and 1160 cm-l. g) In a solution of 2.59 g (3.0 mmol) 2- {4- (p-toluenesulfonylthio) - - 3- [2-tert-butyloxycarbonylamino-2- (3-methylsulfonylaminophenyl), cooled to -70 ° C. -acetylamino] -2-oxoazetidin-l-yl} - i-3-methylene-butyric acid diphenylmethyl ester in 230 ml of methylene chloride is a for 7 min
Ozone / oxygen stream (0.5 mmol ozone per min) initiated.

   After 1 ml of dimethyl sulfide has been added, the solution is stirred for a further 1 h without cooling and then evaporated in vacuo. The residue,
 EMI11.3
 
4- (p-Toluenesulfonylthio) -3- [2-tert-butyloxycarbonylamino-2- (3-methylsulfonylaminophenyl) acetyl-an; IR spectrum (methylene chloride, characteristic bands at 3430.1785, 1720.1680, 1665 (shoulder), 1620.1385 and 1160 cm-1; thin-layer chromatogram: Rf value -0.56 (silica gel; toluene / ethyl acetate 1: 1) h) A solution of 6.06 g (0.7 mmol) 2- {4- (p-toluenesulfonylthio) -3- [2-tert-butyloxycarbonylamino-2- (3-methylsulfonylaminophenyl) acetylamino] -2-oxo -azetidin-1-yl} -3-hydroxycrotonic acid diphenylmethyl ester in 20 ml of methylene chloride / methanol 1: 1 is stirred at 0 C with an excess of an ethereal diazomethane solution for 15 min and then evaporated in vacuo.



  Preparative layer chromatography of the residue on silica gel with toluene / ethyl acetate 1: 1 as the mobile phase and elution of the zone visible in UV light yields the 2- {4- (p-toluenesulfonylthio) -
 EMI11.4
 
3- [2-tert-butyloxycarbonylamino-2- (3-methylsulfonylaminophenyl) acetylamino] -2-oxoazetidin-1-yl} -toluene-ethyl acetate 1: 1).



   Example 2: A solution of 0.723 g (1 mmol) 7ss- [D-2-tert. -Butyloxycarbonyl-
 EMI11.5
 Lene chloride is added and washed successively with 25 ml each of a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and evaporated under reduced pressure. The raw product

 <Desc / Clms Page number 12>

 
 EMI12.1
 spectrum (in methylene chloride): characteristic bands at 3420.1780, 1700.1490, 1333.1160 and 1050 cm- '.



   Example 3: A solution, cooled to −10 ° C., of 1.48 g (2. mmol) of 7 ss- D-2-tert-butyloxycarbonylamino-2- (3-methylsulfonylamonophenyl) acetylamino] -3-methoxy Diphenylmethyl-3-cephem-4-carboxylic acid 1-oxide in 30 ml of dimethylformamide is mixed with 2.80 g of phosphorus trichloride with the exclusion of air. After standing for 15 minutes, the reaction mixture is poured onto a mixture of ice and an aqueous dipotassium hydrogen phosphate solution; the aqueous mixture becomes
Extracted twice with 100 ml of ethyl acetate each time. The organic extract is washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated.



   The residue is chromatographed on silica gel; the amorphous is eluted with toluene: acetone 3: 1
7 ss- [D-2-tert-butyloxycarbonylamino-2- (3-methylsulfonylaminophenyl) -acetyl-amino] -3-methoxy-3-cephem-4-carboxylic acid-diphenylmethyl ester as a substance pure according to thin layer chromatography, Rf - 0, 22 (silica gel; toluene-acetone 3: 1, development with iodine vapor); Ultraviolet absorption spectrum
 EMI12.2
 



   Example 4: a) A mixture of 0.557 g of 7ss- [D-2-tert-butyloxycarbonylamino-2- (3-methylsulfonylamino-phenyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid 2.5 ml of pre-cooled trifluoroacetic acid and 2.5 ml of methylene chloride are stirred for 30 min at 0 under an argon atmosphere and then 25 ml of a 1: 1 mixture of petroleum ether and diethyl ether are added at 0.



