CH605985A5 - 7-Alpha-methoxy-penicillanic and cephalosporanic acid derivs - Google Patents

Abstract

7-Alpha-methoxy-penicillanic and cephalosporanic acid derivs with broad-spectrum antibacterial activity

Description

  

  
 



   The present invention relates to a process for the production of methoxylated aminomethylheterocycles, in particular 6ss-acylamino-6a-methoxy-penam-3-carboxylic acid compounds and 7ss-acylamino-7-methoxy-3-cephem-4-carboxylic acid compounds of the formula
EMI1.1
 in which X is sulfur or oxygen, and in which the grouping of the formula -S-A- is a radical of the formula
EMI1.2
 denotes in which R1 is hydrogen or a radical of the formula -CH2-R2, in which R2 is hydrogen. a free, etherified or esterified hydroxyl or mercapto group or a quaternary ammonium group, and R denotes hydroxyl or together with the carbonyl group -C (= 0) - an esterified carboxy group which can be cleaved under physiological conditions, and salts thereof, and their further use .



   The radical X in the five-membered heterocycle is primarily sulfur, but can also be oxygen. The aminomethyl heterocycle therefore represents a 4- or 5-aminomethyl-2- or 3-thienyl radical, also a 3-aminomethyl -2-thienyl or 2-aminomethyl-3-thienyl radical, or a corresponding furyl, e.g. the 4- or 5-aminomethyl-2-fural radical.



   An etherified hydroxy or mercapto group R2 is e.g.



  a hydroxy or mercapto group etherified by a lower aliphatic hydrocarbon radical. An etherified mercapto group R2 can furthermore represent a mercapto group etherified by an optionally substituted heterocyclic radical with 1 to 4 ring nitrogen atoms and optionally a further ring heteroatom from the group oxygen and sulfur, bonded to the sulfur via a ring carbon atom.



   An esterified hydroxy or mercapto group R2 is esterified by a lower aliphatic carboxylic acid or by an optionally N-substituted carbamic acid esterified hydroxy or mercapto group.



   Quaternary ammonium groups R2 are quaternary ammonium groups derived from tertiary organic bases, preferably from corresponding aliphatic amines or primarily from corresponding heterocyclic nitrogen bases, connected via the nitrogen atom to the methyl carbon atom.



   Hydroxy and mercapto groups R2 etherified with an aliphatic hydrocarbon radical are in particular lower alkoxy, preferably with up to 7, in particular with up to 4 carbon atoms, primarily methoxy, as well as ethoxy, n-propyloxy or isopropyloxy, furthermore straight-chain or branched butyloxy, pentyloxy, hexyloxy or heptyloxy, or lower alkylthio, preferably with up to 7, in particular with up to 4 carbon atoms, primarily methylthio, as well as ethylthio, n-propylthio or isopropylthio, also straight or branched butylthio, pentylthio, hexylthio or heptylthio.



   In a mercapto group R2 which is etherified by said heterocyclic radical, this has aromatic properties or can be partially saturated. Substituents include Lower alkyl. especially methyl, as well as ethyl, n-propyl, isopropyl or straight-chain or branched butyl, pentyl or hexyl, hydroxy-lower alkyl, e.g. Hydroxymethyl, cycloalkyl, e.g. Cyclopentyl or cyclohexyl, aryl, as optionally substituted by halogen, e.g. Chlorine, or nitro substituted phenyl, aryl lower alkyl, e.g. Benzyl, or heterocyclyl such as furyl, e.g. 2-furyl. Thienyl, e.g. 2-thienyl, or oxazolyl, e.g. 2 oxazolyl, or functional groups such as halogen, e.g. Fluorine, chlorine or bromine, optionally substituted amino, such as amino optionally mono- or disubstituted by lower alkyl, e.g.

  Amino, methylamino or dimethylamino, nitro, lower alkoxy, e.g. Methoxy, alkoxy n-butyloxy or 2 ethylhexyloxy, or optionally functionally modified carboxy such as carboxy, esterified carboxy such as lower alkoxycarbonyl, e.g. Methoxy- or ethoxycarbonyl, optionally substituted, such as N-mono- or N, N-di-lower alkylated carbamoyl, e.g. N-methylcarbamoyl, or cyano, as well as oxo or oxido, where one or more such substituents, which are primarily associated with ring carbon atoms, e.g. Lower alkyl and oxido, but also linked to ring nitrogen atoms, may be present.



   Such heterocyclic radicals are primarily optionally substituted. e.g. the above substituents, especially lower alkyl, e.g. Methyl, containing, monocyclic, five-membered diaza, triaza, tetraza, thiaza, thiadiaza, thiatriaza, oxaza or oxydiazacyclic radicals of aromatic character or corresponding, optionally substituted, e.g. the above-mentioned substituents containing radicals with a fused-on benzene ring, such as benzodiaza or benzooxazacyclic radicals, optionally substituted, e.g. the above-mentioned substituents, primarily oxido-containing, monocyclic, six-membered monoaza- or diazacyclic radicals of aromatic character or corresponding, partially saturated, optionally substituted, e.g. radicals containing the above substituents, primarily oxo, or optionally substituted, e.g.

   Bicyclic triaza- or tetrazacyclic radicals of aromatic character containing the abovementioned substituents or corresponding partially saturated, optionally substituted. e.g. radicals containing the above substituents, primarily oxo.



   Preferred heterocyclically etherified mercapto groups R2, in which the heterocyclic radical is a corresponding monocyclic, five-membered radical or a corresponding benzoheterocyclic radical, are i.a. Imidazolylthio, e.g. 2-imidazolylthio, triazolyl optionally substituted by lower alkyl and / or phenyl, e.g.

   s-triazol-3-yl-thio, 5-methyl-s-triazol-2-ylthio, 1 H-1, 2,4-triazol-5-ylthio, 3-methyl-1-phenyl-1 H-1 , 2,4-triazol-5-ylthio, 4,5-dimethyl-4H -1,2,4-triazol-3-ylthio or 4-phenyl-4H-1,2,4-triazol-3-ylthio, optionally Tetrazolylthio substituted by lower alkyl, phenyl or halophenyl, e.g. 1 H-tetrazol-5-ylthio, 1 methyl I H-tetrazol-5-ylthio, 1-phenyl- I H-tetrazol-5-yl-thio or 1 - (4-chlorophenyl) - 1 H-tetrazol-5- ylthio, thiazolylthio optionally substituted by lower alkyl or thienyl, e.g.

   2-thiazolylthio, 4- (2-thienyl) -2-thiazolylthio or 4,5-dimethyl-2-thiazolylthio, thiadiazolylthio optionally substituted by lower alkyl, e.g. 1,3,4-thiadiazol-2-yl-thio, 2-methyl-1,3,4-thiadiazol-5-ylthio or 1,2,4-thiadiazol -5-ylthio, thiatriazolylthio, e.g. 1,2,3,4-thiatriazolyl-5-ylthio, optionally substituted by lower alkyl or phenyl oxazolylthio or isoxazolylthio, e.g.

   5-oxazolylthio, 4-methyl-5-oxazolylthio, 2-oxazolylthio, 4,5-diphenyl-2-oxazolylthio or 3-methyl-5-isoxazolylthio, oxadiazolylthio optionally substituted by lower alkyl, phenyl, nitrophenyl or thienyl, e.g. 1,2,4-oxadiazol-5-ylthio. 2-methyl-1,3-4 -oxadiazol-5-ylthio, 2-phenyl-1,3,4-oxadiazol-5-ylthio, 5- (4-nitrophenyl) -l, 3,4-oxadiazol-2- ylthio or 2- (thienyl) -1,3,4-oxadiazol-5-ylthio, optionally halogen-substituted benzimidazolylthio, e.g. 2-benzimidazolylthio or 5-chloro-2-benzimidazolylthio, or benzoxazolylthio optionally substituted by halogen or nitro, e.g. 2 benzoxazolylthio, 5-nitro-2-benzoxazolylthio or 5-chloro -2-benzoxazolylthio.



   Preferred heterocyclically etherified mercapto groups R2, in which the heterocyclic radical is a corresponding monocyclic, six-membered radical or a corresponding partially saturated radical, are i.a. 1-oxido-pyridylthio optionally substituted by halogen, e.g. I-oxido-2-pyridylthio or 4-chloro-1 -oxido-2-pyridylthio, optionally N-oxido-pyridazinylthio substituted by lower alkyl, lower alkoxy or halogen, e.g.

   2-oxido-6-pyridazinylthio, 3-chloro-l-oxido-6-pyridazinylthio, 3-methyl-2-oxido-6-pyridazinylthio, 3-methoxy-l-oxido-6-pyridazinylthio, 3-ethoxy l- oxido-6-pyridazinylthio, 3-n-butyloxy-1-oxido-6- pyridazinylthio or 3- (2-ethylhexyloxy) -l-oxido-6-pyridazinylthio, or optionally substituted by lower alkyl, amino, di-lower alkylamino or carboxy 2-oxo-1,2-di-hydro-pyrimidinylthio, e.g.

   2-oxo-1,2-dihydro-4-pyrimidinylthio, 6-methyl-2-oxo-1,2-dihydro-4-pyrimidinylthio, 5-methyl -2-oxo-1,2-dihydro-4-pyrimidinylthio, 6- Amino-2-oxo-1,2-dihydro-4-pyrimidinylthio, 6-dimethylamino-2-oxo-1,2-dihydro-4-pyrimidinylthio, 5-carboxy-2-oxo-1, 2-dihydro- 4- pyrimidinylthio or 6-carboxy-2-oxo-1,2-dihydro-4-pyrimidinylthio.



   Preferred heterocyclic etherified mercapto groups R2, in which the heterocyclic radical is a corresponding bicyclic, optionally partially saturated radical, are i.a. Triazolopyridylthio, e.g. 3-s-triazolo [4,3-a] pyridylthio or 5-v-triazolo [4,5-bjpyridylthio, or purinylthio optionally substituted by halogen and / or lower alkyl, e.g. 2-purinylthio, 6-purinylthio or 8-chloro-2-methyl-6-purinylthio, furthermore 2-oxo-1,2-dihydro-purinylthio. e.g. 2-oxo- 1, 2-dihydro-6-purinylthio.



   Hydrixy groups R2 esterified with aliphatic carboxylic acids are in particular lower alkanoyloxy, in particular acetyloxy, also formyloxy, propionyloxy, valeryloxy, hexanoyloxy, heptanoyloxy or pivalyloxy.



   An esterified hydroxy group R2 is also a hydroxy group esterified by an optionally N-substituted half-amide of carbonic acid. N-substituents are optionally halogen, e.g. Chlorine containing lower alkyl, e.g.



  Methyl, ethyl or 2-chloroethyl. or lower alkanyl, e.g.



  Acetyl or propionyl. Hydroxy groups R2 esterified in this way are e.g. Carbamoyloxy, N-methylcarbamoyloxy, N ethylcarbamoyloxy, N - (2-chloroethyl) carbamoyloxy or N acetylcarbamoyloxy.



   In a quaternary ammonium group R2, which is derived from a tertiary organic base, the nitrogen atom is bonded to the methyl carbon atom and is accordingly present in a quaternized, positively charged form. Quarternary ammonium groups are i.a. Tri-lower alkylammonium, e.g. Trimethylammonium, triethylammonium, tripropylammonium or tributylammonium, especially but optionally substituted, e.g. Lower alkyl, such as methyl, hydroxy-lower alkyl, such as hydroxymethyl, amino, sulfonamido, such as p-aminobenzenesulfonamido, hydroxy, halogen, such as fluorine, chlorine, bromine or iodine, halo-lower alkyl, such as trifluoromethyl, sulfo, optionally functionally modified carboxy, such as carboxy, lower alkoxycarbonyl, e.g. Methoxycarbonyl, cyano, optionally by lower alkyl, e.g. Methyl or ethyl, or hydroxy lower alkyl, e.g.

  Hydroxymethyl, N-mono- or N, N-disubstituted carbamoyl, e.g. Carbamoyl, N-methyl-carbamoyl or N, N-dimethyl-carbamoyl, hydrazinocarbonyl optionally N-substituted by lower alkyl, e.g. Hydrazinocarbonyl, carboxy-lower alkyl, such as carboxymethyl, lower alkanyl, such as acetyl, or l-lower alkyl-pyrrolidinyl, such as l-methyl-2-pyrrolidinyl, mono- or polysubstituted, monocyclic or bicyclic azacyclic ammonium groups of aromatic character. with 1 or 2 ring nitrogen and optionally one ring sulfur atom, such as pyrimidinium, pyridazinium, thiazolium. Quinolinium and primarily pyridinium.



   Heterocyclic ammonium groups R2 are primarily optionally lower alkyl, hydroxy-lower alkyl, sulfonamido, hydroxy, halogen, trifluoromethyl, sulfo, carboxy, lower alkoxycarbonyl, cyano, lower alkanyl, I-lower alkyl-pyrrolidinyl or optionally N-substituted by lower alkyl or hydronower alkyl-containing carbamoyl-containing pyridinium, e.g.

  Pyridinium, 2-, 3- or 4-methyl-pyridinium, 3,5-dimethyl-pyridinium, 2,4,6-trimethyl-pyridinium, 2-. 3 or 4-ethyl-pyridinium, 2-, 3- or 4-propyl-pyridinium or in particular 4-hydroxymethyl-pyridinium, furthermore 2-amino- or 2-amino-6-methyl-pyridinium. 2-sulfanilamido-pyridinium, 3-hydroxypyridinium, 3-fluoro-, 3-chloro-, 3-iodo- or especially 3-bromopyridinium, 4-trifluoromethyl-pyridinium, 3-sulfopyridinium, 2- , 3- or 4-carboxy- or 2,3-dicarboxy-pyridinium, 4-methoxycarbonyl-pyridinium.

   3- or 4-cyano-pyridinium, 3-carboxymethyl-pyridinium, 3- or 4-acetyl-pyridinium, 3- (1-methyl-2-pyrrolydinyl) -pyridinium, and especially 4-carbamoyl-. as well as 3-carbamoyl-, 3- or 4-N-methylcarbamoyl-, 4-N, N-dimethylcarbamoyl-, 4-N -ethylcarbamoyl-, 3-N, N-diethylcarbamoyl, 4-N-propylcarbamoyl-, 4- Isopropylcarbamoyl- and 4-hydroxymethylcarbamoyl-pyridinium, also optionally appropriately substituted pyrimidinium, pyridazinium, thiazolium or quinolinium.



