CH611904A5 - Process for the preparation of novel 2-lower alkyl-2- and -3-cephem-4-carboxylic acid derivatives - Google Patents

Abstract

Novel 2-lower alkyl-2- and -3-cephem-4-carboxylic acid derivatives of the formula: <IMAGE> in which R<1b'> denotes acylamino, R<2> denotes carboxyl or protected carboxyl, R<3> denotes lower alkyl and X denotes S or SO, are obtained by transacylation of a compound of the formula: <IMAGE> in which R<1b> denotes an acylamino other than R<1b'>. The process products are active against a number of microorganisms. They can be used in a suitable formulation for the treatment of disorders which are produced in humans and animals by such microorganisms.

Description

  

  
 

** WARNING ** Beginning of DESC field could overlap end of CLMS **.

 



   PATENT CLAIMS
1. Process for the preparation of 2-lower alkyl-2- or -3cephem-4-carboxylic acid derivatives of the formula:
EMI1.1
 in which RtF is an acylamino group, R2 is a carboxy or protected carboxy group, R3 is a lower alkyl group and X is -5- or
EMI1.2
 mean, and their pharmaceutically acceptable salts, characterized in that a compound of the formula:

  :
EMI1.3
 in which R2, R3 and X have the above meanings and Rib is an acylamino group other than Reib ', with a trialkyloxonium haloborate or an iminohalide-forming agent and an iminoether-forming agent and then the compound obtained with one of the acyl group of R'b' corresponding Acylating agent converts, which is followed, if necessary, by hydrolysis in order to complete the transacylation reaction.



   2. The method according to claim 1, characterized in that trimethyloxonium chloroborate, trimethyloxonium fluoroborate or triethyloxonium fluoroborate is used as the trialkyloxonium haloborate.



   3. The method according to claim 1, characterized in that a halogenating agent, for example phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride or phosgene is used as the iminohalide-forming agent.



   4. The method according to claim 1, characterized in that an alcohol or a metal alcoholate derived from this alcohol is used as the imino ether-forming agent.



   The invention relates to a process for the preparation of antimicrobially active 2-lower alkyl-2- and -3-cephem-4carboxylic acid derivatives which have an activity against a number of microorganisms.



   The 2-lower alkyl-2- and -3cephem-4-carboxylic acid derivatives obtainable according to the invention are new compounds.



  In fact, 2-lower alkyl derivatives of the cephalosporin series were previously unknown, while 3-lower alkyl derivatives, such as u. a. Cephalexin (J. Med. Chem. 12 [1969], 310; Belg. Patent No. 696 026) and Cephradin (J. Med. Chem. 14 [1971], 117; US Patent No. 3,485,819) have long been described and proposed for therapeutic use.



   The new compounds are represented by the following formula:
EMI1.4
 in which R'b 'is an acylamino group, R2 is a carboxy or protected carboxy group, R3 is a lower alkyl group and X is -S- or
EMI1.5
 mean.



   According to the invention, the compounds If are prepared by adding a compound of the formula:
EMI1.6
 in which R2, R3 and X have the above meanings and Rib is an acylamino group other than Rib, reacts with a trialkyloxonium haloborate or an iminohalide-forming agent and an iminoether-forming agent and then reacts the compound obtained with an acylating agent corresponding to the acyl group of Reib ', which, if necessary, is followed by hydrolysis to complete the transacylation reaction.



   The term an acylamino group used here for friction and Rlb is to be understood as meaning groups in which the acyl radical is, for example, the following: a carbamoyl radical, an aliphatic acyl group and an acyl group which contains an aromatic or heterocyclic ring, which are illustrated below by examples .



   That is, suitable examples of aliphatic acyl groups include saturated or unsaturated lower or higher alkanoyl groups which may be branched or which may contain a cyclic ring, e.g. lower or higher aliphatic acyl groups such as lower alkanoyl (e.g.



  Formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl and the like. the like), higher alkanoyl (e.g. octanoyl, lauroyl, palmitoyl, and the like), lower alkanoyl (e.g. acryloyl, crotonoyl, and the like), lower alkinoyl (e.g.



  Propinoyl et al. like), lower or higher cycloalkanecarbonyl (e.g. cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl and the like), lower or higher cycloalkyl-lower alkanoyl (e.g. cyclopentylacetyl, cyclohexylacetyl, cycloheptyglionlacetyl), cyclohexylpropionylpro, cycloheptylpro, cycloheptyl



  lower or higher cycloalkadiene carbonyl (e.g. dihydrobenzoyl and the like), lower or higher cycloalkadienyl lower alkanoyl (e.g. dihydrophenylacetyl, dihydrophenylpropionyl and the like) and the like. like; as well as lower or higher aliphatic acyl groups containing an oxygen or sulfur atom, e.g.



  lower alkoxy-lower alkanoyl (e.g. methoxyacetyl, ethoxyacetyl, methoxypropionyl and the like), lower alkylthio-lower alkanoyl (e.g. methylthioacetyl, ethylthioacetyl, methylthiopropionyl and the like), lower alkenylesionyl-higher alkanoyl-lower alkanoyl, alkenylthio-lower alkylthioyl, lower alkenylthio-lower alkylthio-lower, alkenylthio-lower alkylthioyl or lower alkenylthio-higher alkenylthio-lower alcetyl, alkenylthio-lower alkylthioyl, or lower alkenylthio-lower alkylthio-higher, alkenylthio-lower alcetyl, alkenylthio-lower alkylthio-alkyl (e.g. cyclopentylthio acetyl, cyclohexylthiopropionyl, cycloheptylthioacetyl and the like), lower or higher cycloalkoxy lower alkynoyl (e.g. cyclopentyloxyacetyl, cyclohexyloxypropionyl and the like), lower or higher dihydroxyacetanoyl alkanoic, lower or higher dihydroxyalkanoyl alcohol (e.g. lower or higher cycloalkane-hydroxy-alkanoyl-alkanoic, lower or higher cycloalkandyl-alkanoyl-alkanoic, lower or higher cycloalkane-hydroxy-alkanoic, lower or higher cycloalkandyl-alkanoyl-alkanoate, lower or higher cycloalkandyl-alkanoyl-alkanoic, lower or e.g. Dihy drophenylthioacetyl, Dihydrophenylthiopropionyl and the like.), Lower alkoxycarbonyl (e.g.

  Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-Ciclopropyläthoxycarbonyl, Iso propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl and. Like.), lower or higher cyclohexyloxycarbonyl, cyclo heptyloxycarbonyl u. the like), lower or higher cycloalkanedienyloxycarbonyl (e.g. dihydrophenoxycarbonyl and the like) and the like. like



   Examples of suitable acyl groups forming an aromatic ring, e.g. a benzene, naphthalene ring and the like. like., are e.g. Arylcarbamoyl (e.g. phenylcarbamoyl and the like), aryloyl (e.g. benzoyl, toluoyl, naphthoyl, a
Methylnaphthoyl, phthaloyl, benzenesulfonyl, tetrahydronaphthoayl, indanecarbonyl and the like. the like), amine-lower alkanoyl (e.g. phenyl acetyl, phenylpropionyl, phenylbutyryl, tolylacetyl, xylylacetyl, naphthylacetyl, tetrahydronaphthylacetyl, indanylacetyl and the like), and the carbon atom in the alkyl radical of
Arlowalkanoyl group can be replaced by an oxygen or
Sulfur atom or the carbonyl group, e.g.



   in aryloxy lower alkanoyl (e.g. phenoxyacetyl, phenoxypropionyl, phenoxybutyryl, xylyloxyacetyl and the like), aryloxycarbo nyl (e.g. phenoxycarbonyl, xylyloxycarbonyl, naphthyloxy carbonyl, indanyloxycarbonyl, e.g. benzyloxycarbonyl, e.g.
Arylthio-lower alkanoyl (e.g. phenylthioacetyl, phenylthiopropionyl, and the like), arylglyoxyloyl (e.g. phenylglyoxyloyl, and the like), and the like. like



   Examples of suitable acyl groups which contain a heterocyclic ring are e.g. heterocyclic carbonyl or heterocyclic lower alkanoyl and the heterocyclic one
Ring in the heterocyclic carbonyl or heterocyclic
Lower alkanoyl can be saturated or unsaturated, monocyclic or polycyclic and it can be at least one hetero atom, e.g. an oxygen, sulfur, nitrogen atom or the like, such as e.g. in unsaturated 3 to 8-membered hetero monocyclic compounds containing a sulfur atom (e.g. thienyl and the like), unsaturated condensed heterocyclic compounds containing a sulfur atom (e.g.



   Benzothienyl et al. Like.), unsaturated 3- to 8-membered hetero monocyclic compounds which contain an oxygen atom (e.g. furyl, 2 (or 4-) pyranyl, 5,6-dihydro-2H-pyran-3-yl and the like) , unsaturated 3 to 8-membered heteromonocyclic
Compounds containing 1 to 4 nitrogen atoms (e.g.



   Pyrrolyl, 2 (or 3-) H-pyrrolyl, 2 (or 3-) pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1H
Tetrazolyl, 2H-tetrazolyl and the like. Like.), saturated 3- to 8-membered heteromonocyclic compounds containing 1 to 2 nitrogen atoms (for example pyrrolidinyl, imidazolidinyl, piperidino-, piperadinyl and the like), unsaturated condensed heteromonocyclic compounds containing 1 to 3 Contains nitrogen atoms (e.g. indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, 1 (or 2-) H-indazolyl, 1 (or 2-) benzotriazolyl and the like), saturated 3- to 8-membered heteromonocyclic compounds, which contain one oxygen atom and 1 to 3 nitrogen atoms (e.g.

  Oxazolyl, isoxazolyl, oxadiazolyl and the like. The like.), saturated 3- to 8-membered heteromonocyclic compounds containing 1 to 2 oxygen atoms and 1 to 2 nitrogen atoms (e.g. sydnonyl and the like.), unsaturated 3 to 8-membered heteromonocyclic compounds containing one sulfur atom and 1 to Contain 3 nitrogen atoms (e.g. thiazolyl, thiadiazolyl, etc.), unsaturated condensed heterocyclic compounds containing one oxygen atom and 1 to 2 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl, etc.) and unsaturated condensed heterocyclic compounds containing a sulfur atom and 1 to Contain 2 nitrogen atoms (e.g. benzothiazolyl, benzothiadiazolyl, etc.) and the like.



   The carbon atom in the lower alkyl radical in the above-mentioned heterocyclic lower alkanoyl may also be replaced by an oxygen or sulfur atom, e.g. in heterocyclic lower alkoxycarbonyl, heterocyclic oxycarbonyl, heterocyclic oxy-lower alkanoyl and heterocyclic thio-lower alkanoyl.