  The beige precipitate is filtered off, washed with a little diethyl ether and dried under reduced pressure. The trifluoroacetic acid salt of 7ss- [D-2-amino-2- (3-methylsulfonylami- nophenyl) acetylamino] -3-methoxy-3-cephem-4-carboxylic acid thus obtained is dissolved in 5 ml of water, twice with each 3 ml of ethyl acetate are extracted, and the acidic aqueous phase (PH 1.8) is adjusted to pH 5.2 by adding a 2N aqueous sodium hydroxide solution dropwise. The solution is concentrated to about half the volume, 12 ml of acetone are added and the mixture is left to stand at about -18 for 16 hours.

   The precipitate formed is filtered off, with acetone and
 EMI12.3
 drat, which decomposes from 1700; Thin-layer chromatogram: (silica gel; identification with ninhydrin): Rf - 0.22, (system: sec-butanol / acetic acid / water 67:10:23) ultraviolet absorption spectrum
 EMI12.4
 The same compound can also be obtained as follows: ai) A solution, cooled to 0 C, of 8.0 g (14.4 mmol) of 7ss- [D-2-tert-butyloxycarbonylamino-
 EMI12.5
 stirred under an argon atmosphere and then treated with 500 ml of a 1: 1 mixture of petroleum ether and diethyl ether at 0 C. The beige precipitate is filtered off, washed with a little diethyl ether and dried under reduced pressure.

   The resulting trifluoroacetic acid salt of 7ss- [D-2-amino-2- (3-methylsulfonylaminophenyl) acetylamino] -3-methoxy-3-cephem-4-carboxylic acid is dissolved in 70 ml of ice water and extracted 3 times with 30 ml of ethyl acetate each time . The acidic aqueous phase (pH 2.0) is adjusted to pH 5.2 by the dropwise addition of a 20% strength triethylamine solution in methanol and 160 ml of isopropanol are added at 0 C. The precipitate formed is recrystallized from isopropanol / water 2: 1, filtered off, washed with a little isopropanol and dried.

   Since the crystallizate still contains little organic solvent even after drying, this is still 1/2 hour in 50% aqueous solution at 400 digits.
 EMI12.6
 

 <Desc / Clms Page number 13>

 
 EMI13.1
 

 <Desc / Clms Page number 14>

 
 EMI14.1
    [D-2-Amino-2- (3-methylsulfonylaminophenyl) acetylamino] -3-methoxy-3-cephem - 3-cephem-4-carboxylic acid diphenylmethyl ester with 4.5 ml of trifluoroacetic acid and 0.8 ml of anisole in 10 ml of methylene chloride liberate the amino group and the protected 4-carboxyl group and the trifluoroacetic acid salt obtained by treatment with 20% triethylamine solution in methanol is converted to the isoelectric point in the inner salt of the 7ss - [D-2-amino-2- (3 -methylsulfonylaminophenyl) -3-methoxy-3-cephem-4-carboxylic acid;

   M.p. from 1720 (decomposition). ai) A mixture of 10, 12 g (14 mmol) 7ss- [D-2-tert-butyloxycarbonylamino-2- (3-methylsulfo-
 EMI14.2
 Toluene was added and the mixture was evaporated under reduced pressure. The residue is dried under high vacuum, digested with diethyl ether and filtered off. This is how the powder is obtained
 EMI14.3
 ester and adjusts the pH with a 20% triethylamine solution in methanol to about 5.6, with a colorless precipitate forming after addition of 160 ml of isopropanol. The mixture is stirred in an ice bath for 1 h. The colorless precipitate is filtered off, washed with isopropanol and diethyl ether and dried under reduced pressure. Since the crystals still have a little isopropanol or even after drying.

