NO751338L - - Google Patents

Description

"Analog method for the preparation of pharmaceutically active 2-lower-alkyl-2- or -3-cephem-4-carboxylic acid derivatives"

The present invention relates to an analogous process for the production of hitherto unknown 2-lower alkyl-2- or -3-cephem-4-carboxylic acid derivatives, which have antimicrobial activities, and which can be used in pharmaceutical preparations, which can be used to treat infections.

The purpose of the present invention is to provide an analogous method for the production of antimicrobially active 2-lower alkyl-2- or -3-cephem-4-carboxylic acid derivatives, which are active against a number of microorganisms.

The 2-lower alkyl-2- or -3-cephem-4-carboxylic acid derivatives referred to here are hitherto unknown compounds, which can be represented by the general formula I where R 1 denotes araino or substituted 3amino, R 2 denotes carboxy or protected carboxy, and R denotes lower alkyl.

According to the invention, the 2-lower alkyl-2- or -3-cephem-4-carboxylic acid derivatives mentioned here can be prepared using different methods, which for the sake of simplicity can be collectively illustrated with the help of the following reaction core, where process step II -* I is a fundamental method, and the others are alternative methods.

1 2

where R denotes amino or substituted amino, R denotes

3 - 4 carboxy or protected carboxy, R denotes lower alkyl, R

' 5 -6

represents aryl, R and R each represents lower alkyl,

R<la> denotes protected amino, R' and R<1> each denote acylamino, R denotes acylamino with protected amino, R denotes acylamino with amino, Rle denotes acylamino with protected

1 f *2a

hydroxy, R denotes acylamino with hydroxy, and R denotes protected carboxy.

The compound with the general formula II used as starting material is hitherto unknown and can be prepared by reacting the corresponding 2-lower alkyl-2-halomethyl-6-substituted penam-3-carboxylic acid or its 1-oxide or derivatives thereof at the carboxyl group with a base.

The term "substituted amino" in R"^ denotes here suitable substituted amino groups, including hydrazino, mono- or di-lower alkylamino, mono- or di-lower alkenylamino, lower alkylideneamino, ar(lower)alkylideneamino, 2,2-di(lower )alkyl-4-aryl-5-oxo-imidazolidin-1-yl, acylamino and amino groups, which are substituted with amino protecting groups other than acyl groups.

In the above indicated suitable substituted amino groups

suitable lower alkyl moieties in mono- or di-lower alkylamino may include methyl, ethyl, propyl, isopropyl and butyl,

suitable lower alkenyl moieties in mono- or di-lower alkenylamino may include allyl and 2-butenyl,

r

suitable lower alkylidene moieties in lower alkylideneamino may include ethylidene, propylidene and butylidene,

suitable ar(lower)alkylidene moieties in the ar(lower)alkylidene may include benzylidene and phenethylidene,

suitable 2,2-di(lower)alkyl-4-aryl-5-oxoimidazolidin-1-yl may include 2,2-dimethyl-4-phenyl-5-oxoimidazolidin-1-yl and 2,2-diethyl-4- phenyl-5-oxoimidazolidin-1-yl,

suitable acyl moieties in acylamino may include carbamoyl, aliphatic acyl and acyl groups containing an aromatic or heterocyclic ring,

and in the following, examples thereof are given.

Suitable aliphatic acyl groups may include saturated or unsaturated, lower or higher alkanoyl groups, which may be branched, or which may contain a cyclic ring such as lower or higher aliphatic acyl groups, e.g. lower alkanoyl (eg formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl and pivaloyl), higher alkanoyl (eg octanoyl, lauroyl and palmitoyl), lower alkenoyl (eg acryloyl and crotonoyl), lower alkynyl (eg propynoyl), lower or higher cycloalkane carbonyl. (e.g. cyclopentanecarbonyl, cyclohexanecarbonyl and cycloheptanecarbonyl), lower or higher cycloalkyl(lower)alkanoyl (e.g. cyclopentylacetyl, cyclohexylacetyl, cycloheptylacetyl, cyclohexylpropionyl and cycloheptylpropionyl), lower or higher cycloalkadienecarbonyl (e.g. dihydrobenzoyl), lower or higher cycloalkadienyl(lower)alkanoyl (e.g. dihydrophenylacetyl and dihydrophenylpropionyl), and lower or higher aliphatic acyl groups containing an oxygen or sulfur atom, e.g. lower alkoxy(lower)alkanoyl (e.g. methoxyacetyl, ethoxyacetyl and methoxypropionyl), lower alkylthio(lower)alkanoyl (e.g. methylthioacetyl, ethylthioacetyl and methylthiopropionyl)", lower alkenylthio-(lower)alkanoyl (e.g. allylthioacetyl and allylthiopropionyl),

lower or higher cycloalkylthio(lower)alkanoyl (e.g. cyclopentylthioacetyl, cyclohexylthiopropionyl and cycloheptylthioacetyl), lower or higher cycloalkylthio(lower)alkanoyl (e.g. cyclopentyloxyacetyl and cyclohexyloxypropionyl), lower or higher cyclo-

alkandienyloxy(lower)alkanoyl (e.g. dihydrophenoxyacetyl and dihydrophenoxypropionyl), lower or higher cycloalkandienylthio-(lower)alkanoyl (e.g. dihydrophenylthioacetyl and dihydrophenylthio-propionyl), lower alkoxycarbonyl (e.g. raethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1 -cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and tert.butoxycarbonyl), lower or higher cycloalkyloxycarbonyl (e.g. cyclopentyloxycarbonyl, cyclohexyloxycarbonyl and cycloheptyloxycarbonyl) and lower or higher cycloalkanedienyloxycarbonyl (e.g. dihydro-.phenoxycarbonyl).