   In addition, the carbamoyl group, the aliphatic acyl group and the acyl groups containing an aromatic or heterocyclic ring as mentioned above may contain 1 to 10 suitable substituents, e.g. Lower alkyl (e.g.



  Methyl, ethyl, propyl, isopropyl and the like. the like), lower alkenyl (e.g.



   1-propenyl, allyl and the like. the like), lower or higher cycloalkyl (e.g. cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like), lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy and the like), lower alkylthio (e.g. methylthio, ethylthio and the like) , Aryl (e.g. phenyl, xylyl, tolyl, indanyl and the like),
Amlower alkyl (e.g. benzyl, phenethyl, etc.), halogen (e.g.



   Chlorine, bromine, fluorine and the like like), halophenyl (e.g. chlorophenyl,
Bromophenyl et al. like), halophenoxy (e.g. chlorophenoxy,
Bromophenoxy et al. the like), cyano, lower alkyl sulfinyl (e.g.



   Methylsulfinyl, ethylsulfinyl and the like. Like.), lower alkanesulphonyl (e.g. methanesulphonyl, ethanesulphonyl and the like), lower alkoxy carbonyl-lower alkoxy (e.g. methoxycarbonylmethoxy, ethoxycarbonylethoxy, 1-cyclopropylethoxycarbonylmethoxy, tert-butoxycarbonylmethoxy, tert.-butoxycarbonylmethoxy, amino, azo, azo, carbonylmethoxy, mercapto, azo, carbonylmethoxy, and the like), mercapto, azo carbonylmethoxy, mercapto, azo carbonylmethoxy, and the like, mercapto, carbo-carbonylmethoxy, mercapto, carbohydrate and the like. Hydroxy, hydroxyamino, mono (or di) alkylamino, e.g. Mono (or di) methylamino, mono (or di) ethylamino, mono (or di) propylamino,
Mono (or di) isopropylamino and the like like.) u. like



   When the above-mentioned acyl group has a functional
Group, e.g. an amino, hydroxy, mercapto, carb oxy group and. Like., may contain the functional
Group also be protected by a suitable protecting group. Examples of suitable protecting groups for the
Amino groups are the usual protecting groups, e.g.



   Acyl groups or groups other than acyl groups, such as trityl, 2-nitrophenylthio, 2,4-dinitro-phenylthio, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene, 2-hydroxy-4-pyridylmethylene, 1-methoxycarbonyl-2-propylidene, 1-ethoxycarbonyl-2-propylidene, 3-ethoxycarbonyl-2-butylidene, 1-acetyl-2-propylidene, 1-benzoyl-2-propylidene, 1- (N- [ 2-methoxyphenyl] carbamoyl) -
2-propylidene, 1- (N- [4-methoxyphenyl] carbamoyl) -2-propylidene, 2-ethoxycarbonyl-cyclohexylidene, 2-ethoxycarbonyl cyclopentylidene, 2-acetylcyclohexylidene,

   3,3-dimethyl
5-oxocyclohexylidene (among these, the 1-methoxycarbonyl-2-propylidene group and the 2-ethoxycarbonylcyclohexylidene group can be represented as 1-methosacarbonyl-1-propen-2-yl group or as 2-ethoxycarbonyl-1-cyclohexenyl group), mono (or di) silyl u. like;
Examples of suitable protective groups for the hydroxy or mercapto groups are the customary protective groups for hydroxy or mercapto groups, such as e.g. the acyl groups or groups other than the acyl groups such as benzyl, trityl, methoxymethyl, 2-nitrophenylthio, 2,4-dinitrophenylthio and the like. like; and suitable protecting groups for the carboxy group are e.g. the usual protecting groups used to protect a carboxy group, e.g. Lower alkyl esters (e.g.

  Methyl ester, ethyl ester, propyl ester, butyl ester, 1-cyclopropyl ethyl ester, tert. Butyl ester u. the like), mono (or di- or tri) halo-lower alkyl esters (e.g. chloromethyl ester, 2,2,2-trichloroethyl ester, 3,3-dibromopropyl ester and the like), aryl esters (e.g.



  Phenyl ester, nitrophenyl ester, indanyl ester and the like the like), amine-lower alkyl esters (e.g. benzyl ester, diphenylmethyl ester, triphenylmethyl ester, p-nitrobenzyl ester, p-bromobenzyl ester and the like), tri-lower alkylsilyl ester (e.g.



     Trimethylsilyl ester, triethylsilyl ester and the like. like.) u. like



   Examples of amino-protecting groups other than the acyl groups mentioned in the above section explaining the expression a substituted amino group are the same amino-protecting groups as given as examples of the protecting groups for the amino residue in the above-mentioned acyl group. Particularly suitable examples of acyl groups are as follows: (1) lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, and the like), (2) phenyl-lower alkoxycarbonyl (e.g.

  Benzyloxycarbonyl, Phenäthyloxycarbonyl u. like), (3) phenylcarbamoyl, (4) phenylglyoxyloyl, (5) lower alkoxyphenylglyoxyloyl (e.g. 2- (2- [or 3 or 4] methoxyphenyl) glyoxyloyl, 2- (2- [or 3- or 4-] ethoxyphenyl) glyoxyloyl and the like), (6) phenylthiocarbonyl, (7) cyano-lower alkanoyl (e.g. 2-cyanoacetyl, 3-cyanopropionyl, 4-cyanobutyryl and the like), (8) lower alkylthio-lower alkanoyl (e.g. 2-methylthioacetyl, 2-methylthiobutyryl, 2-methylthiobutyryl -Ethylthioacetyl, 3-methylthiopropionyl and the like), (9) lower alkenylthio-lower alkanoyl (e.g. 2-allylthioacetyl, 3-allylthiopropionyl and the like), (10) phenylthio-lower alkanoyl (e.g. 2-phenylthioacetyl) (e.g. 2-phenylthioacetyl, 3-phenylthioacetyl) 11) Phenoxy-lower alkanoyl (e.g. 2-phenoxyacetyl, 3-phenoxypropionyl, 4-phenoxybùtyryl, etc.), (12) Phenyl-lower alkanoyl (e.g.

   2-phenylacetyl, 3-phenylpropionyl, 4-phenylbutyryl and the like. the like), (13) halophenyl-lower alkanoyl (e.g. 2- (2- [or 3 or 4-] chlorophenyl) acetyl, 2- (2- [or 3- or 4-] bromophenylacetyl, 3- (2- [or 3- or 4-] chlorophenyl) propionyl and the like, (14) phenyl- and amino-substituted lower alkanoyl (e.g. phenylglycyl, 3-amino-3-phenylpropionyl and the like), (15) phenyl- and lower alkoxycarbonylamino-substituted lower alkanoyl (e.g. N- Methoxycarbonylphenylglycyl, N-ethoxycarbonylphenylglycyl, N- (1-cyclopropylethoxy) -carbonyl-phenylglycyl, N-tert-butoxycarbonylphenylglycyl, 2- (1-cyclopropylethoxy) -carbonylamino-3-phenyl-propionyl, and the like - and trihalo-lower alkoxycarbonylamino-substituted lower alkanoyl (e.g.

  N-trichloroethoxycarbonylphenylglycyl, 3-trichloroethoxycarbonylamino-3-phenylpropionyl, N-tribromoethoxycarbonylphenylglycyl and the like), (17) phenyl- and nitrophenoxy-lower alkanoylamino-substituted-lower lower alkanoylamino (e.g. N-] acetyl [or 3- or 4- alkanoyl) (eg N-] acetyl [or 3- or 4- alkanoyl] -nitrophenoxyglycyl (e.g. u. the like), (18) phenyl- and thiadiazolylthio-lower alkanoylamino-substituted lower alkanoyl (e.g. N- (1,3,4-thiadiazol2-yl) -thioacetylphenylglycyl, 2- (3- [1,3,4-thiadiazol 2-yl] thiopropionyl) amino -3-phenylpropionyl and the like, (19) hydroxyphenyl- and amino-substituted lower alkanoyl (e.g. 2-amino-2- (2- [or 3- or 4-] hydroxyphenyl) acetyl, 2-amino-3- [2- (or 3- or 4-) hydroxyphenyl] propionyl and the like.



   (20) Hydroxyphenyl and lower alkoxycarbonylamino-substituted lower alkanoyl (e.g. 2-methoxycarbonylamino-2- (2- [or 3- or 4-] hydroxyphenyl) acetyl, 2- (1-cyclopropylethoxy) carbonylamino-2- (2- [or 3 - or 4-] hydroxyphenyl) acetyl, 2-tert-butoxycarbonylamino-2- (2- [or 3- or 4-] hydroxyphenyl) acetyl and the like), (21) lower alkoxyphenyl- and amino-substituted lower alkanoyl (e.g. 2-amino-2- (2- [or 3- or 4-] methoxyphenyl) -acetyl, 2-amino-3- (2- [or 3- or 4-] methoxyphenyl) acetyl, and the like).



   (22) lower alkoxyphenyl and lower alkoxycarbonylamino-substituted lower alkanoyl (e.g. 2-methoxycarbonylamino 2- (2- [or 3- or 4-] methoxyphenyl) acetyl, 2- (1-cyclopropylethoxy) carbonylamino-2- (2- [or 3- or 4 -] methoxyphenyl) acetyl, 2-tert-butoxycarbonylamino-2 (2- [or 3- or 4-] methoxyphenyl) acetyl 2-tert-butoxycarbonylamino-2- [2- (or 3- or 4-) methoxyphenyl] acetyl and the like), (23) lower alkylthiophenyl and amino-substituted lower alkanoyl (e.g. 2-amino-2- (2- [or 3- or 4 -] - methylthiophenyl) -acetyl, 2-amino-3- (2- [or 3- or 4-] ethylthiophenyl) propionyl and the like), (24) lower alkylthiophenyl and lower alkoxycarbonyl amino-substituted lower alkanoyl (e.g.

   2-methoxycarbonylamino-2- (2- [or 3- or 4-] methylthiophenyl) -acet- yl, 2- (1-cyclopropylethoxy) carbonylamino-2- (2- [or 3 or 4 -] - methylthiophenyl) acetyl, 2-tert-butoxycarbonylamino-2- (2- [or 3- or 4-] methylthiophenyl) acetyl, 2-tert-butoxycarbonylamino-3- (2- [or 3- or 4-] ethylthiophenyl) propionyl and the like. like), (25) lower alkylsulfinylphenyl and amino-substituted lower alkanoyl (e.g. 2-amino-2- [2- (or 3- or 4-) methylsulfinylphenyl] acetyl, 2-amino-3- [2- (or 3- or 4-) ethylsulfinyl-phenyl] propionyl and the like.), (26) lower alkylsulfinylphenyl and lower alkoxycarbonyl-amino-substituted lower alkanoyl (e.g.