   In an esterified carboxyl group of the formula -C (= O) -R which can be cleaved under physiological conditions, R is primarily an acyloxymethoxy group in which acyl is e.g. the remainder of an organic carboxylic acid. is primarily an optionally substituted lower alkanecarboxylic acid, or in which acyloxymethyl forms the residue of a lactone. Such groups R2 are lower alkanoyloxymethoxy, e.g. Acetyloxymethyloxy or pivaloyloxymethoxy, amino-lower alkanoyloxymethoxy, especially ee-amino-lower alkanoyl oxymethoxy, e.g. Glycyloxymethoxy, L-vallyloxymethoxy or L-leucyloxymethoxy, also phthalidyloxy.



   Salts are, in particular, those of compounds of formula 1 with a free carboxy group —C (= O) -R. primarily metal or ammonium salts such as alkali metal and alkaline earth metal, e.g. Sodium, potassium, magnesium or calcium salts, and ammonium salts with ammonia or suitable organic amines, primarily aliphatic cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di- or polyamines, and heterocyclic bases for salt formation in Question come, such as lower alkylamines, e.g.

  Triethylamine, hydroxy lower alkylamines, e.g. 2-hydroxyethylamine, bis (2-hydroxyethyl) amine or tri- (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, e.g. 4-aminobenzoic acid-2-diethylaminoethyl ester, lower alkyleneamines, e.g. I-ethyl-piperidine, cycloalkylamines, e.g. Dicyclohexylamine, or benzylamines, e.g. N, N'-dibenzyl-ethylenediamine, also bases of the pyridine type, e.g. Pyridine, collidine or quinoline. Compounds of the formula I can also contain acid addition salts, e.g. with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, e.g. Trifluoroacetic acid, as well as with amino acids such as arginine and lysine.

  Compounds of formula I with a free carboxyl group can also be used in the form of internal salts, i. in zwitterionic form.



   The compounds of the formula I and their pharmaceutically usable, non-toxic salts are valuable, antibiotic substances which can be used in particular as antibacterial antibiotics. For example, they are against microorganisms, such as against gram-positive bacteria (with minimum concentrations in in vitro tests of about 0.001 mg / ml), e.g. against Staphylococcus aureus (e.g. in mice in doses of about 2 to 10 mg / kg sc, including against penicillin-resistant Stahpylococcus aureus (e.g. in vitro in dilutions of about 0.001 mg / ml), also against Bacillus subtilis, Bacterium megathenum and Bacterium cereus, and against gram-negative bacteria (with minimum concentrations in in vitro tests of about 0.005 to about 0.03 mg / ml), e.g. against Escherichia coli (e.g. in mice in doses of about 20 to about 100 mg / kg sc, ) Incl.

   against ampicillin-, carbencillin- and rifamycin-resistant Escherichia coli (e.g. in vitro in dilutions of about 0.005 mg / ml), furthermore against sticky pneumoniae, Salmonella typhimurium, including ampicillin-, carbencillin- and rifamycin-resistant Salmonella typhimurium (e.g. in vitro in dilutions of about 0.005 mg / ml), Proteus vulgaris, Proteus mirabilis, including carbenicillin-resistant Proteus mirabilis, and Proteus rettgeri (in vitro in dilutions of about 0.03 mg / ml). The new compounds can therefore be used accordingly, e.g. in the form of antibiotic preparations, use.



   The present invention relates primarily to those compounds of the formula I in which X is oxygen or, in particular, sulfur, and the aminomethyl-substituted heterocycle is a 4- or 5-aminomethyl-2-thienyl-, and also a 4- or 5-aminomethyl -2-furyl radical, the grouping of the formula -SA- stands for a radical of the formula Ia, but in particular a radical of the formula Ib in which R1 is the group of the formula -CH2-R2, and R2 is hydrogen, lower alkanoyloxy, especially acetyloxy , optionally substituted carbamoyloxy, etherified mercapto or quaternary ammonium, and where R is hydroxy, as well as salts, in particular the non-toxic, pharmaceutically acceptable salts, in particular the alkali or alkaline earth metal salts, and the internal salts of such compounds.



   The present invention relates primarily to compounds of the formula I in which X is oxygen or, in particular, sulfur, and the aminomethyl-substituted heterocycle is a 4- or 5-aminomethyl-2-thienyl, furthermore a 4- or 5-aminomethyl 2-furyl radical, the grouping of the formula -SA- represents a radical of the formula Ia or Ib, wherein R1 is the group of the formula -CH2-R2 and R2 is hydrogen, lower alkanoyloxy, for example Acetyloxy, optionally N-alkylated carbamoyloxy, e.g.

  Carbamoyloxy, optionally substituted heterocyclylthio, in which heterocyclyl is a monocyclic, five-membered heterocyclic radical of aromatic character which is connected to the thiosulfur atom via a ring carbon atom, and which contains 2 or 3 ring nitrogen atoms and optionally also one ring oxygen, ring sulfur or ring nitrogen atom, one such atom The radical can optionally be substituted by lower alkyl, in particular methyl, or in which heterocyclyl is an unsaturated monocyclic, six-membered heterocyclic radical which is connected to the thiosulfur atom via a ring carbon atom and contains 2 ring nitrogen atoms, either one ring nitrogen atom containing an oxo group or one ring carbon atom containing an oxo group , and where such a heterocyclyl radical is optionally replaced by lower alkyl, for example

  Methyl, lower alkoxy e.g. Methoxy, or halogen, e.g. Chlorine, can be substituted, or a pyridinium radical, which can optionally be substituted by carboxy, carbamoyl or hydrazinocarbanoyl, and in which R stands for hydroxy, as well as salts, in particular pharmaceutically usable, non-toxic salts8, especially the alkali or alkaline earth metal salts, and the internal salts of such compounds.



   The invention relates in particular to 3-cephem compounds of the formula I in which X is sulfur and the aminomethyl-substituted heterocycle is a 4- or, preferably, 5-aminomethyl-2-thienyl radical, the grouping of the formula -SA is the radical of the formula Ib , where R1 is the radical of the formula -CH2-R2, where R2 is hydrogen, acetyloxy, carbamoyloxy, optionally by lower alkyl, for example Methyl, substituted thiadiazolylthio linked to the thiosulfur atom through a ring carbon atom, e.g. 1, 3,4-thiadiazol-2-ylthio, 5-methyl-1,3,4-thiadiazol-2-ylthio or 5-methyl-1, 2,4-thiadiazol-2-ylthio, or tetrazolylthio, e.g. 1 -methyl-5-tetrazolylthio, optionally by lower alkyl, e.g. Methyl, lower alkoxy e.g. Methoxy, or halogen, e.g.

  Chlorine, substituted N-oxidopyridazinylthio linked to the thiosulfur atom through a ring carbon atom, e.g. 3-methyl-2-oxalo-6-pyridazinylthio, 3-methoxy-1 -oxido-6-pyridazinylthio or 3-chloro-1-oxido-6-pyridanizylthio, or pyridinium optionally substituted by carbamoyl, e.g. Pyridinium or 3-carbamoyl-pyridinium, and in which the group R is hydroxy, as well as salts, especially the non-toxic, pharmaceutically acceptable salts, especially the alkali or alkaline earth metal salts, and the internal salts of such compounds.



   The invention relates primarily to 3-cephem compounds of the formula I in which X is sulfur and the aminomethyl-substituted heterocycle is a 4- or, preferably, 5-aminomethyl-2-thienyl radical, the grouping of the formula -SA- the radical of Formula Ib denotes where R1 is the radical of the formula -CH2-R2, where R2 denotes hydrogen, acetyloxy, 1,3,4-thiadiazol-2-ylthio, 1-methyl-5-tetrazolylthio or pyridinium, and where R Represents hydroxy, as well as salts, in particular the non-toxic, pharmaceutically acceptable salts, in particular the alkali or alkaline earth metal salts, and the internal salts of such compounds.



   In particular, the invention relates to 3-acetyloxymethyl-7ss- [2- (5-aminomethyl-2-thienyl) -acetylamino] -7a-methoxy--3-cephem-4-carboxylic acid, 3-acetyloxymethyl-713 - [2- (4 -amino-methyl-2-thienyl) -acetylamino] -7a-methoxy-3-cephem-4-carboxylic acid, 3-acetyloxymethyl-7ss- [2- (5-aminomethyl-2-furyl) -acetylamino] -7a -methoxy-3-cephem-4-carboxylic acid, 7ss- [2- (5-amino-methyl-2-thienyl) -acetylamino] -7a-methoxy- -3-methyl-3-cephem-4-carboxylic acid, 7ss- [2- (5-aminomethyl--2-thienyl) -acetylamino] -7a-methoxy-3- (5-methyl-1,3, 4thia-diazol-2-ylthiomethyl) -3-cephem-4-carboxylic acid, 7ss - [2- (5-Aminomethyl-2-thienyl) -acetylamino] -7a-methoxy-3- (5-methyl-1-tetrazolylthiomethyl) -3-cephem-4-carboxylic acid and <RTI

    ID = 3.24> 7ss - [2- (5-aminomethyl-2-thienyl) -acetylamino] -7a-methoxy--3-pyridiniummethyl-3-cephem-4-carboxylic acid, as well as its internal salts, which are excellent at the given doses have antibiotic effects and are used accordingly in the form of antibiotic preparations.



   The new compounds of the formula I can be obtained if one is in the 6a or 7a position of a Penambzw. 3-cephem compound of the formula
EMI4.1
 wherein the amino of the aminomethyl group is preferably in protected form, and the radical of the formula -SA- is a radical of the formula Ia or Ib, in which R has the meaning given above, with a free carboxyl group of the formula -C (= O) -R preferably is in temporarily protected form, or a salt thereof, which introduces the methoxy group and, if desired or necessary, carries out the additional process steps.



   The introduction of the methoxy group into the 6a-position of a penam or into the 7-position of a 3-cephem starting material of the formula IV can be carried out in a manner known per se.



   So you can get an acylimino compound of the formula
EMI4.2
 wherein the amino of the aminomethyl group is in protected form, and the radical of the formula -SA- has the meaning given above, wherein a free carboxyl group of the formula -C (= O) -R is present in temporarily protected form, treat with methanol and in a preserved form Compound ge: convert protected amino of the aminomethyl group into free amino, and, if necessary or desired, convert a free carboxyl group of the formula -C (= O) -R into a physiologically cleavable esterified carboxyl group of the formula -C (= O) -R and / or, if desired, converting a salt obtained into the free compound or into another salt or a free compound obtained into a salt.



   In the starting material of the formula IVa, free functional groups, in particular amino of the aminomethyl substituent and a free carboxyl group -C (= O) -R in a radical -S-A-, and any free functional groups present in a radical R2, are temporarily protected.



   Temporarily protected amino or carboxyl groups are protected by any of the preferably easily cleavable protecting groups known in peptide or penicillin and caphalosporin chemistry, e.g. in application no.



  14 034/73 described, protected amino and carboxyl groups.



   So an amino group can e.g. as a preferably easily cleavable acylamino, furthermore as an acylmethylamino, 2-carbonyl-1-vinylamino, arylthioamino or aryl-lower alkylthioamino group, a free carboxyl group e.g. as, preferably easily cleavable, esterified carboxyl group, and a free functional group in the radical R2, e.g. a e.g. are in the form of an acyloxy group.



   These protecting groups may be used during or after the above reaction by known, e.g. on the registration no.



  14 034/73 or in the manner described below.



   The above reaction is carried out in a manner known per se, usually in the presence of a solvent or diluent or a mixture of such, wherein methanol can also serve as such at the same time, preferably with cooling, e.g. up to about -80, as well as at room temperature or with gentle heating, and, if necessary, in a closed vessel and / or under an inert gas, e.g. Nitrogen atmosphere.



   The starting material of the formula Wa is mostly reacted with the methanol without being isolated or is prepared in the presence of this reagent. One goes e.g.



  from a compound of the formula IV, in which the amino of the aminomethyl group and the carboxyl group of the formula -C (= O) -Ro, as well as any additional functional groups present in protected form, and treats them with an anion-forming agent, followed by one N-halogenating agent and reacts, if necessary, with a base which splits off hydrogen halide, or a compound of the formula
EMI4.3
 in which RO stands for an organic radical, and in which the amino of the aminomethyl group and the carboxyl group of the formula -C (= O) -R, as well as any additional functional groups present, are in temporarily protected form, is reacted with halogen, followed by a base .



  The 6-acylimino-penam or 7-acylimino-3-cephem compound of the formula IVa, which in the presence of methanol is converted into the desired 6ss-acylamino-6a-methoxy-penam or 7ss- -acylamino-6a-methoxy-3-cephem compound is converted, on which one carries out the additional steps listed above, if necessary or desired.



   A suitable anion-forming agent with which a starting material of the formula IV is reacted is primarily an organometallic base, in particular an alkali metal, primarily an organic lithium base. Such compounds are in particular corresponding alcoholates, such as suitable lithium lower alkanolates, primarily lithium methylate, or corresponding metal hydrocarbon bases, in particular lithium lower alkanes and preferably lithium phenyl.

  The reaction with the anion-forming organometallic base is usually carried out with cooling, e.g. from about OOC to about -80 "C, and in the presence of a suitable solvent or diluent, for example an ether such as tetrahydrofuran, when using lithium methylate also in the presence of methanol, and, if desired, in a closed vessel and / or in an inert gas, for example nitrogen, atmosphere.



   The N-halogenating agent used is usually a sterically hindered organic hypohalite, in particular chlorite, and primarily a corresponding aliphatic hypohalite, e.g. chlorite, such as a tertiary lower alkyl hypohalite, e.g. -chlorite. The tert-butyl hypochlorite, which is reacted with the non-isolated product of the anionization reaction, is primarily used.



   The N-halogenated intermediate compound is converted into the acylimino compound of the formula IVa in the presence of an excess of the anion-forming base, in particular lithium methylate, under the reaction conditions without being isolated, and this is converted directly into the 6a-methoxypenam in the presence of methanol -, or 7a-methoxy -3-cephem compound converted. If necessary, the elements of hydrogen halide, especially hydrochloric acid, have to be split off from the N-halogenated intermediate; this is done with the addition of a base which splits off hydrogen halide, such as a suitable alkali metal lower alkoxide, e.g.