   Contains diethyl ether, this is digested for another 1/2 hour in 50% aqueous solution at 40 ° C., cooled to 00, filtered and dried again. You get in
 EMI14.4
 is present, melting point from 175 ° C. (with decomposition); [a] = + 144 (c = 1.035 in 0.1N hydrochloric acid); Thin-layer chromatogram (silica gel; developing with ninhydrin): Rf -0.19 (system: sec-butanol-acetic acid-
 EMI14.5
 : 1trolle at a p-value less than 7, 6 slowly brought into solution with a total of about 5 ml of 2N sodium hydroxide solution.

   The solution freed from a few residual bodies by filtration gives, after lyophilization, 4.9 g of 7ss- (D-2-amino-2- (3-methylsulfonylaminophenyl) acetylamino] -3-methoxy-3-cephem-4-carboxylic acid sodium salt.

** WARNING ** End of DESC field may overlap beginning of CLMS **.

 

Claims (1)

PATENT CLAIMS: l. Process for the preparation of new $ 7ss- [D-2-amino-2- (lower alkylsulfonylaminophenyl) acetylamino] -3-R-cephem-4-carboxylic acids EMI 14.6 wherein R denotes lower alkoxy or chlorine, and their salts, characterized in that one 7 ss [D-2-amino-2- (lower alkylsulfonlamino-phenyl) -acetylamino] -3-R-2-cephem-4ss-carboxylic acid <Desc / Clms Page number 15> EMI15.1 in which 2-amino and / or carboxyl optionally in protected and / or lower alkylsulfonylamino may optionally be in N-acylated form, isomerized by oxidizing them in the 1-position with a peracid or an organic halite compound and the corresponding 3- Cephem-l-oxide reduced with a reducing agent, and if necessary, in a compound obtained, a protected 2-amino group and / or an N-acylated lower alkylsulfonylamino group into the free amino group or into the lower alkylsulfonylamino group, and / or the protected carboxyl group into the free carboxyl group, and, if desired, a salt obtained into the free one Compound or converted into another salt and / or a free compound into a salt. 2. The method according to claim 1, characterized in that a 2-cephem starting material (VIII) by oxidizing in the 1-position with an organic peracid, such as 3-chloro-perbenzoic acid, and reducing the obtainable 1-oxide of the corresponding 3 -Cephem compound isomerized with a reducing agent such as phosphorus trichloride. 3. The method according to any one of claims 1 and 2, characterized in that a protected 2-amino group and / or an N-acylated lower alkylsulfonylamino group is converted solvolytically or reductively into the free 2-amino group or into the lower alkylsulfonylamino group in a compound obtained according to the process, and / or a protected carboxyl group is solvolytically or reductively, optionally simultaneously, converted into a free carboxyl group. 4. The method according to any one of claims 1 to 3, characterized in that compounds (1) according to claim 1 or salts thereof, from starting compounds of the formula (II) according to claim 1, wherein the lower alkylsulfonylamino is in the 3-position of the phenyl radical . 5. The method according to any one of claims 1 to 4, characterized in that the 7 ss- - [D-2-tert. -Butyloxycarbonylamino-2- (3-methylsulfonylamino-phenyl) -acetylamino] -3-methoxy-2- cephem-4a-carboxylic acid diphenylmethyl ester with 3-chloroperbenzoic acid in the 1-position, the resulting corresponding 3-cephem-l- oxide reduced by treatment with phosphorus trichloride, the corresponding 3-cephem compound obtained is isolated, the protective groups are treated therefrom EMI15.2 Sodium salt, isolated. 6. The method according to any one of claims 1 to 5, characterized in that 7ss - [D-2- tert. Butyloxycarbonylamino-2- (3-methylsulfonylamino-phenyl) -aeetylamino] -3-R'-cephem-4 <* -carboxylic acid diphenylmethyl ester is oxidized with 3-chloroperbenzoic acid, the corresponding 3-cephem- 1-oxide compound obtained reduced with PCl3 and split off the protective groups and the product obtained optionally converted into a salt.