   2-methoxycarbonylamino-2- [2- (or 3- or 4-) methylsulfinylphenyl] acetyl, 2- (1-cyclopropylethoxy) carbonylamino-3 - [2- (or 3- or 4-) ethylsulfinylphenyl] propionyl, 2-tert .-Butoxycarbonylamino-2- [2- (or 3- or 4-) methylsulfinylphenyl] acetyl and the like), (27) carboxy-lower alkoxyphenyl- and amino-substituted lower alkanoyl (e.g. 2-amino-2- (2- [or 3- or 4-] carboxymethoxyphenyl) acetyl, 2-amino-3- (2- [or 3- or 4-] carboxymethoxyphenyl) propionyl and the like), (28) lower alkoxycarbonyl-lower alkoxyphenyl and lower alkoxycarbonylamino-substituted lower alkanoyl (e.g.

   2-methoxycarbonylamino-2- (2- [or 3- or 4 -] - methoxycarbonylmethoxyphenyl) acetyl, 3 - (1 -cyclopropylethoxy) carbonylamino-3- (2- [or 3- or 4-] ethoxycarbonylmethoxyphenyl) propionyl, 2- tert-butoxycarbonylamino-2- (2 [or 3- or 4-] tert-butoxycarbonylmethoxyphenyl) acetyl and the like. Like.), (29) lower alkanesulfonamidophenyl and lower alkoxycarbonylamino-substituted lower alkanoyl (eg 2-methoxycarbonylamino-2- [2- {or 3- or 4-} methanesulfonamidophenyl] acetyl, 3- [1-cyclopropylethoxy] - carbonylamino-3- [ 2- {or 3- or 4 -] - ethanesulfonamidophenyl] propionyl, 2-tert-butoxycarbonylamino-2- [2- {or 3- or 4-) methanesulfonamidophenyl] acetyl and the like. the like), (30) dihydrophenyl- and amino-substituted lower alkanoyl (e.g. 2-amino-2- [2,5-dihydrophenyl] acetyl,
2-amino-3- [2,5-dihydrophenyl] propionyl and the like;

   The like.), (31) dihydrophenyl- and lower alkoxycarbonylamino-substituted lower alkanoyl (eg 2-methoxycarbonylamino2- [2,5-dihydrophenyl] acetyl, 2- [1-cyclopropylethoxy] carbonylamino-2- [2,5-dihydrophenyl] acetyl , 2-tert-butoxy carbonylamino-2- [2,5-dihydrophenyl] acetyl, 2-tert. Butoxycarbonylamino-3- [2,5-dihydrophenyl] propionyl and the like), (32) phenyl and azido substituted lower alkanoyl (e.g. 2-azido-2-phenylacetyl, 3-azido-3-phenylpropionyl and the like), (33) phenyl- and hydroxy-substituted lower alkanoyl (e.g. 2-hydroxy-2-phenylacetyl, 2-hydroxy-3 -phenylpropionyl and the like), (34) phenyl- and lower alkanoyloxy-substituted lower alkanoyl (e.g.

   2-formyloxy-2-phenylacetyl, 2-acetoxy2-phenylacetyl, 3-propionyloxy-3-phenyl-propionyl and the like), (35) phenyl- and pyridylcarbonyloxy-substituted lower alkanoyl (e.g. 2-nicotinoyloxy-2-phenylacetyl, 2- Isonicotinoyloxy-2-phenylacetyl and the like), (36) phenyl- and sulfo-substituted lower alkanoyl (e.g. 2-phenyl-2-sulfoacetyl, 3-phenyl-3-sulfopropionyl and the like), (37) phenyl and indanyloxycarbonyl-substituted lower alkanoyl e.g. 2- (5-indanyloxy) carbonyl-2-phenyl-acetyl, 3- [5-indanyloxy] carbonyl-3-phenylacetyl and the like. like), (38) thienyl lower alkanoyl (e.g. 2- [2-thienyl] acetyl, 3- [2-thienyl] propionyl and the like), (39) thienyl- and amino-substituted lower alkanoyl (e.g. 2-amino-2 - [2-thienyl] acetyl, α-amino-3- [2-thienyl] propionyl and the like.

   Like.), (40) thienyl- and lower alkoxycarbonylamino-substituted lower alkanoyl (eg 2-methoxycarbonylamino-2 [2-thienyl] -acetyl, 2- [1-cyclopropylethoxyjcarbonylamino-2- [2-thiehyl] -acetyl, 2-tert . -Butoxycarbonylamino-2- [2-thienyl] acetyl, 3-tert-butoxycarbonylamino-3 [2-thienyl] propionyl and the like), (41) thienyl- and hydroxy-substituted lower alkanoyl (e.g. 2-hydroxy-2 - [2-thienyl] acetyl, 3-hydroxy-3 [2-thienyl] propionyl and the like), (42) dihydropyranyl- and amino-substituted lower alkanoyl (e.g. 2-amino-2- [5,6- dihydro-2H-pyran-3-yl] acet yl, 2-amino-3- [5, 6-dihydro-2H-pyran-3-yl] propionyl and the like), (43) dihydropyranyl and lower alkoxycarbonylamino substituted lower alkanoyl (e.g.

   2-methoxycarbonylamino 2- [5, 6-dihydro-2H-pyran-3-yl] acetyl, 2- [1-cyclopropyl-ethoxy] carbonylamino-2- [5, 6-dihydro-2H-pyran-3-yl] acetyl, 2-tert-butoxycarbonylamino-2- (5, 6-dihydro-2H-pyran-3-yl] [5, 6-dihydro-2H-pyran-3-yl] acetyl, 2-tert.- Butoxycarbonylamino-3- [5, 6-dihydro-2H-pyran-3-yl] propionyl and the like), (44) pyridyl-substituted lower alkanoyl (e.g. 2 [3-pyridyl] acetyl, 3- [3-pyridyl] propionyl and the like), (45) thiadiazolyl-lower alkanoyl (e.g. 2- [1,2,5-thiadiazol-3-yl] acetyl, 2- [1,3,4-thiadiazol-2-yl] acetyl, 3 [ 1,2,5-thiadiazol-3-yl] propionyl and the like), (46) lower alkylthiadiazolyloxy-lower alkanoyl (e.g.



  2- [5-methyl-1,3,4-thiadiazol-2-yloxy] acetyl, 2- [4-methyl 1, 2,5-thiadiazol-3-yloxy] acetyl, 2- [5-ethyl-1, 3,4-thiadiazol-2-yloxy] propionyl and the like. the like), (47) thiadiazolylthio-lower alkanoyl (e.g. 2- [1,3,4-thiadiazol-2-ylthio] acetyl, 2- [1,2,5-thiadiazol-3-ylthio] acetyl, 3- [1,3 , 4-thiadiazol-2-ylthio] propionyl and the like), (48) tetrazolyl-lower alkanoyl (e.g. 2- [1H-tetrazol-1-yl] acetyl '3- [1H-thetrazol-1-yl] propionyl, 4- [1H-tetrazol-1-yl] -butyryl and the like), (49) 3-halophenyl-5-lower alkylisoxazol-4-ylcarbonyl (e.g. 3- [2- (or 3- or 4-} chlorophenyl] -5 -methylisoxazol-4-ylcarbonyl, 3- [2- {or 3- or 4-} bromophenyl] -5-ethyl-isoxazol-4-ylcarbonyl and the like), (50) halobenzotriazolyl-lower alkanoyl (e.g.

 

  {or 5- or 6- or 7-} chloro-1H-benzotriazol-1-yl] - acetyl, 2- [4- (or 6- or 6 or 7-) bromo-1H-benzotriazol-1-yl] acetyl, 3- [4- {or 5- or 6- or 7-} fluoro-2Hbenzotriazol-2-yl] propionyl and the like. like), (51) sydnonyl-lower alkanoyl (e.g. 2- [sydnon-3-yl] acetyl, 3-sydnon-3-yl] propionyl and the like), (52) phthaloyl, (53) lower alkanoylaminobenzenesulfonyl (e.g. 2- [ or 3- or 4-] acetamidobenzenesulfonyl, 2- [or 3- or 4-] propionamidobenzenesulfonyl and the like), (54) phenyl- and halophenoxy-substituted lower alkanoyl (e.g. 2-phenyl-2- [2- or 3- or 4-] chlorophenoxylacetyl, 2-phenyl-2- [2- {or 3- or 4-} bromophenoxyl] acetyl, and the like).



   By the term a protected hydroxy group in the acylamino group with a protected hydroxy group is e.g. to understand a hydroxy group which is protected by the same usual protecting groups for hydroxy as given above.



   The term a protected carboxy group used for R2 includes e.g. an ester, acid amide, acid anhydride group and the like. like



   Examples of suitable esters are silyl esters, aliphatic esters and esters containing an aromatic or heterocyclic ring. Examples of suitable silyl esters are tri-lower alkylsilyl esters (e.g. trimethylsilyl, triethylsilyl esters, and the like) and the like. The like. Examples of suitable aliphatic esters are saturated or unsaturated, lower or higher alkyl esters, which can be branched or contain a cyclic ring, e.g. lower or higher aliphatic esters, e.g. Lower alkyl esters (e.g. methyl, ethyl, propyl, isopropyl, 1-cyclopropylethyl, butyl, tert-butyl esters, etc.), higher alkyl esters (e.g. octyl, nonyl, undecyl esters, etc.), Lower alkenyl esters (e.g. vinyl, 1-propenyl, allyl, 3-butenyl esters and the like), lower alkynyl esters (e.g. 3-butynyl, 4-pentynyl esters and the like), lower or higher cycloalkyl esters (e.g.