  Lithium tert-butoxide, this reaction usually taking place under the conditions of the anion and N-halogen compound-forming reaction, working in the presence of methanol and instead of the acylimino compound directly the 60L-methoxy-penam- or 7a -Methoxy-3-cephem compound. I.e. starting from a compound of formula IV in which functional groups are usually in protected form, this is combined with an excess of the anion-forming agent, e.g. Lithium methylate or phenyllithium, in the presence of methanol, then treated with the N halogenating agent, e.g. tert-butyl hypochlorite, and thus directly receives the desired compound of the formula I, in which protected functional groups can be released, if necessary or desired.

  Alternatively, the methanol can be added subsequently, the dehydrohalogenation and the addition of methanol being carried out at slightly higher temperatures than the reactions which form anions and N-halogen compounds, e.g. at about 0 C to about - 200C, if necessary, in a closed vessel and / or in an inert gas, e.g. Nitrogen atmosphere.



   In a starting material of the formula IVb, an organic radical Ro means primarily a hydrocarbon radical of aliphatic character, such as lower alkyl and in particular methyl. The reaction with halogen, primarily chlorine, and a base is usually carried out in the presence of a suitable solvent or diluent such as a halogenated hydrocarbon, e.g. Methylene chloride, and with cooling, e.g. to about -80 ° C., working, if necessary, in a closed vessel and / or in an inert gas, eg nitrogen atmosphere. The base used is preferably a suitable organic base, such as a tertiary amine, eg tri-lower alkylamine such as tri-lower alkylamine, which is usually added to the above halogenation mixture together with the methanol and under the conditions of the halogenation process.

  In this way, the 6-acylimino-penam- or 7-acylimino-3-cephem starting material of the formula IV is converted directly into a 6ss -acylamino-6a-methoxy-penam- or 7ss-acylamino-7a-methoxy-3 -cephem compound of the formula I converted, which can be converted into the desired compound of the formula I if necessary or desired.



   The methoxy group can also be introduced into the 6a position of 6ss-acylamino-penam or into the 7a position of 713-acylamino-3-cephem compounds by exchanging an exchangeable group present in this position. For example, a compound of the formula IVb, in which Ro has the meaning given, and primarily an aliphatic hydrocarbon radical. such as lower alkyl and especially methyl, and in which the amino of the aminomethyl group and the carboxyl group of the formula -C (= O) -R, and any additional functional groups present, are present in protected form, react with methanol in the presence of a desulphurizing agent.



   The desulfurization in the presence of methanol is usually carried out using a suitable silver or mercury compound, such as silver oxide or mercury oxide or, in particular, salt. such as a silver I salt or mercury II salt with an organic carboxylic acid, e.g. a silver-I- or mercury-II-lower alkanoate, in particular mercury-II-acetate, made. One works in the presence of a solvent or diluent, e.g.



  an ether, such as dimethoxyethane, or a solvent mixture, it also being possible to use an excess of methanol as such, with cooling, e.g. up to about - 30 "C, at room temperature or with slight heating, e.g. up to about +70, if necessary in a closed vessel and / or in an inert gas, e.g. nitrogen atmosphere.



   In the, according to the variants of the above methoxylation process, which are preferably carried out according to the methods described by Koppel and Kocher, J. Am. Chem. Soc., Vol. 95, p. 2403 (1973), Spitzer and Goodson, Tetrahedron Letters, p. 273 (1973), and Slusarchyk et al., J. Org. Chem., Vol. 38, p. 943 (1973) described methods are carried out, available compounds can, if desired or necessary, functional groups can be converted into other functional groups in a manner known per se.

  First and foremost, in a compound obtainable according to the invention, a protected amino group in the aminomethyl substituent of the acylamino group must be released and / or a protected carboxyl group different from a carboxyl group of the formula -C (= O) -R must be converted into a group of the formula -C (= O ) -R be transferred; Furthermore, if desired, a free carboxyl group of the formula -C (= O) -R can be converted in a manner known per se into a physiologically cleavable carboxyl group of the formula -C (= O) -R. These conversions are carried out in a manner known per se, the sequence in the case of multiple conversions being arbitrary and usually depending on the nature of the radicals to be converted or split off, and on the reactions used for this purpose.

  It is also possible to convert more than one protected functional group at the same time into the corresponding free functional groups. So you can e.g. by treating with a suitable acid such as trifluoroacetic acid, optionally in the presence of anisole, in a compound obtained at the same time a tert-butyloxycarbonylamino or diphenylmethoxycarbonylamino group in the aminomethyl substituent of the acylamino radical in the 6- or 7-position and one, the remainder of the formula -C (= O) -R representing diphenylmethoxycarbonyl group in the 3- or 4-position of a Penambzw obtained. 3-cephem compound into the amino resp.



  Transfer carboxy group.



   A protected amino group can be converted into a free amino group in a manner known per se, usually by solvolysis or reduction.



   A formyl group as an amino protecting group can e.g.



  by treating with an acidic agent, e.g. p-toluenesulfonic or hydrochloric acid, with a weakly basic agent, e.g. dilute ammonia, or with a decarbonylating agent, e.g. Tris (triphenylphosphine) rhodium chloride, are split off.



   In a compound obtained, an acylamino group which can easily be split off, such as an α-poly-branched lower alkoxycarbonyl group, e.g. tert-butyloxycarbonyl, also a polycyclic cycloalkoxycarbonyl group, e.g. I-adamantyloxycarbonyl, an optionally substituted diphenylmethoxycarbonyl group, e.g.

  Diphenylmethoxycarbonyl, or an α-furyl-lower alkoxycarbonyl group, furthermore also a 4-hydroxy-3,5-bis-tert-butyl-benzyloxycarbonyl group, e.g. by treatment with a suitable acid such as a strong, preferably aliphatic, carboxylic acid, e.g. an optionally halogenated, especially fluorinated lower alkanecarboxylic acid, primarily formic or trifluoroacetic acid, optionally in the presence of anisole, and a 2-halo-lower alkoxycarbonyl group, such as 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl, or a phenacyloxycarbonyl group by treatment with a chemical reducing agents, such as a suitable reducing metal or a corresponding metal compound, e.g.

  Zinc, or a chromium (II) compound, such as chloride or acetate, can usually be split off in the presence of a hydrogen-generating agent nascent together with the metal or the metal compound, preferably in the presence of hydrous acetic acid.



  A phenacyloxycarbonyl group can also be split off by treatment with a suitable nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate.



   Furthermore, in a compound obtained, an amino group protected by a suitable substituted benzyloxycarbonyl group, such as 4-methoxy- or 4-nitrobenzyloxycarbonylamino, can be hydrogenolytically, e.g. by treating with hydrogen in the presence of a hydrogenation catalyst, e.g.



  Palladium, to be split.



   A triarylmethyl, such as trityl group, can e.g. by
Treating with an acidic agent such as a mineral acid, e.g. Hydrochloric acid.



   An amino group protected in the form of an enamine or a ketimine tautome ren, as well as the mentioned amino groups protected by arylthio, aryl-lower alkylthio and arylsulfonyl can e.g. by treating with an acidic agent, especially an aqueous acid. such as an organic carboxylic acid. e.g. Formic, acetic or propionic acid, or a mineral acid, e.g. Hydrogen chloride or
Sulfuric acid, optionally in the presence of a water-miscible solvent such as a lower alkanol, e.g.



   Methanol, a ketone, e.g. Acetone, an ether, e.g. Tetrahydrofuran, or a nitrile, e.g. Acetonitrile, are cleaved. The cleavage of said thio-protective groups can take place particularly rapidly in the presence of additional reagents such as sodium thiosulfate, sulphurous acid, thioacetamide.



   Thiourea and potassium iodide.



   An amino group protected with an organic silyl or stannyl group in a compound obtained can be purified by treatment with an aqueous or alcoholic agent, e.g. with a lower alkanol such as methanol, or a
Mixture thereof, are released; usually finds the
Cleavage of an amino group protected in this way takes place during the work-up of the acylation product.



   An amino group in the form of an azido group in the aminomethyl substituent of a compound obtained can be obtained in a manner known per se by means of reduction, e.g. by treating with hydrogen in the presence of a hydrogenation catalyst such as a nickel or palladium catalyst, e.g. from Raney nickel or palladium on carbon, under mild conditions, e.g. under atmospheric
Pressure and / or at room or only slightly elevated temperature, furthermore by treatment with a phosphine, such as a triarylphosphine, e.g. Convert triphenylphosphine, or with tin (II) chloride into the amino group.



   In a compound of the formula I obtainable according to the invention with a temporarily protected, in particular esterified, carboxyl group of the formula -C (= O) -R, this can in a manner known per se by solvolysis or reduction, i.e. depending on the type of temporarily protected group R, can be converted into the free carboxyl group. A suitable 2-halo-lower alkyl, such as 2,2,2-trichloroethyl or 2-iodoethyl, or an arylcarbonylmethyl group, such as phenacyl. esterified carboxyl group can e.g. by treating with a chemical reducing agent such as a metal, e.g.



  Zinc, or a reducing metal salt such as a chromium-II salt, e.g. Chromium (II) acetate usually in the presence of a hydrogen-releasing agent which is able to generate nascent hydrogen together with the metal, such as an acid, primarily acetic acid and formic acid, preferably adding water, an aryl carbonyl, e.g. Phenacyl group-esterified carboxyl group likewise by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide. converted into the free carboxyl group. A carboxyl group esterified by a suitable arylmethyl group can e.g. by irradiation, preferably with ultraviolet light, e.g. below 290 mp when the arylmethyl group is e.g. an optionally in the 3-, 4- and / or 5-position, e.g.



  represents benzyl radical substituted by lower alkoxy and / or nitro groups, or with longer-wave ultraviolet light, e.g. over 290 m when the arylmethyl group is e.g.



  denotes a benzyl radical substituted in the 2-position by a nitro group, can be converted into the free carboxyl group, while one with a suitable branched lower alkyl group, e.g. tert-butyl, one with a suitable cycloalkyl group such as 1-adamantyl, or with a diphenylmethyl group, e.g. Benzhydryl, esterified carboxyl group e.g. 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 anisil, can release the carboxyl group.

  A hydrolytically cleavable, esterified carboxyl group, such as a carboxyl group esterified by a suitably substituted phenyl radical or a diacyliminomethyl radical, and also a carboxyl group esterified with the 4-hydroxy-3,5-di-tert-butylbenzyl radical, depending on the type of ester group, can be , e.g. by treatment with an acidic or weakly basic aqueous agent such as hydrochloric acid or aqueous sodium hydrogen carbonate or an aqueous potassium phosphate buffer of pH about 7 to about 9, and a hydrogenolytically cleavable esterified carboxyl group by hydrogenolysis, e.g. by treating with hydrogen in the presence of a noble metal, e.g. Palladium catalyst, are cleaved.



   A z.R. by silylation or stannylation, as well as by phosphorylation protected carboxyl group can in the usual way, e.g. by hydrolysis or alcoholysis. be released.



   In a compound of the formula 1 obtainable according to the invention which contains a free carboxyl group of the formula -C (= O) -R, and in which the amino of the aminomethyl radical is optionally present in protected form, the free carboxyl group can be converted into a known manner. esterified carboxyl group which can be cleaved under physiological conditions. For example, in a compound of formula I having a free carboxyl group or a salt thereof, for example an alkali metal such as sodium or potassium salt, or an alkaline earth metal such as calcium or magnesium salt, or an optionally substituted ammonium salt such as the triethylammonium salt, by reaction with a suitable halide, e.g. Chloride or bromide, can be converted into the corresponding esterified carboxyl group -C (= O) -R.



   Furthermore, a compound of the formula 1 obtainable according to the invention, in which the amino group in the aminomethyl substituent is preferably protected, and in which the grouping of the formula -SA- corresponds to a radical of the formula Ib, can be used to convert the group Rl in a manner known per se to replace another radical R1 or to convert it into another radical R. So it is e.g. possible, in a compound of the formula I with a radical of the formula Ib as a grouping of the formula -S-A-, wherein R1 is a group of the formula -CH2-R2, and R2 is e.g. represents a radical which can be replaced by nucleophilic substituents, or, in a salt thereof, to replace such a radical R2 by an etherified mercapto group R2 by treatment with a mercaptan compound.

  A suitable radical which can be replaced by an etherified mercapto group is, for example, an esterified, e.g. by a hydrohalic acid, such as hydrochloric or hydrobromic acid, or preferably by an organic carboxylic acid, such as an aliphatic (including formic acid), cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid, furthermore by a carbonic acid half-derivative. like a carbonic acid half ester. esterified hydroxy group. Such esterified hydroxyl groups are e.g. optionally, e.g. lower alkanyloxy substituted by halogen, such as fluorine or chlorine, in particular acetyloxy, and also halogen-lower alkanoyloxy, such as haloacetyloxy, e.g.

  Trifluoroacetyloxy, and dichloroacetyloxy, also formyloxy, or optionally substituted benzoyloxy, such as 4-chlorobenzoyloxy.



   The reaction of such a compound with a suitable mercaptan compound can be carried out under neutral or weakly basic conditions in the presence of water and optionally a water-miscible organic solvent. The basic conditions can be made, for example, by adding an inorganic base such as an alkali metal or alkaline earth metal hydroxide, carbonate or hydrogen carbonate, e.g. of sodium, potassium or calcium hydroxide, carbonate or hydrogen carbonate. As organic solvents e.g. water miscible alcohols, e.g.



  Lower alkanols such as methanol or ethanol, ketones, e.g.



  Lower alkanones such as acetone, amides, e.g. Lower alkanecarboxamides such as dimethylformamide and the like can be used.



   Esterified hydroxy groups R2 in a compound of
Formula 1, in which the group -S-A- is the sub-formula Ib, and R1 is the group -CH2R2, where R2 is a hydroxyl group esterified by an optionally substituted half-amide of carbonic acid, e.g. introduce, in which a corresponding compound of formula 1, wherein
R2 stands for free hydroxy (which can be obtained e.g. by splitting off the acetyl radical from an acetyloxy group R2, e.g.

   by hydrolysis in a weakly basic medium, such as with an aqueous sodium hydroxyl solution at pH 9-10, or by treatment with a suitable esterase, such as a corresponding one
Enzyme from Rhizobium tritolii, Rhiwobisn lupine egg, RhLobürn japonicum or Bacillus subtilis, or a suitable citrus
Esterase, e.g. from orange peel), with a suitable carbonic acid derivative, in particular with an isocyanate or carbamic acid compound, such as a silyl isocyanate, e.g. Silyl tetraisocyanate, a sulfonyl isocyanate, e.g.



   Chlorosulfonyl isocyanate, or carbamic acid halide, e.g.



   chloride (which lead to N-unsubstituted 3-aminocarbonyloxyme thyl compounds), or then with an N-substituted isocyanate or with an N-mono- or N, N-disubstituted carbamic acid compounds, such as a corresponding carbamic acid halide, for example -chloride, where you usually in the presence of a solvent or diluent and United. if necessary, with cooling or heating, in a closed vessel and / or in a
Inert gas, e.g. Nitrogen atmosphere, works.



   You can also use a compound of formula 1, wherein the
Grouping -S-A- corresponds to a radical of the formula Ib, where for R2 e.g. represents the radical defined above, replaceable by nucleophilic substitution, with a tertiary organic
Base, in particular an optionally substituted pyridine, under neutral or weakly acidic conditions, preferably at a pH of about 6.5, in the presence of
React water and optionally with a water-miscible organic solvent. The weakly acidic conditions can be changed by adding a suitable organic or inorganic acid, for example acetic acid,
Hydrochloric acid, phosphoric acid or sulfuric acid can be adjusted. The above-mentioned water-miscible solvents, for example, can be used as organic solvents.

  To increase the yield, certain salts can be added to the reaction mixture, for example alkali salts, such as sodium and especially potassium salts, of inorganic acids such as hydrohalic acids, e.g. Hydrochloric and especially hydroiodic acid, and thiocyanic acid, or organic acids, such as
Lower alkanoic acids, e.g. Acetic acid. Representative of such
Salts are, for example, potassium iodide and potassium thiocyanate.



  Salts of suitable anion exchangers, e.g. liquid
Ion exchangers in salt form, e.g. Amberlite LA-1 (liquid secondary amines with a molecular weight of 351 to 393; oil-soluble and water-insoluble; mEq. / G = 2.5-2.7, e.g. in acetate form), with acids, e.g. Acetic acid, can be used for this purpose.



   Quaternary ammonium groups R2 can advantageously be made using an intermediate of the formula
1, in which R2 of the radical Rl in a sub-formula Ib stands for a substituted, in particular an aromatically substituted, carbonylthio group and primarily for the benzoylthio group. Such an intermediate, which is e.g.



  by reacting a compound of the formula I in which -S-A stands for the sub-formula Ib, in which R2 in the radical Ri is an esterified hydroxyl group, and primarily an acyloxy, in particular a lower alkanoyloxy, e.g. Acetyloxy group means with a suitable salt such as an alkali metal, e.g. Sodium salt, a thiocarboxylic acid such as an aromatic thiocarboxylic acid, e.g. Thiobenzoic acid, can be obtained, is reacted with the tertiary amine, in particular a tertiary heterocyclic base, such as an optionally substituted pyridine, to give the quaternary ammonium compound.

  The reaction is usually carried out in the presence of a suitable desulphurising agent, especially a mercury salt, e.g. Mercury (II) perchlorate, and a suitable solvent or diluent or a mixture, if necessary, with cooling or heating, in a closed vessel and / or in an inert gas, e.g. Nitrogen atmosphere.



   Salts of compounds of the formula I can be prepared in a manner known per se. Thus, salts of compounds of formula I with acidic groups, e.g. by treating with metal compounds such as alkali metal salts of suitable carboxylic acids, e.g. the sodium salt of a -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 of compounds of the formula I are obtained in a conventional manner, e.g.



  by treatment with an acid or a suitable anion exchange reagent. Internal salts of compounds of formula 1 which contain a free carboxyl group can e.g. by neutralizing salts such as acid addition salts to the isoelectric point, e.g. with weak bases, or by treatment with liquid ion exchangers.



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



   The 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 above as particularly preferred are obtained.



   The starting materials of the formula IV can by introducing the group of the formula
EMI7.1
 in which the amino of the aminomethyl group is preferably in protected form, in the amino group of compounds of the formula VI, in which the amino group can optionally be substituted by a group permitting acylation, and in which the grouping of the formula -SA- has the meaning given above, primarily by acylation, e.g.

   according to the acylation process described in the application 14 034/73, starting from the starting materials of the formula II described there
EMI8.1
 in which the amino group can be substituted by a group permitting acylation, and in which the grouping of the formula -SA- is a radical of the formula Ia or Ib, in which R has the meaning given above, where a free hydroxyl group R can be temporarily protected, getting produced.



   The starting materials of the formula IVb can e.g. obtained if one of a 6ss-amino-penam or 7ss-amino -3-cephem compound of the formula VI, in which functional groups present, such as e.g. a carboxyl group of the formula -C (= O) -R, preferably in protected form, proceeds, and this by reaction with an aldehyde, in particular an aromatic aldehyde such as benzaldehyde, converts into the Schiff base and this with an anion-forming agent such as a, preferably sterically hindered alkali metal lower alkanoate, such as potassium tert-butoxide, an alkali metal hydride, for example

  Sodium hydride, an alkali metal hydrocarbon compound, e.g. n-butyllithium or phenyllithium, or a suitable alkali metal compound of a secondary organic base, e.g. the lithium compound of a di-lower alkylamine or alkyleneamine, such as lithium diethylamide, preferably with cooling, e.g. at temperatures of about - 300C to about 0 C, and in the presence of a solvent or diluent, such as glycol dimethyl ether. The etherified mercapto group of the formula Ro-S- can be incorporated directly into the anion thus obtained, e.g. by treating with a suitable thiosulfonic acid ester such as a lower alkyl thiosulfonic acid lower alkyl ester, e.g. Methanethiolsulphonic acid methyl ester, or with a sulfenyl halide such as lower alkyl sulfenyl halide, e.g.

  Introduce methylsulfenyl chloride, or indirectly via the corresponding 6z-fluoropenam or 7a-fluoro-3-cephem Schiff base; the latter is obtained e.g. by treating with fluoroperchlorate and can make it by reacting with a mercaptan such as a lower alkyl mercaptan, e.g. Methyl mercaptan, in the presence of a strong acid such as an optionally halogenated lower alkanecarboxylic acid, e.g. Convert trifluoroacetic acid into the desired 6ol-RO-S-penam- or 7a-Ro-S-3-cephem-Schiff base.

  In such an intermediate, the nitrogen atom of the methylene amino group is obtained by introducing the group of the formula Liga, wherein the amino of the aminomethyl group is preferably in protected form, e.g. acylated by the process described above, and so the starting material of the formula IVb is obtained. This sequence of reactions is e.g. according to the methods described by Slusarchyk et al., J. Org. Chem., Vol. 38, p. 943 (1973) and Spitzer and Goodson, Tetrahydron Letters, p. 273 (1973).



   In the process according to the invention, as well as in any additional measures to be carried out, furthermore in the preparation of the starting materials, free functional groups not participating in the reaction can, if necessary, be in the starting materials or in the compounds obtainable according to the process as described above, e.g. free amino groups by acylation, tritylation or silylation, free hydroxy or mercapto groups e.g. by etherification or esterification, and free carboxyl groups e.g. temporarily protected by esterification, including silylation, in a manner known per se and, if desired, released in a manner known per se by solvolysis or reduction after the reaction has taken place.



   The pharmacologically useful compounds of the present invention can e.g. can 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 preferably suitable for parenteral administration.



   Preferably the pharmacologically active compounds of the present invention are used in the form of injectables, e.g. intravenous, administrable preparations or from infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, these e.g. from lyophilized preparations which contain the active substance alone or together with a carrier material, e.g.



  Mannitol, contained, can be prepared before use.



  The pharmaceutical preparations can be sterilized and / or auxiliary materials, e.g. Contain preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts to regulate the osmotic pressure and / or buffers. The present pharmaceutical preparations, which, if desired, can contain further pharmacologically valuable substances, are made in a manner known per se, e.g. by means of conventional dissolution or lyophilization processes, and contain from about 0.1% to 100%, especially from about
1% to about 50%, lyophilisates up to 100% of the active ingredient.



   Unless otherwise defined, the term used in connection with the definition of organic radicals or compounds means lower, e.g. in lower alkyl, lower alkanol and the like, that the radicals or compounds in question have up to 7, preferably up to 4, carbon atoms.



   The following examples serve to illustrate the invention; Temperatures are given in degrees Celsius.



   Example I.
2.40 g of 3-acetyloxymethyl-7ss- [2- (5-tert-butyl-oxycarbonylaminomethyl-2-thienyl) -acetylamino] -3-cephem -4-carboxylic acid diphenylmethyl ester are dissolved in 180 ml of tetrahydrofuran, the Solution under a nitrogen atmosphere to -70 to -75 "C and a solution of 0.46 g of lithium methoxide in 10 ml of methanol is added with stirring over the course of 1 minute. After 3 minutes, 0.42 ml of tert-butyl hypochlorite is added , stir for 20 minutes at -70 to -75 "C, neutralized with 0.80 ml of acetic acid and concentrated in a water-jet vacuum to about 70 ml. It is mixed with 200 ml of water and extracted twice with 300 ml of ethyl acetate each time.

  The organic extracts are washed with water and with a saturated aqueous sodium chloride solution, dried over magnesium and evaporated under reduced pressure. The crude product is chromatographed on 250 g of silica gel, using a 6: 4 mixture of toluene and ethyl acetate to give 3-acetyloxymethyl-7a-methoxy-7ss- [2- (5-tert-butyloxy-carbonylaminomethyl-2-thienyl) - -acetylaminoj-3-cephem-4-carboxylic acid diphenylmethyl ester eluted; Thin-layer chromatogram (silica gel): Rf = 0.20 (system:

  Toluene / ethyl acetate 6: 4); Ultraviolet absorption spectrum (in 95% aqueous ethanol): Xmax = 243 my (e = 13,900) and 7imiZl = 236 mi (e = 13,600); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.92, 5.61>, 5.74; i, 5.79, 6.23 Il, and 6.67 CL.



   The starting material can be made as follows:
A solution of 20 g of 2-thenylamine hydrochloride in a mixture of 100 ml of trifluoroacetic acid and 100 ml of acetic anhydride is stirred at 55 ° for 2 hours with exclusion of moisture. The reaction mixture is completely concentrated under reduced pressure, 50 ml of toluene are added and the mixture is concentrated again. The crude product is dissolved in ethyl acetate, treated with activated charcoal, filtered through silica gel and concentrated under reduced pressure.



  After recrystallization from diethyl ether, 2-acetyl-5-trifluoroacetylaminomethyl-thiophene, F.83-84, is obtained.



   A solution of 34.2 g of thallium (III) nitrate in 100 ml of methanol is treated with 40 ml of 70% aqueous perchloric acid while cooling with ice, and a solution of 20 g of 2-acetyl-5-trifluoroacetylamino- thiophene in 500 ml of methanol was added dropwise over the course of 15 minutes. The solution is warmed to 50 and stirred at this temperature for 2¸ hours. The reaction mixture is cooled to about + 5 "and poured onto an ice-cold solution of 120 g of dipotassium hydrogen phosphate in 300 ml of water. It is filtered and the filter residue is washed with methanol. The filtrate is concentrated under reduced pressure to about 300 ml and three times with 150 ml of chloroform extracted.

  The extracts are washed with water and then with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in a water-jet vacuum. The methyl 2- (5-trifluoroacetylaminomethyl-2-thienyl) -acetate remains; Thin-layer chromatogram (silica gel: system: toluene / ethyl acetate 60:40): Rf = 0.65; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.93, 3.39, 5.75 and 5.80.



   To a solution of 9.7 g of 2- (5-trifluoroacetylaminomethyl-2-thienyl) -acetic acid methyl ester in 50 ml of dioxane, 40 ml of 2-N are added at 20 under a nitrogen atmosphere. given aqueous sodium hydroxide solution. The mixture is stirred for 2 hours at 20-250, diluted with 50 ml of dioxane and 8.5 ml of tert-butyloxycarbonylazide are added to the solution, whereupon stirring is continued at 20 to 25 for 16 hours. The reaction mixture is cooled to about 5 and adjusted to pH 2.5 with about 40 ml of 20% strength aqueous phosphoric acid. It is concentrated to about 50 ml under reduced pressure and extracted three times with 200 ml of ethyl acetate each time.

  The extracts are washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, decolorized by treatment with an activated charcoal preparation and concentrated under reduced pressure. It is recrystallized from diethyl ether and 2- (5-tert-butyloxycarbonylaminomethyl-2-thienyl) acetic acid, mp 114-1150, is obtained.



   0.90 g of 2- (5-tert-butyloxycarbonylaminomethyl -2-thienyl) -acetic acid are dissolved in 20 ml of methylene chloride (distilled over phosphorus pentoxide) containing 0.334 g of N-methylmorpholine, the solution, which is kept in the absence of moisture, is cooled to 200 and add 0.45 ml isobutyl chloroformate dropwise, keeping the temperature between - 15 and - 20. After 30 minutes, a solution of 1.04 g of 3-acetyloxymethyl-713-amino-3-cephem-4-carboxylic acid diphenylmethyl ester in 5 ml of methylene chloride is added, whereupon stirring is continued for 2 hours at -10 and for 8 hours at room temperature . It is poured into ice-cold water, the pH is adjusted to 8.0 with dipotassium hydrogen phosphate and extracted repeatedly with methylene chloride.

  The organic extracts are washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate, after which the solvent is removed under reduced pressure. The 3-acetyloxymethyl-7ss- [2- (5-tert-butoxycarbony1aminomethyl-2-thienyl) -acetylaminoj3ce phem-4-carboxylic acid-diphenylmethyl ester is obtained as a colorless foam, which is directly processed further, thin-layer chromatogram (silica gel): Rf = 0.71 (system: hexane / ethyl acetate / methanol 20:40:40).