  Cyclopentyl, cyclohexyl, cycloheptyl ester and the like. like.) u. The like. As well as lower or higher aliphatic esters containing a nitrogen, sulfur or oxygen atom, e.g.



  lower alkoxy lower alkyl esters (e.g. methoxymethyl, ethoxyethyl, methoxyethyl esters and the like), lower alkylthio lower alkyl esters (e.g. methylthiomethyl, ethylthioethyl, methylthiopropyl esters and the like), di-lower alkylamino esters (e.g. dimethylamino, diethylamino), and diphylamino esters (e.g. dimethylamino, diethylamino) lower alkylideneamino esters (e.g. ethylideneamino, propylideneamino, isopropylideneamino esters and the like), lower alkylsulfenyl lower alkyl esters (e.g. methylsulfenylmethyl, ethylsulfenylmethyl esters and the like) and the like. like



   Examples of suitable esters which can contain an aromatic ring are aryl esters (e.g. phenyl, xylyl, tolyl, naphthyl, indanyl, dihydroanthryl esters and the like), arnlower alkyl esters (e.g. benzyl, phenethyl esters and the like) , Aryloxy lower alkyl esters (eg phenoxymethyl, phenoxyethyl, phenoxypropyl esters and the like), arylthio lower alkyl esters (eg phenylthiomethyl, phenylthioethyl, phenylthiopropyl esters and the like), arylsulfenyl lower alkyl esters (eg. , Toluoylethyl ester and the like), aryloylamino ester (e.g. phthalimido ester and the like), and the like. The like. Examples of suitable esters containing a heterocyclic ring are heterocyclic esters, heterocyclic lower alkyl esters and the like.



  like; Examples of suitable heterocyclic esters are saturated or unsaturated, condensed or non-condensed, 3 to 8 membered heterocyclic esters containing 1 to 4 heteroatoms, e.g. an oxygen, sulfur and nitrogen atom (e.g. pyridyl, piperidino, 2-pyridon-1-yl, tetrahydropyranyl, quinolyl, frazolyl esters, and the like) and the like. The like. And examples of suitable heterocyclic lower alkyl esters are, for example, saturated or unsaturated, condensed or non-condensed, 3- to 8-membered heterocyclic groups with 1 to 4 heteroatoms, e.g. an oxygen, sulfur and nitrogen atom (e.g. by pyridyl, piperidino, 2-pyridon-1-yl, tetrahydropyronyl, quinolyl, pyrazolyl and the like) substituted lower alkyl esters (e.g. methyl, ethyl, propyl ester and the like) u. like



   The silyl esters, the aliphatic esters and the aromatic or heterocyclic ring-containing esters as indicated above may have 1 to 10 suitable substituents, e.g. Lower alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), lower alkoxy (such as methoxy-ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, and the like), lower alkylthio (such as methylthio , Ethylthio, propylthio and the like), lower alkylsulfinyl (such as methylsulfinyl, ethylsulfinyl, propylsulfinyl and the like), lower alkanesulfonyl (such as methanesulfonyl, ethanesulfonyl and the like), phenylazo, halogen (such as chlorine, bromine, fluorine and the like). ), Cyano, nitro, etc. The like, and examples thereof are mono (or di- or tri-) halo lower alkyl esters (e.g.

  Chloromethyl, bromoethyl, dichloromethyl 2,2,2-tri-chloroethyl, 2,2,2-tribromoethyl ester u. Like.), cyano lower alkyl esters (e.g. cyanomethyl, cyanoethyl esters and the like), mono (or di- or tri- or tetra or penta) halophenyl esters (e.g. 4-chlorophenyl, 3,5-dibromophenyl, 2,4 , 5-trichlorophenyl, 2,4,6-trichlorophenyl, pentachlorophenyl esters and the like), lower alkanesulfonylphenyl esters (e.g. 4-methanesulfonylphenyl, 2-ethanesulfonylphenyl esters and the like), 2- (or 3- or 4-) phenylazophenyl esters , Mono (or di- or tri-) nitrophenyl ester (e.g. 4-nitrophenyl, 2,4-dinitrophenyl, 3,4,5 trinitrophenyl ester, etc.), mono (or di- or tri- or tetra- or penta) halophenyl lower alkyl esters (e.g. 2-chlorobenzyl, 2,4-dibromobenzyl, 3,4,5-trichlorobenzyl, pentachlorobenzyl esters and the like), mono (or di or tri) - nitrophenyl lower alkyl esters (e.g.

   2-nitrobenzyl, 2,4-di-nitrobenzyl, 3,4,5-trinitrobenzyl esters and the like. Like.), mono (or di- or tri-) lower alkoxyphenyl lower alkyl esters (eg 2-methoxybenzyl, 3, 4-dimethoxybenzyl, 3,4,5-trimethoxybenzyl esters and the like), hydroxy and di-lower alkylphenyl lower alkyl esters (eg 3,5 -Dimethyl-4-hydroxybenzyl, 3,5-di-tert-butyl-4-hydroxybenzyl ester and the like) and the like. like



   Examples of suitable acid amides are N-lower alkyl acid amides (for example N-methyl acid amide, N-ethyl acid amide and the like), N, N-di-lower alkyl acid amides (e.g. N, N-dimethyl acid amide, N, N-diethyl acid amide, N-methyl-N-ethyl acid amide and the like). the like), N-phenyl acid amide or an acid amide with pyrazole, imidazole, 4-lower alkylimidazole (such as 4-methylimidazole, 4-ethylimidazole and the like) and the like. like



   Examples of suitable acid anhydrides are acid anhydrides with a di-lower alkyl phosphate (eg dimethyl phosphate, diethyl phosphate and the like), dibenzyl phosphate, phosphoric acid halide (eg phosphoric acid chloride, phosphoric acid bromide and the like), di-lower alkyl phosphite (eg dimethyl acid phosphite, diethyl phosphite), thi-lower alkyl phosphite (eg dimethyl acid phosphite, diethyl phosphite) , Sulfuric acid, lower alkyl carbonate (e.g. methyl carbonate, ethyl carbonate and the like), hydrazoic acid, hydrohalic acid (e.g. hydrochloric acid, hydrobromic acid, etc.), a saturated or unsaturated lower aliphatic carboxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutanoic acid, Valeric acid, propionic acid and the like), a saturated or unsaturated halogen-lower aliphatic carboxylic acid (e.g.

  Chloroacetic acid, 3-chloro-2-pentanoic acid, 3-bromo-2-butenoic acid and the like the like), a substituted lower aliphatic carboxylic acid (e.g.



  Phenylacetic acid, phenoxyacetic acid, furanacetic acid, thiophenacetic acid and the like. the like), an aromatic carboxylic acid (e.g.



  Benzoic acid and the like Like.) or a symmetrical acid anhydride u. like



   The term lower alkyl used for R3 is to be understood as meaning a straight-chain, branched-chain or cyclic radical having 1 to 6 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclohexyl radical and the like. like



   Under the expression low resp.



   lower is to be understood as meaning a chain with 1 to 6 carbon atoms, while the term higher as used here is to be understood as meaning a chain with 7 to 16 carbon atoms, which can be branched or contain a cyclic ring.



   The starting products of the formula Ie can advantageously be prepared as follows.



   First, a 2-lower alkyl-2-halomethyl-6-substituted penam-2-carboxylic acid or its 1-oxide or a derivative on the carboxy group thereof is treated with a base to form a compound of the formula:
EMI6.1
 in which R1b, R2, R9 and X have the above meanings, implemented; the compounds of formula II are also new.



  The starting compounds of the formula Ie are obtained from these by reaction with a Lewis acid.



   Examples of suitable Lewis acids that can be used in this reaction are boron halides (e.g.



  Boron trichloride, boron tribromide, boron trifluoride and the like the like), titanium halides (e.g. titanium tetrachloride, titanium tetrabromide and the like), zirconium halides (e.g. zirconium tetrechloride, zirconium tetrabromide and the like), tin (IV) halides (e.g. tin (IV) chloride, tin (IV) bromide and the like. ), Antimony halides (e.g. antimony trichloride, antimony pentachloride and the like), bismuth chloride, aluminum halides (e.g. aluminum chloride, aluminum bromide and the like), zinc chloride, iron (III) chloride, toluenesulphonic acid, polyphosphoric acid ester, sulfuric acid, trichloroacetic acid, trifluoroacetic acid III) sulfate u. like



   This reaction is usually carried out in the presence of a solvent.



   Examples of suitable solvents that can be used are those solvents that do not adversely affect the reaction, e.g. Methylene chloride, chloroform, benzene, tetrahydrofuran, dimethylformamide, carbon disulfide and the like. like



   There is no particular restriction on the reaction temperature, and the reaction can be carried out under mild conditions such as cooling to ambient temperature.



   After the reaction, the compound of the formula Ie is sometimes obtained in the form of a mixture of a 2-cephen compound and a 3-cephen compound and / or the 3-cephen stereoisomers in the 2-position of the cephen ring and these mixtures can, if necessary, by customary methods, for example by Recrystallization, are separated.



   The compound of the formula Ie with or without isolation and / or purification can be used as the starting product; H. it can be used in the form of a mixture of a 2-cephen compound and a 3-cephen compound and / or the 3-cephem stereoisomers in the 2-position of the cephem ring.



   Examples of suitable trialkyloxonium haloborates are trimethyloxonium chloroborate, triethyloxonium fluoroborate, triethyloxonium fluoroborate and the like. The like. Examples of suitable imino halogenating agents are phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride, phosgene and the like. The like. Examples of suitable imino-etherifying agents with which the compound obtained in the iminohalogenation reaction is reacted are an alcohol, e.g. an alkanol (such as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, etc.) or the corresponding alkanol with alkoxy (e.g.



  Methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like. The like.) as substituent (s) on its alkyl radical and a metal alkoxide derived from this alcohol, e.g. an alkali metal alkoxide (such as sodium alkoxide, potassium alkoxide and the like) or an alkaline earth metal alkoxide (such as calcium alkoxide, barium alkoxide and the like).



   These reactions are usually carried out in a solvent that does not adversely affect these reactions, e.g. in chloroform, methylene chloride, tetrahydrofuran, dioxane and the like. The like. There is no particular limitation on the reaction temperature, and the reactions are often carried out at ambient temperature or under cooling.



   The acylation reaction can be carried out under customary conditions. The reaction product obtained is hydrolyzed if necessary. The hydrolysis proceeds to a sufficient extent when the reaction mixture is in water or a mixture of water and a hydrophilic solvent such as methanol, ethanol and the like. like., pours.



  In this hydrolysis the water can be a base, e.g. an alkali metal bicarbonate, trialkylamine and the like. the like, or an acid, e.g. dilute hydrochloric acid, acetic acid, etc. Like., included.



   In the above reactions, the acylamino group Rib in the compound of the formula Ie is converted into the other acylamino group R'b 'in the compound of the formula If which is derived from the acylating agent.



   The present invention also includes the cases where, during the reactions and post-treatment after these reactions, the free carboxy group is converted into a protected carboxy group and the protected carboxy group is converted into another protected carboxy group or into the free carboxy group.



   The present invention also includes the cases in which the 2-cephem compound, the 3-cephem compound and the 3-cephem stereoisomers in the 2-position of the 3-cephem ring are sometimes each converted into one another during the above-mentioned reactions in alternative processes or in the aftertreatment thereof will.



   If the compound of the formula If obtained according to the invention has one or more free carboxy groups, it can be converted into a metal salt (e.g. a sodium, potassium, magnesium salt and the like) or into an organic amine salt (e.g. a methylamine, diethylamine, Trimethylamine, triethylamine, aniline, pyridine, picoline, N, N'-dibenzylethylenediamine salt and the like) can be converted by a conventional method and if the compound of the formula If according to the invention has one or more free amino groups, it can be converted according to a common process into an inorganic acid salt (e.g.

 

  a hydrochloride, sulfate and the like. The like) or an organic acid salt (e.g. an acetate, maleate, tartrate and the like).