  The product can be crystallized from diethyl ether, mp 134-136; Infrared absorption spectrum (in mineral oil): characteristic bands 3.03, 5.68, 5.77, 6.02, 6.26 and 6.57; Ultraviolet absorption spectrum (in 95% aqueous ethynol): & ax = 245 m, a (e = 15100).



   The 2- (5-tert-butyloxycarbonylaminomethyl-2-thienyl) acetic acid can also be obtained as follows:
A solution of 1.34 g of N-hydroxymethyl-acetamide (Einhorn, Ann. Chem., Vol. 343, p. 264 (1905)) in 10 ml of trifluoroacetic acid is added in portions with stirring to 1.42 g of 2 -Thienylacetic acid added. The mixture is stirred for 2 hours at 0-5 and the trifluoroacetic acid is distilled off under reduced pressure. The residue is mixed with 30 ml of water and extracted twice with 50 ml of ethyl acetate each time. The organic extracts are washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, concentrated under reduced pressure and filtered through silica gel.

  The residue is crystallized from ethyl acetate and gives 2- (5-acetylaminomethyl-2-thienyl) acetic acid, thin-layer chromatogram (silica gel): Rf = 0.61 (system: butanol / acetic acid / water 45: 45 10); Infrared absorption spectrum (mineral oil): characteristic bands at 2.95 Il, 5.82, 6.23 y, 6.38,
0.3 ml of a 2-n is added to a solution of 0.6 g of 2- (5-acetylaminomethyl-2-thienyl) acetic acid in 5 ml of dioxane.



  aqueous sodium hydroxide solution. The mixture is stirred for 12 hours at 55-600, cooled to 25, treated with 0.2 ml of tert. Butyloxycarbonylazid, stirred for 16 hours at room temperature and isolates the 2- (5-tert-butyloxycarbonylaminomethyl-2-thienyl) acetic acid by the method described above.



   Example 2
A solution of 0.90 g of 3-acetyloxymethyl-70c-methoxy- -7ss- [2- (5-tert.-butyloxycarbonylaminomethyl-2-thienyl) acetylamino] -3-cephem-4-carboxylic acid diphenylmethyl ester in 5 ml of trifluoroacetic acid is left to stand for 30 minutes and evaporated with the addition of 20 ml of toluene in a water jet vacuum. The residue is triturated with 10 ml of diethyl ether and 40 ml of petroleum ether and filtered. The filter residue, which contains the trifluoroacetic acid salt of 3-acetyloxymethyl-7ss- [2- (5-aminomethyl-2-thienyl) acetylamino] -7a-methoxy-3-cephem-4-carboxylic acid, is dried for 5 hours on High vacuum at room temperature and then dissolve it in 30 ml of methanol; the solution is decolorized by adding activated charcoal and filtered.

  The filtrate is adjusted to pH 6.0 with triethylamine and then left to stand at 0-5 for 2 hours. The precipitated inner salt of 3-acetyloxymethyl-7ss- [2- (5-aminomethyl-2-thienyl) -acetylamino] -7a-methoxy-3-cephem-4-carboxylic acid is filtered off and dried under for 20 hours High vacuum and at room temperature, m.p. over 180 (with decomposition); [α] D20 = + 271 # 1 (c = 0.886 in a 0.15 molar aqueous potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer solution, pH 7.3-7.4); Thin-layer chromatogram (silica gel):

  Rf = 0.12 (system: n-butanol / acetic acid / water 75: 7.5: 21); Ultraviolet absorption spectrum (in a 0.15 molar aqueous potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer solution, pH 7.3-7.4): = = 241 m (E = 16000) and Xmin = m (e = 9200);

  Infrared absorption spectrum (in mineral oil): characteristic bands at 5.66 ti, 5.75, 6.00 Il, 6.34 IL and 6.55 p
Example 3
A solution of 0.15 g of the inner salt of 3-acetyl oxymethyl-7ss- [2- (5-aminomethyl-2-thienyl) -acetylamino] - 7α-methoxy-3-cephem-4-carboxylic acid and 0.053 g of des The sodium salt of 5-mercapto-1-methyl-tetrazole in 7 ml of acetone and 10 ml of water is mixed with 0.028 g of sodium hydrogen carbonate and heated to 60 for 5 hours. It is filtered, the filtrate is concentrated under reduced pressure to a volume of about 10 ml, adjusted to pH 5.5 with acetic acid and left to stand at 0-5 for a few hours.

  The precipitate is filtered off and washed with acetone. The inner salt of 7ss- [2- (5-aminomethyl-2-thienyl) -acetyl-amino] -7z-methoxy-3 - (1-methyl-5-tetrazolyl-thiomethyl) -3-cephem is obtained in this way -4-carboxylic acid, which is dried in a high vacuum for 12 hours; Thin-layer chromatogram (silica gel): Rf = 0.25 (system: chloroform / methanol 1: 1); Rf = 0.10 (system and n-butanol / acetic acid / water 45: 45:10).



   Example 4
Dissolve 9,1 3-acetyloxymethyl-713- [2- (5-tert-butyloxycarbonylaminomethyl-2-furyl) -acetylamino] -3-cephem-4-carboxylic acid diphenylmethyl ester in 400 ml of tetrahydrofuran, the cools Solution under a nitrogen atmosphere to -70 to -75 "C and add a solution of 1.80 g of lithium methoxide in 50 ml of methanol within 1 minute with stirring.



  After 2 minutes, 1.62 ml of tert-butyl hypochlorite are added, the mixture is stirred for a further 20 minutes at -70 to -75 ", neutralized with 2.5 ml of acetic acid and concentrated to about 100 ml in a water-jet vacuum 500 ml of water and extracted twice with 500 ml of ethyl acetate each time The organic extracts are washed with water and with a saturated aqueous sodium chloride solution, dried over magnesium and evaporated under reduced pressure.

  The crude product is chromatographed on 600 g of silica gel, 3-acetyloxymethyl-7z-methoxy-713- [2- (5-tert-butyloxycarbonylaminomethyl-2-furyl) being used with a 6: 4 mixture of toluene and ethyl acetate -acetylamino] -3-cephem-4-carboxylic acid diphenylmethyl ester eluted; Thin-layer chromatogram (silica gel): Rf = 0.30 (system: toluene / ethyl acetate 6: 4); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.92 y, 5.61 I1.5.76 (broad), 6.24 11 and 6.67.



   The starting material can be made as follows:
A mixture of 50 g of furfurylamine and 150 ml of trifluoroacetic anhydride is stirred with exclusion of moisture for 2 hours at room temperature. 150 ml of acetic acid are added and stirring is continued for 2 hours at 55 ".



  The reaction mixture is completely concentrated under reduced pressure, 50 ml of toluene are added and the mixture is concentrated again. The crude product is dissolved in ethyl acetate, treated with activated charcoal, filtered through silica gel and concentrated under reduced pressure. After recrystallization from diethyl ether, 2-acetyl-5-trifluoroacetamino methyl-furan is obtained, mp 99-100; Ultraviolet absorption spectrum (in ethanol): Xmax = 275 m (i = 15,500).



   A solution of 39.8 g of thallium (III) nitrate trihydrate in
100 ml of methanol are treated with 50 ml of 70% perchloric acid while cooling with ice and a solution of 20 g of 2-acetyl-5-trifluoroacetamino methyl-furan in 500 ml of methanol is added dropwise at +5 under a nitrogen atmosphere over the course of 15 minutes. The solution is heated to 50 and at this
Temperature stirred for 2¸ hours. The reaction mixture is cooled to about +5 and poured onto an ice-cold solution of 120 g of dipotassium hydrogen phosphate in 300 ml of water. It is filtered and the filter residue is washed with
Methanol. The filtrate is concentrated to about 300 ml under reduced pressure and extracted three times with 150 ml of chloroform.

  The extracts are washed with water and then with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo using a water jet. The methyl 2- (5-trifluoroacetamino methyl-2-furyl) -acetate remains, thin-layer chromatogram (silica gel): Rf = 0.35 (system: toluene / ethyl acetate 60:40); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94 11. 3.39 cm and 5.80 Il.



   To a solution of 18.4 g of 2- (5-trifluoroacetaminomethyl -2-furyl) -acetic acid methyl ester in 100 ml of dioxane at 20 under a nitrogen atmosphere, 75 ml of a 2-n. given aqueous sodium hydroxide solution. The mixture is stirred for 4 hours at 20-25, diluted with 100 ml of dioxane and 34 ml of tert-butyloxycarbonylazide are added to the solution, whereupon stirring is continued at 20-25 for 16 hours. The reaction mixture is cooled to about 50 and adjusted to pH 2.5 with about 40 ml of 20% strength aqueous phosphoric acid. It is concentrated under reduced pressure to a volume of about 100 ml and extracted three times with 200 ml of ethyl acetate each time.

  The extracts are washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, decolorized by treatment with an activated charcoal preparation and concentrated. After recrystallization from diethyl ether, 2- (5-tert-butyloxycarbonylaminomethyl-2-furyl) acetic acid, mp 72-73, is obtained.



   1.87 g of 2- (5-tert-butyloxycarbonylaminomethyl -2-furyl) acetic acid are dissolved in 200 ml of methylene chloride (distilled over phosphorus pentoxide) and 0.80 ml of 4-methylmorpholine, the solution, which is kept in the absence of moisture, is cooled to 20 and add 1.0 ml of isobutyl chloroformate dropwise, keeping the temperature between -15 and -200. After 30 minutes, a solution of 2.31 g of 3-acetyloxymethyl-713-amino-3-cephem-4-carboxylic acid diphenylmethyl ester is added, whereupon stirring is continued for 2 hours at -10 and for 8 hours at room temperature.



  The mixture is poured into ice-cold water, the pH is adjusted to 8.0 with dipotassium hydrogen phosphate and extracted repeatedly with methylene chloride. The organic extracts are washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate, whereupon the solvent is removed under reduced pressure. The 3-acetyloxymethyl-713 - [2- (5-tert-butyloxycarbonylamino methyl-2-furyl) -acetylamino] -3-cephem-4-carboxylic acid diphenylmethyl ester is obtained as a colorless foam which is directly processed further, Thin-layer chromatogram (silica gel): Rf = 0.84 (system: hexane / ethyl acetate / methanol 20:40:40).



      Example 5
A solution of 2.95 g of 3-acetyloxymethyl-7rx-methoxy- -7ss- [2- (5-tert-butyloxycarbonylaminomethyl-2-furyl) acetylamino] -3-cephem-4-carboxylic acid diphenylmethyl ester in 3 ml of anisole and 12 ml of trifluoroacetic acid are left to stand at 0 for 30 minutes and then evaporated in a water-jet vacuum with the addition of 100 ml of toluene. The residue is triturated with 50 ml of diethyl ether and filtered.

  The filter residue, which contains the trifluoroacetic acid salt of 3-acetyloxymethyl-7ss - [2- (5-aminomethyl-2-furyl) -acetyl-amino] -7 (x-methoxy-3-cephem-4-carboxylic acid) is dried, during 5 Hours in a high vacuum at room temperature and then dissolve it in 30 ml of methanol; the solution is decolorized by adding activated charcoal and filtered. The filtrate is adjusted to pH 6.0 with triethylamine and then left to stand at 0-5 for 2 hours.

  The precipitated inner salt of 3-acetyloxymethyl-7ss- [2- (5-aminomethyl-2-furyl) -acetylamino] -7 (x-methoxy-3-cephem-4-carboxylic acid) is filtered off and dried during 20 hours under high vacuum and at room temperature, m.p. over 165 (with decomposition); thin layer chromatogram (silica gel):

  Rf = 0.22 (system: chloroform / methanol 1: 1); Ultraviolet absorption spectrum (in 95% aqueous ethanol): Man = 222 mp (e = 12500) and) \ marx2 = 266 mF (e = 6200); Infrared absorption spectrum (in mineral oil): characteristic bands at 5.66 11, 5.77 y, 5.91 I1, 6.22 IL and 6.52.



   Example6
4.0 g of 3-acetyloxymethyl-7ss- [2- (5-tert-butyloxycarbonylaminomethyl-2-thienyl) -acetylamino] -3-cephem-4-carboxylic acid tert-butyl ester are dissolved in 250 ml of tetrahydrofuran, and the solution is cooled a nitrogen atmosphere to -70 to -75 and, while stirring, within one minute adds a lithium methylate solution prepared by dissolving 0.170 g of lithium wire in 30 ml of methanol. After 3 minutes, 0.80 ml of tert-butyl hypochlorite are added, the mixture is stirred for 20 minutes at -70 to -75, neutralized with 4.0 ml of acetic acid and concentrated to a volume of about 70 ml in a water jet vacuum. It is mixed with 200 ml of water and extracted twice with 300 ml of ethyl acetate each time. The organic
Extracts are washed with water and with a saturated aqueous sodium chloride solution, dried over magnesium and evaporated under reduced pressure.

  The crude product is reprecipitated from a mixture of ethyl acetate and petroleum ether, and the 3-acetyl oxymethyl-7al-methoxy-7ss- [2- (5-tert-butyloxycarbonylamino-methyl-2-thienyl) -acetylamino] -3- tert-butyl cephem-4-carboxylate is filtered off and dried; Thin-layer chromatogram (silica gel): Rf = 0.48 (system: ethyl acetate / chloroform / acetic acid 80: 19: 1); Ultraviolet absorption spectrum (in 95% ethanol): Xmax = 243 my (e = 15,800); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.88, 2.93 Il, 5.61 i, 5.75, 5.83 IL and 6.66.



   The starting material can be made as follows:
8.15 g of 2- (5-tert-butyloxycarbonylaminomethyl -2-thienyl) -acetic acid are dissolved in 500 ml of methylene chloride containing 3.06 ml of N-methylmorpholine, the solution kept under exclusion of moisture is cooled to 200 and 4, added dropwise 13 ml of isobutyl chloroformate are added, the temperature being kept between - 150 and - 200. After 30 minutes, a solution of 9.85 g of 3-acetyloxymethyl-7ss-amni-3-cephem-4-carboxylic acid tert-butyl ester in 50 ml of methylene chloride is added, whereupon the solution is slowly increased to 20 bis 25 further stirred for 15 hours. The mixture is poured into ice-cold water, neutralized with dipotassium hydrogen phosphate and extracted repeatedly with methylene chloride.

  The organic extracts are washed with an aqueous saturated sodium chloride solution and dried over magnesium sulfate, and the solvent is removed under reduced pressure. The residue is recrystallized from diethyl ether and gives 3-acetyloxymethyl-7ss- [2- (5-tert-butyloxycarbonylaminomethyl-2-thienyl) -acetylamino] -3-cephem-4-carboxylic acid-tert-butyl ester, m.p. 76 -78. Thin-layer chromatogram (silica gel): Rf = 0.44 (system: chloroform / ethyl acetate / acetic acid 80: 19 1).



   Example 7
A solution of 3.80 g of 3-acetyloxymethyl-7o-methoxy- -7ss- [2- (5-tert-butyloxycarbonylaminomethyl-2-thienyl) -acetylamino] -3-cephem-4-carboxylic acid tert-butyl ester in 15 ml of trifluoroacetic acid is left to stand for 30 minutes and evaporated with the addition of 50 ml of toluene in a water jet vacuum. The residue is triturated with 30 ml of diethyl ether and filtered. The filter residue, which contains the trifluoroacetic acid salt of 3-acetyloxymethyl-7ss- [2- (5- aminomethyl-2-thienyl) -acetylamino] -7α-methoxy-3-cephem-4-carboxylic acid, is introduced, as in Example 4 described, into the inner salt of 3-acetyloxymethyl-7P- [2- (5-aminomethyl--2-thienyl) -acetylaminoj-7a-methoxy-3-cephem-4-carboxylic acid.



   Example 8
1.55 g of 3-acetyloxymethyl-7ss- [2- (3-tert-butyloxycarbonylaminomethyl-2-thienyl) -acetylamino] -3-cephem-4-carboxylic acid tert-butyl ester with 0.065 g of lithium in 20 ml
Methanol and 0.31 ml of tert-butyl hypochlorite according to the im
Example 8 described method and thus obtains the 3 -acetyloxymethyl-7ec-methoxy-7ss- [2- (3-terf. -Butyloxycarbonylaminomethyl: 2-thienyl) acetylamino] -3 -cephem-4-carboxylic acid- tert-butyl ester; Thin-layer chromatogram (silica gel): Rf = 0.52 (system:

  Toluene / ethyl acetate 3: 2); Ultraviolet absorption spectrum (in 95% aqueous ethanol): Xmax = 241 mm (e = 14,200); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.88 I1, 2.93, 5.59 IL, 5.74, 5.83 IL and 6.64.



   The starting material can be made as follows:
A mixture of 75.0 g of 3-bromomethylthiophene and 78.5 g of phthalimide potassium in 1000 ml of dimethylformamide is stirred at 100 for 90 minutes. The reaction mixture is cooled, poured onto a mixture of ice and water and extracted four times with a total of 1500 ml of ethyl acetate.

  The organic extracts are washed with water, dried over magnesium sulfate and concentrated under reduced pressure, the 3-phthaloylaminomethylthiophene crystallizing out, thin-layer chromatogram (silica gel): Rf = 0.78 (system: toluene / ethyl acetate 1); Ultraviolet absorption spectrum (in 95% aqueous Ethynol): Xmax = 220 ml (e = 44,000); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.59, 5.86 IL and 6.20 u
90.8 g of 3-phthaloylaminomethylthiophene are taken up in 250 ml of acetic anhydride, 250 ml of trifluoroacetic acid are added dropwise with exclusion of moisture, and the mixture is stirred at 500 ml for 3 hours.

  The reaction solution is then concentrated under reduced pressure, 500 ml of water are added, and a 2-n. aqueous sodium hydroxide solution neutralized while cooling with ice and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated. A mixed crystal consisting of 2-acetyl -3-phthaloxylaminomethyl thiophene and 2-acetyl-4-phthaloylaminomethyl thiophene is obtained; Thin-layer chromatogram (silica gel): Rf = 0.53 and 0.45 (system: toluene / ethyl acetate 4: 1).



   38.0 g of the mixture of 2-acetyl-3-phthaloylaminomethylthiophene and 2-acetyl-4-phthaloylaminomethylthiophene are dissolved in 1500 ml of methanol, and 65 g of thallium (III) nitrate trihydrate are added under a nitrogen atmosphere u. stirs for 6 hours at 50. The reaction mixture is cooled to 5-10, with a 2-n. aqueous sodium hydroxide solution, concentrated under reduced pressure and extracted with 1000 ml of chloroform. The organic extract is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated.



  A mixture of 2- (3-phthaloylaminomethyl-2-thienyl) -acetic acid methyl ester and 2- (4-phthaloylaminomethyl-2-thienyl) -acetic acid methyl ester is obtained; Thin-layer chromatogram (silica gel): Rf = 0.59 and 0.54 (system: toluene / ethyl acetate 1).

 

   21 g of the mixture of 2- (3-phthaloylaminomethyl-2-thienyl) -acetic acid methyl ester and 2- (4-phthaloylaminomethyl-2-thienyl) -acetic acid methyl ester are dissolved in 400 ml of dioxane, 50 ml of a 2-n. aqueous sodium hydroxide solution and stir for 2 hours at 20 to 25. It is concentrated to a volume of about 200 ml, diluted with 200 ml of water, acidified with 20% aqueous phosphoric acid and extracted three times with a total of 400 ml of ethyl acetate.



  The extracts are dried over magnesium sulphate and evaporated under reduced pressure.



   3.0 g of hydrazine hydrate are added to the evaporation residue taken up in 250 ml, heated to 60 for 31/2 hours and then evaporated. The residue is taken up in 200 ml of dioxane, with 75 ml of a 2-n. aqueous sodium hydroxide solution and 5.0 ml of tert-butyloxycarbonylazid implemented. The mixture is stirred for 20 hours at 20 to 25, concentrated to a volume of about 100 ml, diluted with 100 ml of water and extracted with 200 ml of ethyl acetate.



  The aqueous solution is adjusted to pH 2 with about 50 ml of 20% aqueous phosphoric acid. The precipitate is filtered off, the filter residue is washed with ethyl acetate and the filtrate is extracted three times with 200 ml of ethyl acetate each time. The organic extracts are washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate solution and concentrated under reduced pressure.

  The residue is dried under reduced pressure at 30 and contains a mixture of 2- (3-tert-butyloxycarbonylaminomethyl-2-thienyl) -acetic acid and 2- (4-tert-butyloxycarbonylaminomethyl-2-thienyl) -acetic acid, which by Chromatography on 200 g of silica gel with a mixture of chloroform / ethyl acetate / acetic acid (80: 19: 1) as the mobile phase can be separated, thin-layer chromatogram: Rf = 0.44 or 0.34 (system: chloroform / ethyl acetate / acetic acid 80:19 : 1). In the next stage, however, the mixture of the two compounds is used.



   4.0 g of the mixture of 2- (3-tert-butyloxycarbonylaminomethyl-2-thienyl) -acetic acid and 2- (4-tert-butyloxycarbonylaminomethyl-2-thienyl) -acetic acid are dissolved in 125 ml of methylene chloride, cooled to -20 and treated with exclusion of moisture with 1.80 ml of N-methylmorpholine and 0.864 isobutyl formate. After 30 minutes, a solution of 1.97 g of 3-acetyloxymethyl-7ss-amino-3-cephem-4-carboxylic acid tert-butyl ester in 10 ml of methylene chloride is added, whereupon for 2 hours at -10 and for 14 hours at 20 can react. It is diluted with water, the organic layer is separated and washed with a saturated aqueous sodium chloride solution.

  It is dried over magnesium sulphate and evaporated under reduced pressure. The crude product is chromatographed on 200 g of silica gel. In this case, the 3-acetyloxymethyl-7ss- [2- (3-tert-butyloxycarbonylaminomethyl-2-thienyl) -acetylamino] -3-cephem-4-carboxylic acid-tert.- is eluted with a 4: mixture of methylene chloride / ethyl acetate butyl ester, thin layer chromatogram (silica gel): Rf = 0.55 (system:

  Toluene / ethyl acetate 6: 4); Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max = 241 m (e = 14,000), infrared absorption spectrum (in mineral oil): characteristic bands at 2.97, 3.02 tl, 5.62, 5.72, 5.83, 5.96, 6.05, 6.49 and 6.69; Proton resonance spectrum (chloroform-d): characteristic signals for the two protons on the thiophene ring: 8 = 6.94 and 7.17 (AB / J = 5.5).

  The 3-acetyloxymethyl-7ss- [2- (4-tert-butyloxycarbonylaminomethyl-2-thienyl) -acetylamino] -3-cephem-4-carboxylic acid tert-butyl ester is then eluted with the same solvent mixture, thin-layer chromatogram (silica gel) : RF = 0.41 (system: toluene / ethyl acetate 6: 4); Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max = 242 m; (# = 14,200); Infrared absorption spectrum (in mineral oil): characteristic bands at 2.99, 5.62, u, 5.73, a, 5.83 and 6.59; Proton resonance spectrum (chloroform-d): characteristic signals for the two protons on the thiophene ring: 6 = 6.86 (s) and 8 = 6.99 (s).



      Example 9
A solution of 1.5 g of 3-acetyloxymethyl-7α-methoxy- -7ss- [2- (3-tert-butyloxycarbonylaminomethyl-2-thienyl) -acetylamino] -3-cephem-4-carboxylic acid-tert. -butyl esters are converted into the inner salt of 3-acetyloxy methyl-7ss- [2- (3-aminomethyl-2-thienyl) -acetylamino] -7α-methoxy in 6.0 ml of trifluoroacetic acid and following the procedure described in Example 2 -3-cephem-4-carboxylic acid transferred, thin-layer chromatogram (silica gel):

  Rf = 0.27 (system: n-butanol / acetic acid / water 45: 45: 10); Ultraviolet Absorption Spectrum (in water): #max = 237 m (# = 12,700); Infrared absorption spectrum (in mineral oil): characteristic bands at 5.64, a, 5.57, 5.97 It and 6.55 p; Proton resonance spectrum (formic acid d2): characteristic AB system at 8 = 7.17 and 7.38 (J = 5.5) of the two hydrogen substituents on the disubstinated thiophene ring.



      Example 10
The 3-acetyloxymethyl-7α-methoxy-7ss- [2- (4-tert-butyl-oxycarbonylaminomethyl-2-thienyl) -acetylamino] -3-cephem -4-carboxylic acid-tert-butyl ester is obtained according to Example 8 method described, thin-layer chromatogram (silica gel): Rf = 0.37 (system: toluene / ethyl acetate 3: 2); Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max = 243 m (# = 14,300); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.8911, 2.93, u, 5.60 p, 5.75, 5.84 @ and 6.55.



      Example 11
A solution of 1.5 g of 3-acetyloxymethyl-7α-methoxy- -7ss- [2- (4-tert-butyloxycarbonylaminomethyl-2-thienyl) -acetylamino] -3-cephem-4-carboxylic acid-tert. Butyl ester in 6.0 ml of trifluoroacetic acid is converted into the inner salt of 3-acetyloxy methyl-7ss- [2- (4-aminomethyl-2-thienyl) -acetylamino] -7α-methoxy according to the procedure described in Example 2 -3-cephem-4-carboxylic acid transferred.

  Thin-layer chromatogram (silica gel): Rf = 0.27 (system: n-butanol / acetic acid / water 45: 45: 10); Ultraviolet absorption spectrum (in water) #max = 238 m (# = 13,100); Infrared absorption spectrum (in mineral oil): characteristic bands at 5.64, 5.75, 5.98 p and 6.55 Il.



      Example 12
A lithium methoxide solution prepared by dissolving 0.14 g of lithium wire in 20 ml of methanol is converted into a solution of 4.48 g of 7ss- [2- (5-tert-butyloxycarbonylaminomethyl-2-thienyl) - which is placed under a nitrogen atmosphere at - acetylamino] -3- (1-methyl-5-tetrazolylthiomethyl) -3-cephem-4-carboxylic acid diphenylmethyl ester in 100 ml of tetrahydrofuran and 100 ml of methanol. Immediately thereafter, 0.860 ml of tert-butyl hypochlorite is added, the mixture is stirred at -70 to -75 for 35 minutes, 3.0 ml of acetic acid are added and the mixture is concentrated under reduced pressure. 50 ml of ice-cold water are added to the residue; the aqueous mixture is extracted twice with 100 ml of ethyl acetate each time.

  The organic extracts are washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered through 10 g of silica gel and concentrated. The residue is triturated with petroleum ether and the 7ss- [2- (5-tert-butyloxycarbonylaminomethyl-2-thienyl) -acetylamino] -7α-methoxy-3- (1-methyl-5-tetrazolylthiomethyl) -3- Diphenylmethyl cephem-4-carboxylate is filtered off, thin-layer chromatogram (silica gel): Rf = 0.26 (system: toluene / ethyl acetate 3: 2); Ultraviolet absorption spectrum (in 95% aqueous ethanol):

  Inflections at 239 m (e = 13,100) and 276 m (# = 5800); Infrared absorption spectrum (in mineral oil): characteristic bands at 2.90, 5.60, 5.78 p and 6.59.



   The starting material can e.g. can be obtained as follows:
2 is added with stirring to a suspension of 5.0 g of 7ss-amino-3- (1-methyl-5-tetrazolylthiomethyl) -3-cephem-4-carboxylic acid (US Pat , 09 g of p-toluenesulfonic acid monohydrate; this slowly creates a clear solution which is concentrated under reduced pressure. Diethyl ether is added and the p-toluenesulfonic acid salt of 7ss-amino-3- (1-methyl-5-tetrazolylthiomethyl) -3-cephem-4-carboxylic acid is filtered off. This is dissolved in 100 ml of dioxane and 2.5 g of diphenyldiazomethane are added in portions to the solution. The mixture is stirred for 18 hours at room temperature and concentrated under reduced pressure; the residue is mixed with 100 ml of a 0.1 aqueous sodium hydrogen carbonate solution and extracted twice with 100 ml of ethyl acetate each time.