   The compounds of the formula If obtained according to the invention have antimicrobial activities (activities) against various pathogenic microorganisms and they can be used for the treatment of diseases which are caused by such microorganisms in humans and animals. The antimicrobial activities for the respective compounds according to the invention are given below. The MIC values (11g / ml) for Staphylococcus aureus 209-P JC-1 and Bacillus Subtilis ATCC-6633 of the compounds of the formula If according to the invention are given below.



   Method of determining the antimicrobial
Activity in vitro
In vitro antimicrobial activity was determined by the two-fold agar plate dilution method as described below.



   A platinum loop fill of an overnight culture of each test strain in trypticase soy broth (108 viable cells per ml) was streaked onto heart infusion agar (HI agar) containing a graded concentration of antibiotics, and the minimum inhibition concentration (MIC) was expressed in yml after 20 -hour incubation at 37 "C.



   (1) 2-methyl-7- (N- [2- {1, 3,4-thiadiazol-2-ylthio} acetyl] -phenylglycyl) amino-3-cephem-4-carboxylic acid S. aureus: 1.56; B. subtilis: 3.13 (2) 2-methyl-7- (2-hydroxy-2- [2-thienyl] acetamido) -3-cephem-4-carboxylic acid S. aureus: 0.78; B. subtilis: 0.78 (3) 2-methyl-7- (2- [5 -indanyloxy] carbonyl-2-phenylacetamido) -3-cephem-4-carboxylic acid S. aureus: 1.56; B. subtilis: 6.25 (4) 2-methyl-7- (2-isonicotinoyloxy-2-phenylacetamido) -3cephem-4-carboxylic acid S. aureus: 0.39 B. subtilis: 0.78 (5) 2- Methyl 7- (2- [2-thienyl] acetamido) -3-cephem-4-carboxylic acid S. aureus: 0.78; B. subtilis: 0.39 (6) 2-methyl-7- (2- [3-chlorophenyl] acetamido) -3-cephem-4-carboxylic acid S. aureus: 0.1;

  B. subtilis: 0.2 (7) 2-methyl-7- (2-hydroxy-2-phenylacetamido) -3-cephem-4-carboxylic acid S. aureus: 0.78; B. subtilis 0.39 (8) 2-methyl-7- (2-phenylacetamido) -3-cephem-4-carboxylic acid S. aureus: 0.78; B. subtilis: 0.2 (9) 2-methyl-7- (2-phenylthioacetamido) -3-cephem-4-carboxylic acid S. aureus: 0.2; B. subtilis: 0.2 (10) 2-methyl-7- (2-azido-2-phenylacetamido) -3-cephem-4-carboxylic acid S. aureus: 1.56; B. subtilis: 0.39 (11) 2-methyl-7- (2- [1, 3,4-thiadiazol-2-ylthioj-acetamido) -3-cephem-4-carboxylic acid S. aureus: 1.56; B. subtilis: 0.78 (12) 2-methyl-7- (2- [1,2,5-thiadiazol-3-yl] acetamido) -3-cephem-4-carboxylic acid S. aureus: 3.13; B. subtilis: 1.56 (13) 2-methyl-7- (2-cyanoacetamido) -3-cephem-4-carboxylic acid S. aureus: 3.13;

  B. subtilis: 3.13 (14) 2-methyl-7- (2- [allylthio] acetamido) -3-cephem-4-carboxylic acid S. aureus: 1.56; B. subtilis: 1.56 (15) 2-methyl-7- (2- [3-pyridyl] acetamido) -3-cephem-4-carboxylic acid S. aureus: 3.13; B. subtilis: 0.78 (16) 2-methyl-7- (2-amino-2- [methylthiophenylj-acetamido) -3-cephem-4-carboxylic acid S. aureus: 3.13; B. subtilis: 6.25
The compounds of the formula If according to the invention can be formulated for administration in any suitable manner analogous to other antibiotic substances.

  The preparation containing the compounds of the formula If according to the invention can be used in the form of pharmaceutical preparations, for example in solid, semisolid or liquid form, which contain the active compound of the formula If in a mixture with a pharmaceutical or inorganic carrier or excipient which is suitable for external or parenteral administration is suitable. The active ingredient can be mixed, for example, with the usual carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, aqueous suspensions and other forms suitable for use.

  Examples of carriers that can be used are glucose, lactose, acacia gum, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silicon dioxide, potato starch, urea and other carriers suitable for the production of preparations in solid, semisolid or liquid form, and also can The preparations contain additional auxiliaries, stabilizers, thickeners and coloring agents. The preparations can also contain preservatives or bacteriostatic agents, whereby the active ingredient in the desired preparations is kept stable in the active state.



   The active compound of the formula If is contained in the preparations in an amount sufficient to deliver the desired therapeutic effect in bacterially infected processes or conditions. Although the dosage or therapeutically effective amount of the compound varies and also depends on the age and condition of each individual treated patient, for the treatment of diseases against which the compound of the formula If according to the invention is effective, the compound is generally used in a dose of about 0.5 to 5, preferably from 1 to 2 g per day of the active ingredient administered.



   Production of the raw materials
example 1
A solution of 3.4 g of aluminum bromide in 20 ml of dried dichloromethane became a solution of 4.6 g of 2,2,2-trichloroethyl-2-methyl-2,3-methylene at -10 ° C. over a period of about 10 minutes -6- (2-phenylacetamido) penam-3-carboxylate in 30 ml of dried dichloromethane was added dropwise. After the addition, the reaction mixture was stirred for 4.5 hours at room temperature, then washed three times successively with 30 ml of 2% hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution.

  After drying over magnesium sulfate, the solvent was distilled off and the residue was washed in ether and collected by filtration, 3.3 g of 2,2,2-trichloroethyl-2-methyl-7- (2-phenylacetamido) -3 - cephem-4-carboxylate. This compound was recrystallized from ethanol to give crystals with a melting point (F.) of 175 to 1780 ° C.



   Example 2
A solution of 0.4 g of aluminum bromide in 5 ml of dried dichloromethane was cooled with ice to give a suspension of 0.46 g of 2,2,2-trichloroethyl-2-methyl-2,3-methyl-6- (2- [ 1H-tetrazol-1-yl] acetamido) penam-3-carboxylate in 10 ml of dried dichloromethane was added dropwise. After stirring for 4 hours at room temperature, the reaction mixture was washed successively three times with 2% hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate.

  After drying, the solvent was distilled off and the residue was crystallized from ethanol, 0.24 g of 2,2,2 trichloroethyl-2-methyl-7- (2- [1H-tetrazol-1-yl] acetamido) -3 being added - cephem-4-carboxylate, m.p. 168-170 ° C.



   Example 3
0.19 g of titanium tetrachloride were added to a solution of 0.46 g of 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- (2-phenylacetamido) penam-3-carboxylate in 5 ml of dried dichloromethane and the mixture was stirred for 2.5 hours. After the reaction, the reaction mixture was successively washed three times with 2% hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. After the solvent was distilled off, the residue (0.43 g) was purified by column chromatography on silica gel (10 g) using chloroform as a developing solvent to obtain 0.1 g of 2,2,2-trichloroethyl-2-methyl-7- ( 2-phenylacetamido) -2-cephem-4-carboxylate, m.p. 136 to 1370C.



   Example 4
2.66 g of aluminum chloride were added to a solution of 9.2 g of 2,2,2-trichloroethyl-2-methyl-2,3methylene-6- (2-phenylacetamido) penam-3-carboxylate in ice-cooling
100 ml of dried dichloromethane was added and the mixture was stirred for 7 hours at room temperature.



  After the reaction, the reaction mixture was successively washed three times with 2% hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. After drying, the solvent was distilled off and the residue was purified by column chromatography on silica gel (200 g) using chloroform as a developing solvent to give 2.4 g of 2,2,2-trichloroethyl-2-methyl-7- (2 -phenyl-acetamido) -3-cephem-4-carboxylate, m.p. 175 to 1780C.



   Example 5
A solution of 0.58 g of 2,2,2-trichloroethyl-2-methyl-2,3-methylene-6- (benzyloxycarboxamido) penam-3-carboxylate in 10 ml of dried dichloromethane became a solution at -15 to -120.degree of 0.5 g of aluminum bromide in 10 ml of dried dichloromethane was added dropwise, and the mixture was stirred for 20 minutes at the same temperature and then for 1.5 hours at room temperature. After the reaction, the reaction mixture was washed successively with 5% hydrochloric acid, water, a 5% aqueous sodium bicarbonate solution and water, dried, and the solvent was distilled off to obtain an oily substance.

  The oily substance was dissolved in ethanol, allowed to stand, then the precipitated crystals were collected by filtration and dried, and 2,2,2-trichloroethyl-2-methyl-7-benzyloxycarboxamido-3-cephem-4-carboxylate, F. 143 to 144 "C.



   Example 6
A solution of 3.4 g of 2,2,2-trichloroethyl-2-methyl 2,3-methylene-6- (2- [3-chlorophenyl] acetamido) penam-3-carboxylate in 50 ml of dried dichloromethane was added - 150C was added dropwise to a solution of 2.8 g of aluminum bromide in 20 ml of dried dichloromethane and the mixture was stirred for 3 hours at room temperature. After the reaction, the reaction mixture was washed successively with 5% hydrochloric acid, water, a 5% aqueous bicarbonate solution and water and then dried. After the solvent had been distilled off, the residue was crystallized from ether and 2.9 g of 2,2,2-trichloroethyl-2-methyl-7- (2- [3-chlorophenyl] acetamido) -3-cephem-4 were obtained carboxylate, m.p. 144 to 145.5 C (dec.).



   Example 7
A solution of 1.74 g of 2,2,2-trichloroethyl-2-methyl 2,3-methylene-6- (2- [2-thienyl] acetamido) penam-3-carboxylate in 20 ml of dried dichloromethane was at -150C to a solution of 2.14 g of aluminum bromide in 10 ml of dried dichloromethane was added dropwise and the mixture was stirred for 4 hours at room temperature. After the reaction, the reaction mixture was washed successively with 5% hydrochloric acid, water, a 5% aqueous sodium bicarbonate solution and water and then dried. After the solvent had been distilled off, the residue (powder) was recrystallized from ethanol and 1.46 g of 2,2,2-trichloroethyl-2-methyl-7- (2- [2-thienyl] acetamido] -3-cephem- 4-carboxylate, m.p. 161 to 1620C (dec.).



   Example 8
A solution of 16.5 g of 2,2,2-trichloroethyl-2-methyl 2,3-methylene-6- (2- [1, 2,5-thiadiazol-3-yl] acetamido) penam-3-carboxylate in 100 ml of dried dichloromethane were slowly added dropwise to a solution of 17.5 g of aluminum bromide in 100 ml of dichloromethane below -10 ° C. The mixture was then stirred below 0OC for 2 hours and at room temperature for an additional 2 hours. After the reaction, the reaction mixture was successively washed twice with 100 ml of 2% hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate.