  The organic extracts are washed successively with water and with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. Crystallization from diethyl ether gives the 7ss-amino-3- (1-methyl-5-tetrazolylthio-methyl) -3-cephem-4-carboxylic acid diphenylmethyl ester, thin-layer chromatogram (silica gel): Rf = 0.21 (system: chloroform / Ethyl acetate / acetic acid 80: 19 1); Ultra violet absorption spectrum (ethanol): Xmax = 269 m ml (e = 6400); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.93, 5.60 and 6.15.



   5.43 g of 2- (5-tert-butyloxycarbonylaminomethyl-2-thienyl) -acetic acid are dissolved in 200 ml of methylene chloride containing 2.20 ml of 4-methyl-morpholine, the solution kept under exclusion of moisture is cooled to 20 and added dropwise with 2.86 ml of isobutyl chloroformate. After 30 minutes, a solution of 9.35 g of 7ss-amino-3- (1-methyl-5-tetrazolylthiomethyl) -3-cephem4-carboxylic acid diphenylmethyl ester in 100 ml of methylene chloride is added, whereupon for one hour at - Stirring for 20 and 16 hours while slowly warming to room temperature.



  The mixture is poured into ice-cold water, the organic solution is separated off and the aqueous phase is extracted again with 100 ml of methylene chloride. The organic extracts are washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. Crystallization of the residue from a mixture of methyl acetate and diethyl ether gives 7ss- [2- (5-tert-butyloxycarbonylaminomethyl-2-thienyl) acetylamino] -3- (1-methyl -5-tetrazolylthiomethyl) -3-cephem Diphenylmethyl -4-carboxylate, thin-layer chromatogram (silica gel): Rf = 0.38 (system: chloroform / ethyl acetate / acetic acid 80: 19: 1); to 19 - Ultraviolet absorption spectrum (in 95% aqueous ethanol):

  Shoulders at 242 mp ( <= 16,400) and 274 mp (e = 9200); Infrared absorption spectrum (in mineral oil): characteristic bands at 3.03 u, 5.58, 5.79 1.5.96, u, 6.12 p and 6.51 Il.



   The starting material can also be produced in the following way:
A suspension of 2.0 g of 7ss-amino-3- (1-methyl-5-tetrazolylthiomethyl) -3-cephem-4-carboxylic acid in 60 ml of methylene chloride is mixed with 1.5 ml of triethylamine, 1.6 ml of N, N -Dimethylaniline and 2.3 ml of trimethylchlorosilane added. The mixture is heated to 400 for 20 minutes with stirring and then cooled to 100. A solution of 2- (5-tert-butyloxycarbonylaminomethyl-2-thienyl) -acetic acid chloride in methylene chloride is added as follows: A solution of 1.95 g of 2- (5-tert-butyloxycarbonylaminomethyl -2-thienyl) - acetic acid in 20 ml of methylene chloride is treated with 0.05 ml of dimethylformamide and 5 ml of oxalyl chloride.



  The mixture is stirred under a stream of nitrogen for 30 minutes at reflux temperature, the volatile constituents are distilled off under reduced pressure and the oily components are dissolved
Residue in 20 ml of methylene chloride. The reaction mixture is stirred for 2 hours at 0 to 25, water is poured out, the mixture is adjusted to a pH of about 7 with sodium hydrogen carbonate, extracted with methylene chloride, carefully acidified with concentrated hydrochloric acid and the precipitate formed is filtered off. It is washed with water and the material on the filter is dried under reduced pressure at room temperature.



   The product, containing the 7ss- [2- (5-tert-butyloxycar- bonylaminomethyl-2-thienyl) acetylamino] -3- (1 -methyl-5-tetrazolylthiomethyl) -3-cephem-4-carboxylic acid, is in 30 ml of dioxane are dissolved, 1.5 g of diphenyldiazomethane are added to the solution, the mixture is stirred at room temperature for 12 hours and then concentrated. The residue gives after crystallization from a mixture of methyl acetate u. Diethyl ether 7ss- [2- (5-tert-butyloxycarbonylaminomethyl-2-thienyl) -acetylaminoj-3- (1-methyl-5-tetrazolylthiomethyl-3-cephem-4-carboxylic acid diphenylmethyl ester.



   Example 13
A solution of 3.91 g of 7ss- [2- (5-tert-butyloxycarbonyl-aminomethyl-2-thienyl) -acetylamino] -7a-methoxy-3- (1 -methyl-5-tetrazolylthiomethyl) -3-cephem- Diphenylmethyl 4-carboxylate in 30 ml of trifluoroacetic acid and 5 ml of anisole is left to stand for one hour at 20 with exclusion of moisture, then concentrated under reduced pressure. The residue is dried under high vacuum for 16 hours and then dissolved in 30 ml of methanol. The solution is treated with an activated carbon preparation and filtered.

  About 0.95 ml of triethylamine are added dropwise to the filtrate until a pH of 6.0 is reached; the precipitated inner salt of 7ss- [2- (5-aminomethyl-2-thienyl) -acetylamino] -7α-methoxy-3- (1-methyl-5-tetrazolylthiomethyl) -3-cephem-4- carboxylic acid is filtered off; Thin-layer chromatogram (silica gel): Rf = 0.10 (system: n-butanol / acetic acid / water 45: 45 10); Ultraviolet absorption spectrum (in 0.01 normal aqueous sodium hydrogen carbonate): 7 \ max = 240 mSL (e = 15,900); Infrared absorption spectrum (in mineral oil): characteristic bands at 5.67'1, 5.96 p and 6.48>.



   The product is identical to the compound of Example 3. The following compounds are prepared in an analogous manner when the appropriate starting materials are selected: 7ss- [2- (5-aminomethyl-2-thienyl) -acetylamino] -3,7α-dimethoxy-3 -cephem-4-carboxylic acid; 3-aminocarbonyloxymethyl-7ss- [2- (5-aminomethyl-2-thienyl) - acetylamino] -7a-methoxy-3-cephem-4-carboxylic acid; 7ss- [2- (5-aminomethyl-2-thienyl) -acetylamino] -3-methylamino-carbonyloxymethyl-7α-methoxy-3-cephem-4-carboxylic acid; 7ss- [2- (5-aminomethyl-2-thienyl) -acetylamino] -3-N- (2-chloroethyl) -aminocarbonyloxymethyl-7a-methoxy-3-cephem -4-carboxylic acid; and 7ss - [2- (5-aminomethyl-2-thienyl) acetylamino] -7a-methoxy--3-methylthiomethyl-3-cephem-4-carboxylic acid, which are usually obtained in the form of their internal salts.

 

   Example 14
A solution of 1.96 g of 7ss- [2- (5-tert-butyloxycarbonylaminomethyl-2-thienyl) -acetylamino] -3- (5-methyl-1, 3,4-thiadiazol-2-ylthyiomethyl) -3- tert-butyl cephem-4-carboxylate in 150 ml of tetrahydrofuran is treated at -70 with a solution of 0.073 g of lithium in 20 ml of methanol and immediately thereafter with 0.391 ml of tert-butyl hypochlorite. After a reaction time of 15 minutes at -70, 3 ml of acetic acid are added and the reaction mixture is evaporated in a water jet vacuum. The residue is taken up in 150 ml of ethyl acetate; the organic solution is washed with dilute aqueous sodium thiosulfate solution and with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to a volume of about 10 ml in a water-jet vacuum.

  The concentrated solution is slowly diluted with 100 ml of petroleum ether; the precipitate is filtered off and dried under high vacuum at room temperature. This gives the 7ss- [2- (5-tert-butyloxycarbonyl aminomethyl-2-thienyl) acetylamino] -7a-methoxy-3- (5-methyl-1,3,4-thiadiazol-2-ylthiomethyl) - 3-cephem-4-carboxylic acid tert-butyl ester; Thin-layer chromatogram (silica gel): Rf = 0.12 (system: toluene / ethyl acetate 3: 2).



   The starting material can be made as follows:
4.08 g of 2- (5-tert-butyloxycarbonylaminomethyl -2-thienyl) -acetic acid are dissolved in 200 ml of methylene chloride containing 1.65 ml of N-methylmorpholine, the solution is cooled to 200 with exclusion of moisture and 1 is added dropwise , 95 ml of isobutyl chloroformate to. After 30 minutes, one of 5.16 g of 7ss-amino-3- (5-methyl-1,3,4-thiadiazol-2- -ylthiomethyl) -3-cephem-4-carboxylic acid and 7.20 ml of N, O -Bis- (trimethylsilyl) acetamide in 150 ml of methylene chloride prepared solution, whereupon the reaction mixture is stirred for one hour at -20 and for 4 hours while slowly warming to room temperature and then concentrated under reduced pressure.

  The residue is dissolved in water with the addition of sodium hydrogen carbonate until a pH of 8 is reached. It is washed with ethyl acetate, the separated aqueous solution is acidified with 20% aqueous phosphoric acid to pH 2 and extracted with ethyl acetate. The organic extract is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated.



  The 7ss- [2- (5-tert-butyloxycarbonylaminomethyl-2-thienyl) -acetylamino] -3- (5-methyl-1,3,4-thiadiazol-2 -ylthiomethyl) -3-cephem is obtained in this way -4-carboxylic acid; Thin-layer chromatogram (silica gel): Rf = 0.40 (system: n-butanol / acetic acid / water 45: 45 10), ultraviolet absorption spectrum (ethanol): Xmax = 244 mp (e = 16,900); Infrared absorption spectrum (in mineral oil): characteristic bands at 2.93, 5.60, 5.90, 6.55>.



   A mixture of 6.1 g of dicyclohexylcarbodiimide, 2.1 g of tert-butyl alcohol and 0.06 g of copper (I) chloride is stirred for 5 days at room temperature. The suspension of O-tert-butyl-N, N'-dicyclohexyl-isourea which can be obtained in this way is diluted with 30 ml of methylene chloride and added to a solution of 2.0 g of 7ss- [2- (5-tert.- - Butyloxycarbonylaminomethyl-2-thienyl) acetylamino] -3 - (5-methyl-1,3,4-thiadiazol-2-ylthiomethyl) -3-cephem-4-carboxylic acid in 50 ml of methylene chloride. After 5 hours, it is filtered and the filtrate is concentrated under reduced pressure.

  The residue is chromatographed on 40 g of silica gel, the 7ss- [2- (5-tert-butyloxycarbonylaminomethyl-2-thienyl) -acetylamino] -3 - (5-methyl-1,3,4-thiadiazole) being treated with ethyl acetate -2-ylthiomethyl) -3-cephem-4-carboxylic acid tert-butyl ester eluted; Thin-layer chroma atogram (silica gel): Rf = 0.70 (n-butanol / acetic acid / water 45: 45: 10).



   Example 15
A solution of 1.52 g of 7ss- [2- (5-tert-butyloxycarbonyl-aminomethyl-2-thienyl) -acetylamino] -7a-methoxy- (5-methyl- -1, 3,4-thiadiazole-2- ylthiomethyl) -3-cephem-4-carboxylic acid tert-butyl ester in 20 ml of trifluoroacetic acid is left to stand for 15 minutes at room temperature with exclusion of moisture and then evaporated in a water-jet vacuum with the addition of toluene. The residue is triturated with diethyl ether and the thus obtainable trifluoroacetic acid salt of 713 [2- (5-aminomethyl-2-thienyl) acetylamino] -7a- methoxy-3- (5-methyl-1, 3,4-thiadiazole- 2-ylthiomethyl) -3-cephem-4-carboxylic acid dried in a high vacuum at room temperature and then dissolved in 20 ml of water.

  The aqueous solution is washed with ethyl acetate, adjusted to a pH of 6 with triethylamine and concentrated to a volume of about 5 ml under a water jet vacuum. It is diluted by the dropwise addition of 30 ml of acetone, left to stand at 40 for 2 hours and the precipitate is filtered off.

  This is washed with diethyl ether and dried under high vacuum at room temperature; the inner salt of 713- [2- (5-aminomethyl-2-thienyl) -acetyl-amino] -7a-methoxy-3- (5-methyl-1, 3,4-thiadiazol-2-ylthiome- ethyl) -3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel): Rf = 0.11 (system: n-butanol / acetic acid / water 45: 45: 10): ultraviolet absorption spectrum (0.1 normal aqueous sodium hydrogen carbonate solution): Xmax = 242 mF (e = 16,400); Infrared absorption spectrum (in mineral oil): characteristic bands at 5.66 Il, 5.97 1.6.25 F and 6.50 Il.



   PATENT CLAIM 1
Process for the preparation of 6ss-acylamino-6a-methoxy-penam-3-carboxylic acid compounds and 7ss-acylamino-7a-methoxy-3-cephem-4-carboxylic acid compounds of the formula
EMI14.1
 where X is sulfur or oxygen. and wherein the grouping of the formula -S-A- is a radical of the formula
EMI14.2
 denotes in which Rl is hydrogen or a radical of the formula -CH2-R2, in which R2 is hydrogen, a free, etherified or esterified hydroxyl or mercapto group or a quaternary ammonium group, and R denotes hydroxyl or, together with the carbonyl group -C ( = O) - represents an esterified carboxy group which can be cleaved under physiological conditions, as well as salts thereof, characterized in that the 6a or

   7a-position of a penam or 3-cephem compound of the formula
EMI14.3
 wherein the amino of the aminomethyl group is preferably present in temporarily protected form, and the radical of the formula -SA- has the meaning given above, a carboxyl group of the formula -C (= O) -R preferably being present in temporarily protected form, or a salt thereof , introduces the methoxy group, and in a compound obtained converts optionally still protected amino of the aminomethyl group into free amino, and / or, if desired, converts a salt obtained into the free compound or into another salt or a free compound obtained into a salt.