  After drying, the solvent was distilled off and 13.2 g of powdered 2,2,2 trichloroethyl-2-methyl-7- (2- [1,2,5-thiadiazol-3-yl] acetamido) -3-cephem were obtained -4-carboxylate, m.p. 180 to 1850C (dec.).



   Example 9
A solution of 2.1 g of methyl 2-methyl-2,3-methylene-6- (2-phenoxyacetamido) penam-3-carboxylate in 11 ml of dried dichloromethane became a solution over a period of 8 minutes at -10.degree of 2.32 g of aluminum bromide in 23 ml of dried dichloromethane was added dropwise and the reaction temperature was slowly increased to room temperature, after which the mixture was stirred at room temperature for 4.4 hours. After the reaction, the reaction mixture was poured into 150 ml of ice water and the dichloromethane layer was separated, after which the aqueous layer was extracted once with chloroform.

  The combined dichloromethane and chloroform extracts were washed successively with water, 2% hydrochloric acid, water, a dilute aqueous sodium bicarbonate solution and water and then dried over magnesium sulfate. After the solvent was distilled off, the yellow oil obtained was purified by column chromatography on silica gel (15 g) using chloroform as a developing solvent to give 0.7 g of methyl-2-methyl-7- (2-phenoxyacetamido) -3-cephem-4 carboxylate in the form of an orange oil. Infrared absorption spectrum (chloroform): 3400, 1785, 1726, 1689 cm-i.



   Example 10
A solution of 1.39 g of 2,2,2-trichloroethyl-2-methyl2,3-methylene-6- (2-phenoxyacetamido) penam-3-carboxylate in 7 ml of dried dichloromethane was added at -10 ° C. over a period of 10 minutes was added dropwise to a solution of 1.16 g of aluminum bromide in 12 ml of dried dichloromethane and the reaction temperature was slowly increased to room temperature, after which the mixture was stirred at room temperature for 4 hours. After the reaction, the reaction mixture was poured into 70 ml of ice water and the dichloromethane layer was separated, after which the aqueous layer was extracted once with chloroform.



  The combined dichloromethane and chloroform layers were washed successively with water, 2% hydrochloric acid, water, a dilute aqueous sodium bicarbonate solution and water, and then dried over magnesium sulfate. After the solvent had been distilled off, the pale brown oil obtained (1.2 g) was crystallized by adding ether and a small amount of isopropyl ether.



  The crystals were collected by filtration, then washed with isopropyl ether and recrystallized from a benzene / isopropyl ether (1/3) mixture, 0.9 g of 2,2,2-tri chloroethyl-2-methyl-7- (2- phenoxyacetamido) -3 -cephem-4-carboxylate, m.p. 118 to 1200C, in the form of colorless granules.



   Example 11
A solution of 0.92 g of 2,2,2-trichloroethyl-2-methyl 2,3-methylene-6- (2-phenylacetamido) penam-3-carboxylate in 5 ml of dried dichloromethane was at -10oC for a period of about Added dropwise for 5 minutes to a solution of 0.8 g of aluminum bromide in 10 ml of dried dichloromethane, and the mixture was stirred at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was washed successively with 2% hydrochloric acid, an aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution and then dried over magnesium sulfate, after which the solvent was distilled off under reduced pressure.

  The crystals which remained were washed with ether and dried, and 0.74 g of 2,2,2-trichloroethyl-2-methyl-7- (2-phenylacetamido) -3-cephem-4-carboxylate, mp 175 to 1780 ° C., were obtained. The residue obtained by concentrating the ether solution obtained on washing with ether was purified by column chromatography on silica gel and 0.05 g of 2,2,2-trichloroethyl-2-methyl-7- (2-phenylacetamido) -3cephem-4-carboxylate was obtained , F. 118 to 120 cm, which is a stereoisomer in the 2-position of the 2,2,2 trichloroethyl-2-methyl-7- (2-phenylacetamido) -3-cephem-4-carboxylate obtained above, F. 175 to 178 C, and 0.05 g of 2,2,2-tri chloroethyl-2-methyl-7- (2-phenylacetamido) -2-cephem-4-carbo-oxylate, mp 136 to 137 C.



   The 2,2,2-trichloroethyl-2-methyl-7- (2-phenylacetamido) -3-cephem-4-carboxylate obtained above, melting point 118 to 1200 ° C., was recrystallized from benzene and crystals were obtained, F.



   120 to 1230C.



   Example 12
A solution of 1.7 g of aluminum bromide in 40 ml of carbon disulfide was added dropwise with stirring at room temperature to a suspension of 0.66 g of 2-methyl-2,3-methylene-6- (2phenylacetamido) penam-3-carboxylic acid in 70 ml of carbon disulfide and the mixture was stirred for 20 hours at the same temperature. After the completion of the reaction, the reaction mixture was poured into 200 ml of 5% hydrochloric acid, and the hydrochloric acid layer was separated and then extracted with ethyl acetate. The extract was washed with water and dried, after which the solvent was distilled off. The residue was recrystallized from acetonitrile and 0.33 g of 2-methyl-7- (2-phenylacetamido) -3-cephem-4-carboxylic acid, mp 109ob (decomp.) Was obtained.



   The compounds listed below were prepared using procedures similar to those in Examples 1-1 to 1-12:
1) 2-methyl-7- (N- [1 -cyclopropylethoxyj-carbonyl-phenyl-glycyl) -amino-3-cephem-4-carboxylic acid, F. 168-1 690C,
2) 2-methyl-7- (2- [1H-tetrazol-1-yl] acetamido) -3-cephem-4-carboxylic acid, m.p. 202-2030C (dec.),
3) 2-methyl-7- (2- [2-thienyl] acetamido) -3-cephem-4-carboxylic acid, m.p. 1750C (dec.),
4) 2-methyl-7-benzyloxycarboxamido-3-cephem-4-carboxylic acid, F.

   167-1690C (decomp.),
5) 2-methyl-7- (2-phenylthioacetamido) -3-cephem-4-carboxylic acid, m.p. 168-171 "C (dec.),
6) 2-methyl-7- (2- [3-chlorophenyl] acetamido) -3-cephem-4-carboxylic acid, m.p. 173-1740C (dec.),
7) 2-methyl-7- (3- [N-tert-butoxycarbonylamino] -3 - [2-thienyl] propionamido) -3-cephem-4-carboxylic acid, m.p. 167-1700C (dec.),
8) 2-methyl-7- (2-cyanoacetamido) -3-cephem-4-carboxylic acid, m.p. 162-166 "C,
9) 2-methyl-7- (3-phenylureido) -3-cephem-4-carboxylic acid, m.p. 148-151 C,
10) 2-methyl-7- (2- [1, 3,4-thiadiazol-2-ylthio] -acetamido) -3-cephem-4-carboxylic acid,

   F. 1 97-199 "C,
11) 2-methyl-7- (N-tert-butoxycarbonyl-2- [2-thienyl] gly- cyl) -amino-3-cephem-4-carboxylic acid, powder,
12) 2-methyl-7- (2- [5-methyl-1,3,4-thiadiazol-2-yloxy] acetamido) -3-cephem-4-carboxylic acid, m.p. 113-1 16 "C,
13) 2-Methyl-7- (3- [2-chlorophenyl] -5-methylisoxazol-4-yl) -carboxamido-3-cephem-4-carboxylic acid, mp 202-203 C,
14) 2-methyl-7- (2-methylthioacetamido) -3-cephem-4-carboxylic acid, m.p. 181-183 C (dec.),
15) 2-methyl-7- (2-allylthioacetamido) -3-cephem-4-carboxylic acid, m.p. 121-123 "C,
16) 2-methyl-7- (2-formyloxy-2-phenylacetamido) -3cephem-4-carboxylic acid, powder,
17) 2-methyl-7- (1-cyclopropylethoxy) carboxamido-3cephem-4-carboxylic acid,

   M.p. 158.5-160 C (dec.),
18) 2,2,2-trichloroethyl-2-methyl-7- (N- [1 -cyclopropyl-ethoxy] -carbonylphenylglycyl) amino-3-cephem-4-carboxylate, m.p. 165-167.50C,
19) 2,2,2-trichloroethyl-2-methyl-7- (2-phenylthioacetamido) -3-cephem-4-carboxylate, m.p. 140-1420C,
20) 2,2,2-trichloroethyl-2-methyl-7- (3- [N-tert-butoxy- yl] acetamido) -3-cephem-4-carboxylate hydrochloride, which is also known as pivaloyloxymethyl-2-methyl -7- (2- [2-imino-2,3-dihydrothiazol-4-yl] acetamido) -3-cephem-4-carboxylate hydrochloride can be prepared, m.p. 185-190 C (dec. ).



   Process examples
example 1
0.296 g of pyridine and 0.616 g of phosphorus pentachloride were successively with stirring and cooling to -150C to a solution of 1.12 g of 2,2,2-trichloroethyl-2-methyl-7- (2-phenylacetamido) -3-cephem-4- carboxylate, mp 175 to 1780C, in 20 ml of dried dichloromethane was added and the mixture was stirred for 20 minutes at the same temperature and for a further 2 hours at room temperature. To the mixture was added 5 ml of absolute methanol with cooling to -150 ° C., and then the mixture was stirred for 1 hour at the same temperature. To the mixture were sequentially added dropwise 2.2 g of dimethylaniline and a solution of 0.42 g of 2-thienylacetyl chloride in 5 ml of dried dichloromethane at the same temperature, and then the mixture was stirred at the same temperature for 2.5 hours.

  After the reaction, the reaction mixture was washed successively with 5% hydrochloric acid, water, a 5% aqueous sodium bicarbonate solution and water and then dried. After the solution had been concentrated, the oily substance obtained was crystallized by adding ether and 750 mg of 2,2,2-trichloroethyl-2-methyl-7- (2- [2-thienyl] acetamido) -3 -cephem-4 were obtained carboxylate, m.p. 161 to 1620C (dec.).



   In the same way as in the example above, the following compounds were made:
1) 2,2,2-trichloroethyl-2-methyl-7- (2- [3-chlorophenyl] acetamido) -3-cephem-4-carboxylate, mp 144-144.50C (dec.),
2) 2,2,2-Trichloroethyl-2-methyl-7- (2- [1,2,5-thiadiazol3-yl] -acetamido) -3-cephem-4-carboxylate, m.p. 180-185 "C (Decomp.),
3) methyl 2-methyl-7- (2-phenoxyacetamido) -3 -cephem-4carboxylate, oil,
4) 2,2,2-trichloroethyl-2-methyl-7 - (2-phenoxyacetamido) - 3-cephem-4-carboxylate, m.p. 118-1200C,
5) 2-methyl-7- (N- [1 -cyclopropylethoxy] carbonylphenyl glycyl) -amino-3-cephem-4-carboxylic acid, m.p. 168-169 "C,
6) 2-methyl-7- (2- [1H-tetrazol-1-yl] acetamido) -3-cephem-4-carboxylic acid,

   F. 202-2030C (dec.),
7) 2-methyl-7- (2- [2-thienyl] acetamido) -3-cephem-4-carboxylic acid, m.p. 175 C (dec.),
8) 2-methyl-7- (2-phenylthioacetamido) -3 -cephem-4-carboxylic acid, m.p. 168-171 C (dec.),
9) 2-methyl-7- (2- [3-chlorophenyl] acetamido) -3-cephem-4-carboxylic acid, m.p. 173-1740C (dec.),
10) 2-methyl-7- (3- [N-tert-butoxycarbonylamino] -3 [2-thienyl] propionamido) -3 -cephem-4-carboxylic acid, m.p. 167-1700C (dec.),
11) 2-methyl-7- (2-cyanoacetamido) -3-cephem-4-carboxylic acid, m.p. 162-1660C,
12) 2-Methyl-7- (2- [1,3,4-thiadiazol-2-ylthio] acetamido) -3-cephem-4-carboxylic acid, F.

   197-199 C,
13) 2-Methyl-7- (N-tert-butoxycarbonyl-2-thienylglycyl) -amino-3-cephem-4-carboxylic acid, powder,
14) 2-methyl-7- (2- [5-methyl-1,3,4-thiadiazol-2-yloxy] acetamido) -3-cephem-4-carboxylic acid, m.p. 113-1 160C,
15) 2-methyl-7- (3- [2-chlorophenyl] -5-methylisoxazol-4-yl) -carboxamido-3-cephem-4-carboxylic acid, m.p. 202-2030C,
16) 2-methyl-7- (2-methylthioacetamido) -3 -cephem-4-carboxylic acid, m.p. 181-1830C (dec.),
17) 2-methyl-7- (2-allylthioacetamido) -3-cephem-4-carboxylic acid, m.p. 121-1230C,
18) 2-methyl-7- (2-azido-2-phenylacetamido) -3-cephem-4carboxylic acid,

   F. 65-68 C,
19) 2,2,2-Trichloroethyl-2-methyl-7- (N-tert-butoxycarbonyl-2- [4-hydroxyphenyl] -D-glycyl) amino-3-cephem-4-carboxylate, m.p. 130 -1350C (dec.),
20) 2-methyl-7- (2- [3-pyridyl] acetamido) -3-cephem-4-carboxylic acid, m.p. 147-149 "C (dec.),
21) 2-Methyl-7- (N-tert-butoxycarbonyl-2- [2,5-dihydro phenylglycyl) amino-3-cephem-4-carboxylic acid, F.

   126-1310C (decomp.),
22) 2-methyl-7- (N-tert-butoxycarbonyl-2- [4-hydroxyphenyl] -D-glycyl) amino-3-cephem-4-carboxylic acid, powder,
23) 2-methyl-7- (N-tert-butoxycarbonyl-2- [4-methylthiophenyl] glycyl) amino-3-cephem-4-carboxylic acid, m.p. 110-120 C,
24) 2-methyl-7- (N-tert-butoxycarbonyl-2- [4-methoxyphenyl] -glycyl) amino-3-cephem-4-carboxylic acid, m.p. 81-860C (decomp.),
25) 2,2,2-trichloroethyl-2-methyl-7- (N-tert-butoxy-carbonyl-2- [4-methylthiophenyl] glycyl) amino-3-cephem-4-carboxylate, F. 115- 1200C,
26) 2,2,2-trichloroethyl-2-methyl-7- (N-tert-butoxycarbonyl-2- [4-methoxyphenyl] glycyl) amino-3-cephem-4-carboxylate, F.

   92-95 "C (dec.),
27) 2,2,2-Trichloroethyl-2-methyl-7- (N-tert-butoxycarbonyl-2- [2,5-dihydrophenyl] glycyl) amino-3-cephem-4-carboxylate, m.p. 103-111oC (Decomp.),
28) 2,2,2-Trichloroethyl-2-methyl-7- (N- [1-cyclopropyl ethoxy] carbonyl-2- [5,6-dihydro-2H-pyran-3-yl] glycyl) amino-3 -cephem-4-carboxylate, m.p. 118-1260C (dec.),
29) 2,2,2-trichloroethyl-2-methyl-7- (N-tert-butoxycarbonyl-2- [4-tert-butoxycarbonylmethoxyphenyl] glycyl) amino-3-cephem-4-carboxylate, powder,
300 2,2,2-trichloroethyl-2-methyl-7- (N- [1,3,4-thiadiazol2-yl] -thiomethylcarbonyl-2-phenylglycyl) amino-3-cephem4-carboxylate, m.p. 148-1500C ( Decomp.),
31) 2,2,2-trichloroethyl-2-methyl-7- (N-tert-butoxycarbonyl-2- [4-methylsulfinylphenyl] glycyl) amino-3-cephem-4carboxylate,

   M. 115-1250C, carbonylamino] -3- [2-thienyl] propionamido) -3-cephem-4-carboxylate, m.p. 188-1920C,
21) 2,2,2-trichloroethyl-2-methyl-7- (2-cyanoac cephem-4-carboxylate, m.p. 160-1650C (dec.),
22) 2,2,2-trichloroethyl-2-methyl-7- (3-phenylureido) -3cephem-4-carboxylate, F. 172-1740C,
23) 2,2,2-trichloroethyl-2-methyl-7- (2- [1,3,4-thiadiazol2-ylthio] acetamido) -3-cephem-4-carboxylate, F.

   130-140 C, (dec.),
24) 2,2,2-trichloroethyl-2-methyl-7- (N-tert-butoxycarbon yl-2- [2-thienyl] glycyl) amino-3-cephem-4-carboxylate, powder,
25) 2,2,2-trichloroethyl-2-methyl-7- (2- [5-methyl-1,3,4thiadiazol-2-yloxy] acetamido) -3-cephem-4-carboxylate, amorphous,
26) 2,2,2-trichloroethyl-2-methyl-7- (3- [2-chlorophenyl] methylisoxazol-4-yl) carboxamido-3-cephem-4-carboxylate, amorphous,
27) 2,2,2-trichloroethyl-2-methyl-7- (2-methylthioacetamido) -3-cephem-4-carboxylate, mp 151-153 C,
28) 2,2,2-trichloroethyl-2-methyl-7- (2-allylthioacetamido) -3-cephem-4-carboxylate, F.

   96 C,
29) 2,2,2-trichloroethyl-2-methyl-7- (2-formyloxy-2-phenyl acetamido) -3-cephem-4-carboxylate, powder,
30) 2,2,2-trichloroethyl-2-methyl-7- (1-cyclopropylethoxy) carboxamido-3-cephem-4-carboxylate, colorless powder,
31) 2,2,2-Trichloroethyl-2-methyl-7- (N-tert-butoxycarbonyl-2- [4-hydroxyphenyl] -D-glycyl) amino-3-cephem-4-carboxylate, m.p. 130-1350C (Decomp.),
32 2,2,2-trichloroethyl-2-methyl-7- (N-tert-butoxycarbonyl-2- [4-methylthiophenyl] glycyl) amino-3-cephem-4-carboxylate, m.p. 115-120 C,
33) 2,2,2-trichloroethyl-2-methyl-7- (N-tert-butoxycarbonyl-2- [4-methoxyphenyl] glycyl) amino-3-cephem-4-carboxylate, F.

   92-950C (decomp.),
34) 2,2,2-Trichloroethyl-2-methyl-7- (N-tert-butoxycarbonyl) -2- [2,5-dihydrophenyl] glycyl) amino-3-cephem-4-carboxylate, F. 104 -111oC (dec.),
35) 2,2,2-trichloroethyl-2-methyl-7- (2-sulfo-2-phenyl acetamido) -3-cephem-4-carboxylate, m.p. 150 C (decomp.),
36) 2,2,2-Trichloroethyl-2-methyl-7- (N- [1-cyclopropyl ethoxy] carbonyl-2- [5,6-dihydro-2H-pyran-3-yl] glycyl] amino-3 -cephem-4-carboxylate, F. 118-1200C (dec.)
37) 2,2,2-trichloroethyl-2-methyl-7- (N-tert-butoxycarbonyl-2- [4-tert-butoxycarbonylmethoxyphenyl] glycyl) am no-3-cephem-4-carboxylate, powder,
380 2,2,2-trichloroethyl-2-methyl-7- (N- [1,3,4-thiadiazol2-yl] thiomethylcarbonyl-2-phenylglycyl) amino-3-cephem-4 carboxylate,

   148-150oC (dec.),
39) 2,2,2-trichloroethyl-2-methyl-7- (N-tert-butoxycarbonyl-2- [4-methylsulfinylphenyl] glycyl) -amino-3-cephem4-carboxylate, m.p. 115-1250C,
40) 2,2,2-trichloroethyl-2-methyl-7- (2-isonicotinoyloxy 2-phenylacetamido-3-cephem-4-carboxylate, m.p. 100-115oC (dec.),
41) 2,2,2-trichloroethyl-2-methyl-7- (2- [tindanyl] oxycarbonyl-2-phenylacetamido) -3-cephem-4-carboxylate, m.p. 165-1700C,
42) 2-methyl-7- (D-2- [4-hydroxyphenyl] glycyl) cephem-4-carboxylic acid, powder,
43) 2-methyl-7- (2- [5,6-dihydro-2H-pyran-3-yl] glycyl) amino-3-cephem-4-carboxylic acid, m.p. 125-128 C (dec.),
44) 2-Methyl-7- (2- [3-methanesulfonamidophenyl] glycyl) amino-3-cephem-4-carboxylic acid, F.

   192-193 C (decomp.),
45) 2-methyl-7- (2- [4-carboxymethoxyphenyl] glycyl) amino-3-cephem-4-carboxylic acid, powder,
46) 2-methyl-7- (2- [4-methylthiophenyl] glycyl) amino-3 cephem-4-carboxylic acid, m.p. 165-1750C,
47) 2-methyl-7- (2- [4-methoxyphenyl] glycyl) am cephem-4-carboxylic acid, m.p. 165-1680C,
48) 2-methyl-7- (2- [2,5-dihydrophenyl] glycyl) cephem-4-carboxylic acid, m.p. 1680C (dec.),
49) 2-Methyl-7- (2- [4-methylsulfinylphenyl] glycyl) -amino 3-cephem-4-carboxylic acid, powder,
50) 2,2,2-trichloroethyl-2-methyl-7- (2- [5,6-dihydro-pyran-3-yl] acetamido) -3-cephem-4-carboxylate, mp 149.5-150, 5oC,
51) 2-Methyl-7- (2- [5,6-dihydro-2H-pyran-3-yl] -acetamido) -3-cephem-4-carboxylic acid, F.