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



   

 

Claims (1)

** WARNING ** Beginning of CLMS field could overlap end of DESC **. is filtered off and dried under high vacuum at room temperature. This gives the 7ss- [2- (5-tert-butyloxycarbonyl aminomethyl-2-thienyl) acetylamino] -7a-methoxy-3- (5-methyl-1,3,4-thiadiazol-2-ylthiomethyl) - 3-cephem-4-carboxylic acid tert-butyl ester; Thin-layer chromatogram (silica gel): Rf = 0.12 (system: toluene / ethyl acetate 3: 2). The starting material can be made as follows: 4.08 g of 2- (5-tert-butyloxycarbonylaminomethyl -2-thienyl) -acetic acid are dissolved in 200 ml of methylene chloride containing 1.65 ml of N-methylmorpholine, the solution is cooled to 200 with exclusion of moisture and 1 is added dropwise , 95 ml of isobutyl chloroformate to. After 30 minutes, one of 5.16 g of 7ss-amino-3- (5-methyl-1,3,4-thiadiazol-2- -ylthiomethyl) -3-cephem-4-carboxylic acid and 7.20 ml of N, O -Bis- (trimethylsilyl) acetamide in 150 ml of methylene chloride prepared solution, whereupon the reaction mixture is stirred for one hour at -20 and for 4 hours while slowly warming to room temperature and then concentrated under reduced pressure. The residue is dissolved in water with the addition of sodium hydrogen carbonate until a pH of 8 is reached. It is washed with ethyl acetate, the separated aqueous solution is acidified with 20% aqueous phosphoric acid to pH 2 and extracted with ethyl acetate. The organic extract is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. The 7ss- [2- (5-tert-butyloxycarbonylaminomethyl-2-thienyl) -acetylamino] -3- (5-methyl-1,3,4-thiadiazol-2 -ylthiomethyl) -3-cephem is obtained in this way -4-carboxylic acid; Thin-layer chromatogram (silica gel): Rf = 0.40 (system: n-butanol / acetic acid / water 45: 45 10), ultraviolet absorption spectrum (ethanol): Xmax = 244 mp (e = 16,900); Infrared absorption spectrum (in mineral oil): characteristic bands at 2.93, 5.60, 5.90, 6.55>. A mixture of 6.1 g of dicyclohexylcarbodiimide, 2.1 g of tert-butyl alcohol and 0.06 g of copper (I) chloride is stirred for 5 days at room temperature. The suspension of O-tert-butyl-N, N'-dicyclohexyl-isourea which can be obtained in this way is diluted with 30 ml of methylene chloride and added to a solution of 2.0 g of 7ss- [2- (5-tert.- - Butyloxycarbonylaminomethyl-2-thienyl) acetylamino] -3 - (5-methyl-1,3,4-thiadiazol-2-ylthiomethyl) -3-cephem-4-carboxylic acid in 50 ml of methylene chloride. After 5 hours, it is filtered and the filtrate is concentrated under reduced pressure. The residue is chromatographed on 40 g of silica gel, the 7ss- [2- (5-tert-butyloxycarbonylaminomethyl-2-thienyl) -acetylamino] -3 - (5-methyl-1,3,4-thiadiazole) being treated with ethyl acetate -2-ylthiomethyl) -3-cephem-4-carboxylic acid tert-butyl ester eluted; Thin-layer chroma atogram (silica gel): Rf = 0.70 (n-butanol / acetic acid / water 45: 45: 10). Example 15 A solution of 1.52 g of 7ss- [2- (5-tert-butyloxycarbonyl-aminomethyl-2-thienyl) -acetylamino] -7a-methoxy- (5-methyl- -1, 3,4-thiadiazole-2- ylthiomethyl) -3-cephem-4-carboxylic acid tert-butyl ester in 20 ml of trifluoroacetic acid is left to stand for 15 minutes at room temperature with exclusion of moisture and then evaporated in a water-jet vacuum with the addition of toluene. The residue is triturated with diethyl ether and the thus obtainable trifluoroacetic acid salt of 713 [2- (5-aminomethyl-2-thienyl) acetylamino] -7a- methoxy-3- (5-methyl-1, 3,4-thiadiazole- 2-ylthiomethyl) -3-cephem-4-carboxylic acid dried in a high vacuum at room temperature and then dissolved in 20 ml of water. The aqueous solution is washed with ethyl acetate, adjusted to a pH of 6 with triethylamine and concentrated to a volume of about 5 ml under a water jet vacuum. It is diluted by the dropwise addition of 30 ml of acetone, left to stand at 40 for 2 hours and the precipitate is filtered off. This is washed with diethyl ether and dried under high vacuum at room temperature; the inner salt of 713- [2- (5-aminomethyl-2-thienyl) -acetyl-amino] -7a-methoxy-3- (5-methyl-1, 3,4-thiadiazol-2-ylthiome- ethyl) -3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel): Rf = 0.11 (system: n-butanol / acetic acid / water 45: 45: 10): ultraviolet absorption spectrum (0.1 normal aqueous sodium hydrogen carbonate solution): Xmax = 242 mF (e = 16,400); Infrared absorption spectrum (in mineral oil): characteristic bands at 5.66 Il, 5.97 1.6.25 F and 6.50 Il. PATENT CLAIM 1 Process for the preparation of 6ss-acylamino-6a-methoxy-penam-3-carboxylic acid compounds and 7ss-acylamino-7a-methoxy-3-cephem-4-carboxylic acid compounds of the formula EMI14.1 where X is sulfur or oxygen. and wherein the grouping of the formula -S-A- is a radical of the formula EMI14.2 denotes in which Rl is hydrogen or a radical of the formula -CH2-R2, in which R2 is hydrogen, a free, etherified or esterified hydroxyl or mercapto group or a quaternary ammonium group, and R denotes hydroxyl or, together with the carbonyl group -C ( = O) - represents an esterified carboxy group which can be cleaved under physiological conditions, as well as salts thereof, characterized in that the 6a or 7a-position of a penam or 3-cephem compound of the formula EMI14.3 wherein the amino of the aminomethyl group is preferably present in temporarily protected form, and the radical of the formula -SA- has the meaning given above, a carboxyl group of the formula -C (= O) -R preferably being present in temporarily protected form, or a salt thereof , introduces the methoxy group, and in a compound obtained converts optionally still protected amino of the aminomethyl group into free amino, and / or, if desired, converts a salt obtained into the free compound or into another salt or a free compound obtained into a salt. SUBCLAIMS 1. The method according to claim I, characterized in that a free carboxyl group of the formula -C (= O) -R in a compound of the formula I into a physiologically cleavable esterified carboxyl group. like a pivaloyloxymethoxy 'carbonyl group, is converted. 2. The method according to claim I, characterized in that any free functional groups present in a starting material in addition to a carboxyl group of the formula -C (= O) -R are present in temporarily protected, preferably easily cleavable form. 3. The method according to claim I, characterized in that in a starting material, amino of the aminomethyl group is protected by amino protective groups, which are preferably easily split off. 4. The method according to claim I, characterized in that a methoxy group is introduced into the 6a or 7a position of a penam or 3-cephem compound of the formula IV by adding an acylamino compound of the formula EMI15.1 wherein the amino of the aminomethyl group is in protected form, and the radical of the formula -S-A- has the meaning given above, a carboxyl group of the formula -C (= O) -R being in temporarily protected form. treated with methanol. 5. The method according to dependent claim 4, characterized in that a starting material of the formula IVa is used in the form of a crude reaction mixture, as can be obtained by adding a compound of the formula IV in which the amino of the aminomethyl group and the carboxyl group of the formula = = O) -R, and any additional functional groups present in temporarily protected form, treated with an anion-forming agent, followed by an N-halogenating agent, and, if necessary, reacted with a base which splits off hydrogen halide. or as it can be obtained by adding a compound of the formula EMI15.2 in which R0 stands for an organic radical, and in which amino of the aminomethyl group and the carboxyl group of the formula = = O) -R, as well as any additional functional groups present, are present in temporarily protected form, treated with halogen followed by a base. 6. The method according to claim 5, characterized in that the anion-forming agent is an organometallic base, such as an alkali metal, in particular lithium alcoholate, in particular an alkali metal, e.g. Lithium lower alkoxide, such a base being able to serve at the same time as a hydrogen halide-releasing agent, and using a sterically hindered organic hypohalite, such as a tert-lower alkyl hypohalite, as the N-halogenating agent. 7. The method according to dependent claim 6, characterized in that Ro in a starting material of the formula IVb is a hydrocarbon radical of aliphatic character, such as lower alkyl, in particular methyl. 8. The method according to dependent claims 5 or 7, characterized in that a starting material of formula IVb is mixed with chlorine followed by an organic base such as a tertiary aliphatic amine, e.g. a tri-lower alkylamine. 9. The method according to claim I or one of the dependent claims 1-3, characterized in that a methoxy group is in the 6a or 7ol position of a penam or 3-cephem compound of the formula W is introduced by adding a compound of the formula IVb according to dependent claim 5, in which Ro has the meaning given in dependent claim 5 or 7, and in which amino of the aminomethyl group and the carboxyl group of the formula -C (= O) - R, and any additional functional groups present in protected form, are reacted with methanol in the presence of a desulfurizing agent. 10. The method according to dependent claim 9, characterized in that a silver or mercury compound, such as a silver or mercury oxide or a silver-I or mercury-II salt is used as the desulfurizing agent. 11. The method according to claim I or one of the dependent claims 1-4, characterized in that compounds of the formula I according to claim I or salts thereof are prepared, wherein X has the meaning given in claim I, and the remainder of the formula -SA- for partial formula Ia or Ib according to claim I, in which R has the meaning given in claim I, and R1 is hydrogen or the group -CH2-R2, in which R2 is hydrogen, hydroxy, a hydroxy or mercapto group etherified by a lower aliphatic hydrocarbon radical, a mercapto group etherified by an optionally substituted, bonded to the sulfur via a ring carbon atom, heterocyclic radical with 1 to 4 ring nitrogen atoms and optionally a further ring heteroatom from the group oxygen and sulfur, represents a hydroxyl or mercapto group esterified by a lower aliphatic carboxylic acid or by an optionally N-substituted carbamic acid, or a quaternary ammonium group derived from a tertiary organic base and linked to the methyl carbon atom via the nitrogen atom. 12. The method according to claim I or one of the dependent claims 1-4, characterized in that compounds of the formula I according to claim I or salts thereof are prepared, in which X is oxygen or, in particular, sulfur, and the aminomethyl-substituted heterocycle has a 4- or represents 5-aminomethyl-2-thienyl or a 4 or 5-aminomethyl-2-furyl radical, the grouping of the formula -SA- represents a radical of the formula Ia or Ib according to claim 1 in which Ri is the group of the formula -CH2 R2, and R2 is hydrogen, lower alkanoyloxy, optionally N-alkylated carbamoyloxy, optionally substituted heterocyclylthio, in which heterocyclyl is a monocyclic, five-membered heterocyclic radical of aromatic character, which is connected to the thiosulfur atom via a ring carbon atom, and which contains 2 or 3 ring nitrogen atoms and optionally additionally a ring oxygen atom, ring sulfur atom or ring nitrogen atom, where such a radical can optionally be substituted by lower alkyl, or in which heterocyclyl is an unsaturated monocyclic, six-membered heterocyclic radical, which is connected to the thiosulfur atom via a ring carbon atom and contains 2 ring nitrogen atoms, where either one ring nitrogen atom contains an oxo group or a ring carbon atom contains an oxo group, and such a heterocyclyl radical can optionally be substituted by lower alkyl, lower alkoxy or halogen, or a pyridinium radical, which optionally means can be substituted by carboxy, carbamoyl or hydrazinocarbonyl, and where R is hydroxy. 13. The method according to claim I or one of the Un claims 1-4, characterized in that 3-cephem compounds of the formula I according to claim I or salts thereof are prepared, in which X is sulfur and the aminomethyl-substituted heterocycle is a 4- or 5-aminomethyl-2-thienyl radical, the grouping of the formula -SA- denotes the radical of the formula Ib according to claim I, in which R1 stands for the radical of the formula -CH2R2, where R2 is hydrogen, acetyloxy, carbamoyloxy, optionally substituted by lower alkyl, thiadiazolylthio connected via a ring carbon atom to the thiosulfur atom or Tetrazolylthio, optionally substituted by lower alkyl, lower alkoxy or halogen, N-oxidoparidazinylthio linked to the thiosulfur atom via a ring carbon atom, or is pyridinium which is optionally substituted by carbamoyl, and in which R is hydroxy. 14. The method according to claim I or one of the dependent claims 1-4, characterized in that 3-cephem compounds of the formula I according to claim I or salts thereof, in which X is sulfur, and the aminomethyl-substituted heterocycle is a 4- or 5-aminomethyl-2-thienyl radical, the grouping of the formula -SA- denotes the radical of the formula Ib according to claim 1, in which R1 stands for the radical of the formula -CH2-R2, where R2 is hydrogen, acetyloxy, 1,3,4 Is thiadiazol-2-ylthio, 1-methyl-5-tetrazolylthio or pyridinium, and wherein R is hydroxy. 15. The method according to claim I or one of the dependent claims 1-4, characterized in that 3-acetyloxymethyl-7ss- [2- (5-aminomethyl-2-thienyl) acetylamino] - -7a-methoxy-3-cephem -4-carboxylic acid or salts thereof. 16. The method according to claim I or one of the subclaims 1-4, characterized in that 7ss- [2- - (5-aminomethyl-2-thienyl) acetylamino] -7Y-methoxy-3- - (5-methyl- 1-tetrazolyl-thiomethyl) -3-cephem-4-carboxylic acid or salts thereof. 17. The method according to claim I or one of the dependent claims 1-4, characterized in that 7ss- [2 - (5-aminomethyl-2-thienyl) acetylamino] -7a-methoxy-3- (5 -methyl- l, 3.4-thiadiazol-2-ylthiomethyl) -3-cephem-4-carboxylic acid or salts thereof. PATENT CLAIM II Use of the compounds of formula 1 obtained by the process of claim I in which the group -SA- is the sub-formula Ib and R 1 is a group -CH2-R2, in which R2 is an esterified hydroxyl or mercapto group according to claim I, or their Salts, characterized in that in such a compound, optionally with intermediate protection of free functional groups, such a radical R2 is converted into an etherified mercapto group R2 by treatment with a mercapto compound. CLAIM TO CLAIM 11 Use according to claim 11, characterized in that the 3-acetyloxymethyl-7ss- [2- (5-aminomethyl-2-thienyl) -acetylamino] -7a-methoxy-3-cephem-4-carboxylic acid is treated with 5-mercapto-1-methyl-tetrazole into the 7ss- [2- (5-aminomethyl-2-thienyl) -acetylamino] -7a-methoxy-3- (1 -methyl-5-tetrazolyl-thiomethyl) -3 -cephem-4-carboxylic acid transferred.