   172.5-173.5 C (dec.),
52) 2,2,2-trichloroethyl-2-methyl-7- (N-tert-butoxycarbonyl-2- [3-methanesulfonamidophenyl] glycyl) -amino-3-cephem-4-carboxylate, amorphous,
53) 2-methyl-7- (N-tert-butoxycarbonyl-2- [3-methanesulfonamidophenyl] glycyl) amino-3-cephem-4-carboxylic acid, oil,
54) 2-methyl-7- (4-methoxyphenyl) glyoxylamido-3-cephem-4-carboxylic acid, m.p. 188-1890C (dec.),
55) 2-methyl-7- (N-tert-butoxycarbonylphenyl-D-glycyl) amino-3-cephem-4-carboxylic acid, m.p. 125-127 C (dec.),
56) 2-Methyl-7- (N- [2- {2-nitrophenoxy) acetyl] phenylglycyl) -amino-3-cephem-4-carboxylic acid, m.p. 135-137 C (dec.),
57) 2,2,2-trichloroethyl-2-methyl-7- (N-tert-butoxycarbonylphenyl-d-glycyl) amino-3-cephem-4-carboxylate, m.p. 115-1160C (dec.).

 

   58) 2-methyl-7- (2- [2-aminothiazol-4-yl] acetamido) -3cephem-4-carboxylic acid, which is also known as 2-methyl-7- (2- [2imino-2,3-dihydro- thiazol-4-yl] acetamido) -3-cephem-4-carboxylic acid, m.p. 250-255oC (dec.).



   590 pivaloyloxymethyl-2-methyl-7- (2- [2-aminothiazo
32) 2-methyl-7- (2-isonicotinoyloxy-2-phenylacetamido) -3cephem-4-carboxylic acid, m.p. 217-2 190C,
33) 2,2,2-trichloroethyl-2-methyl-7- (2-isonicotinoyloxy-2phenylacetamido) -3-cephem-4-carboxylate, m.p. 100-115 "C (dec.),
34) 2,2,2-trichloroethyl-2-methyl-7- (2- [5-indanyl] oxycarbonyl-2-phenylacetamido) -3-cephem-4-carboxylate, F. 165-1700L,
35) 2-Methyl-7- (N- [1,3,4-thiadiazol-2-yl] thiomethylcarbonyl-2-phenylglycyl) amino-3-cephem-4-carboxylic acid, m.p. 143-1450C (dec.),
36) 2-methyl-7- (N-tert-butoxycarbonyl-2- [4-tert-butoxy carbonylmethoxyphenyl] glycyl) amino-3-cephem-4-carboxylic acid,

   Powder,
37) 2-Methyl-7- (N- [1-cyclopropylethoxy] carbonyl-2- [5,6-dihydro-2H-pyran-3 -yl] glycyl) amino-3-cephem-4-carboxylic acid, F. 195 -1970C,
38) 2-Methyl-7- (2- [1,2,5-thiadiazol-3-yl] acetamido) -3-cephem-4-carboxylic acid, m.p. 188-190 "C (dec.),
39) 2-methyl-7- (N-tert-butoxycarbonyl-2- [3-methanesulfonamidophenyl] glycylamino-3-cephem-4-carboxylic acid, oil,
40) 2-methyl-7- (N-tert-butoxycarbonyl-2- [4-methyl-sulfinylphenyl] glycyl) amino-3-cephem-4-carboxylic acid, F.

   110-120 C,
41) 2-Methyl-7- (2- [5-indanyl] oxycarbonyl-2-phenylacet-amido) -3-cephem-4-carboxylic acid, m.p. 90-950C (softening), 150-160 "C (dec. ),
42) 2,2,2-trichloroethyl-2-methyl-7- (N- [1-cyclopropyl ethoxy] carbonylphenylglycyl) amino-3-cephem-4-carboxylate, m.p. 165-167.50C,
43) 2,2,2-trichloroethyl-2-methyl-7- (2- [1H-tetrazol-1-yl] acetamido) -3-cephem-4-carboxylate, m.p. 168-1700C,
44) 2,2,2-trichloroethyl-2-methyl-7- (2-phenylthioacetamido) -3-cephem-4-carboxylate, $. 140-142 C,
45) 2,2,2-trichloroethyl-2-methyl-7- (3- [N-tert-butoxycarbonylamino] -3- [2-thienyl] -propionamido) -3-cephem-4-carboxylate, F.

   188-192 C,
46) 2,2,2-trichloroethyl-2-methyl-7- (2-cyanoacetamido) -3cephem-4-carboxylate, m.p. 160-165 C (decomp.),
47) 2,2,2-Trichloroethyl-2-methyl-7- (2- [1,3,4-thiadiazol-2-ylthio] acetamido) -3-cephem-4-carboxylate, m.p. 130-140 "C (Decomp.),
48) 2,2,2-trichloroethyl-2-methyl-7- (N-tert-butoxycarbonyl-2-thienylglycyl) amino-3-cephem-4-carboxylate, powder,
49) 2,2,2-trichloroethyl-2-methyl-7- (2- [5-methyl-1,3,4thiadiazol-2-yloxy] acetamido) -3-cephem-4-carboxylate, colorless crystals,
50) 2,2,2-trichloroethyl-2-methyl-7- (3- [2-chlorophenyl] -5methylisoxazol-4-yl) carboxamido-3-cephem-4-carboxylate, amorphous,
51) 2,2,2-trichloroethyl-2-methyl-7- (2-methylthioacetamido) -3-cephem-4-carboxylate,

   F. 151-153 C,
52) 2,2,2-trichloroethyl-2-methyl-7- (2-allylthioacetamido) -3-cephem-4-carboxylate, m.p. 960C,
53) 2-methyl-7- (2-sulfo-2-phenylacetamido) -3-cephem-4carboxylic acid, m.p. 1150C (formation of bubbles), 200-220 C (decomp.),
54) 2,2,2-trichloroethyl-2-methyl-7- (2-sulfo-2-phenyl-acetamido) -3-cephem-4-carboxylate, amorphous,
55) 2-methyl-7- (2-hydroxy-2- [2-thienyl] acetamido) -3-cephem-4-carboxylic acid, m.p. 91-960C (dec.),
56) 2,2,2-Trichloroethyl-2-methyl-7- (2- [5,6-dihydro-2Hpyran-3-yl] acetamido) -3-cephem-4-carboxylate, m.p. 149.5-150 , 5 "C,
57) 2-Methyl-7- (2- [5,6-dihydro-2H-pyran-3-yl] acetamido) 3-cephem-4-carboxylic acid, m.p. 172.5-173.50C (dec.).

 

   58) 2-Methyl-7- (2- [2-aminothiazol-4-yl] acetamido) -3-cephem-4-carboxylic acid, also known as 2-methyl-7- (2 [2-amino-2,3 -dihydro-thiazol-4-yl] acetamido) -3-cephem-4-carboxylic acid, m.p. 250-255 "C (dec.).

 

Claims (1)

PATENT CLAIMS 1. Process for the preparation of 2-lower alkyl-2- or -3cephem-4-carboxylic acid derivatives of the formula: EMI1.1 in which RtF is an acylamino group, R2 is a carboxy or protected carboxy group, R3 is a lower alkyl group and X is -5- or EMI1.2 mean, and their pharmaceutically acceptable salts, characterized in that a compound of the formula: : EMI1.3 in which R2, R3 and X have the above meanings and Rib is an acylamino group other than Reib ', with a trialkyloxonium haloborate or an iminohalide-forming agent and an iminoether-forming agent and then the compound obtained with one of the acyl group of R'b' corresponding Acylating agent converts, which is followed, if necessary, by hydrolysis in order to complete the transacylation reaction. 2. The method according to claim 1, characterized in that trimethyloxonium chloroborate, trimethyloxonium fluoroborate or triethyloxonium fluoroborate is used as the trialkyloxonium haloborate. 3. The method according to claim 1, characterized in that a halogenating agent, for example phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride or phosgene is used as the iminohalide-forming agent. 4. The method according to claim 1, characterized in that an alcohol or a metal alcoholate derived from this alcohol is used as the imino ether-forming agent. The invention relates to a process for the production of antimicrobially active 2-lower alkyl-2- and -3-cephem-4carboxylic acid derivatives which have activity against a number of microorganisms. The 2-lower alkyl-2- and -3cephem-4-carboxylic acid derivatives obtainable according to the invention are new compounds. In fact, 2-lower alkyl derivatives of the cephalosporin series were previously unknown, while 3-lower alkyl derivatives, such as u. a. Cephalexin (J. Med. Chem. 12 [1969], 310; Belg. Patent No. 696 026) and Cephradin (J. Med. Chem. 14 [1971], 117; US Patent No. 3,485,819) have long been described and proposed for therapeutic use. The new compounds are represented by the following formula: EMI1.4 in which R'b 'is an acylamino group, R2 is a carboxy or protected carboxy group, R3 is a lower alkyl group and X is -S- or EMI1.5 mean. According to the invention, the compounds If are prepared by adding a compound of the formula: EMI1.6 in which R2, R3 and X have the above meanings and Rib is an acylamino group other than Rib, reacts with a trialkyloxonium haloborate or an iminohalide-forming agent and an iminoether-forming agent and then reacts the compound obtained with an acylating agent corresponding to the acyl group of Reib ', which, if necessary, is followed by hydrolysis to complete the transacylation reaction. The term an acylamino group used here for friction and Rlb is to be understood as meaning groups in which the acyl radical is, for example, the following: a carbamoyl radical, an aliphatic acyl group and an acyl group which contains an aromatic or heterocyclic ring, which are illustrated below by examples . That is, suitable examples of aliphatic acyl groups include saturated or unsaturated lower or higher alkanoyl groups which may be branched or which may contain a cyclic ring, e.g. lower or higher aliphatic acyl groups such as lower alkanoyl (e.g. Formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl and the like. the like), higher alkanoyl (e.g. octanoyl, lauroyl, palmitoyl, and the like), lower alkanoyl (e.g. acryloyl, crotonoyl, and the like), lower alkinoyl (e.g. Propinoyl et al. the like), lower or higher cycloalkanecarbonyl (e.g. cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl and the like), lower or higher cycloalkyl-lower alkanoyl (e.g. cyclopentylacetyl, cyclohexylacetyl, cycloheptyglionlacetyl), cyclohexylpropionylpro, cycloheptylpro, cycloheptylpro, cycloheptylpro. ** WARNING ** End of CLMS field could overlap beginning of DESC **.