Suitable acyl groups containing an aromatic ring such as benzene and naphthalene include e.g. arylcarbamoyl (e.g., phenylcarbamoyl), aryloyl (e.g., benzoyl, toluoyl, naphthoyl, α-methyl-naphthoyl, phthaloyl, benzenesulfonyl, tetrahydronaphthoyl, and indane-carbonyl), ar(lower)alkanoyl (e.g., phenylacetyl, phenylpropionyl, phenylbutyryl, tolylacetyl, xylylacetyl, naphthylacetyl, tetrahydro-naphthylacetyl and indanylacetyl)A and the carbon atom in the alkyl part of the ar(lower)alkanoyl group can be replaced by an oxygen or sulfur atom or a carbonyl group, and as examples of such groups can be stated aryloxy( lower)alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, phenoxybutyryl, and xylyloxyacetyl), aryloxycarbonyl (e.g., phenoxycarbonyl, xylyloxycarbonyl, naphthyloxycarbonyl, and indanyloxycarbonyl), ar(lower)alkyloxycarbonyl (e.g., benzyloxycarbonyl, and phenethyloxycarbonyl), arylthio (lower) alkanoyl (e.g. phenylthioacetyl and phenylthiopropionyl) and arylglyoxyloyl (e.g. phenylglyoxyloyl).

Suitable acyl groups containing a heterocyclic ring include heterocyclic carbonyl or heterocyclic lower alkanoyl,

and the heterocyclic ring in the heterocyclic carbonyl group or heterocyclic lower alkanoyl group may be saturated or unsaturated, monocyclic or polycyclic and may contain at least one heteroatom such as oxygen, sulfur or nitrogen, and examples of such groups are unsaturated 3- to 8-membered heteromonocyclic groups containing a sulfur atom (e.g. thienyl), unsaturated condensed heterocyclic groups containing a sulfur atom

(e.g. benzothienyl), unsaturated 3- - 8-membered heteromonocyclic groups containing an oxygen atom (e.g. furyl, 2-(or 4-)-pyranyl and 5,6-dihydro-2H-pyran-3-yl ), unsaturated 3- - 8-membered heteromonocyclic groups containing 1-4 nitrogen atoms (e.g. pyrrolyl, 2(or 3)H-pyrrolyl, 2-(or 3-)pyrrolinyl, imidazolyl,

pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1H-tetrazolyl and 2H-tetrazolyl), saturated 3- - 8-membered heteromonocyclic groups containing 1-2 nitrogen atoms (e.g. pyrrolidinyl, imidazolidinyl, piperidino and piperadinyl), unsaturated condensed heterocyclic groups containing 1-3 nitrogen atoms (e.g. indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, 1(or 2)H-indazolyl and 1(or 2)H-benzotriazolyl), unsaturated 3-8-membered heteromonocyclic groups containing an oxygen atom and 1 - 3 nitrogen atoms (e.g. oxazolyl, isoxazolyl and oxadiazolyl), saturated 3- - 8-membered heteromonocyclic groups containing 1-2 oxygen atoms and 1 - 2 nitrogen atoms (e.g. sydnonyl), unsaturated 3- - 8-membered heteromonocyclic groups containing a sulfur atom and 1 - 3 nitrogen atoms (e.g. thiazolyl and thiadiazolyl)., unsaturated condensed heterocyclic groups containing an oxygen atom and 1 - 2 nitrogen atoms (e.g. benzoxazolyl and benzoxadiazolyl) and u saturated condensed heterocyclic groups containing a sulfur atom and 1 - 2 nitrogen atoms (e.g. benzothiazolyl and benzothiadiazolyl). The carbon atom in the lower alkyl part of the above-mentioned heterocyclic lower alkanoyl group can be replaced by an oxygen or sulfur atom, and as examples of such groups can be given heterocyclic lower alkoxycarbonyl, heterocyclic-oxycarbonyl, heterocyclic-oxy(lower)alkanoyl and heterocyclic-thio(lower )alkanoyl.

The carbamoyl group, the aliphatic acyl groups and the acyl groups containing an aromatic or heterocyclic ring as indicated above may have 1 - 10 suitable substituents such as lower alkyl (e.g. methyl, ethyl, propyl and isopropyl), lower alkenyl (e.g. 1-propenyl and allyl), lower or higher cycloalkyl (e.g. cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl), lower alkoxy (e.g. methoxy, ethoxy, propoxy and isopropoxy), lower alkylthio (e.g. methylthio and ethylthio ), aryl (e.g. phenyl, xylyl, tolyl and indanyl), ar(lower)alkyl (e.g. benzyl and phenethyl), halogen (e.g. chlorine, bromide and fluorine), halophenyl (e.g. .chlorophenyl and bromophenyl),. halophenoxy (e.g. chlorophenoxy and bromophenoxy), cyano, lower alkylsulfinyl (e.g. methylsulfinyl and ethylsulfinyl), lower alkanesulfonyl (e.g. methanesulfonyl and ethanesulfonyl), lower alkoxycarbonyl (lower) alkoxy (e.g. methoxycarbonylmethoxy, ethoxycarbonylethoxy, 1-cyclopropylethoxycarbonylmethoxy and tert.butoxycarbonylmethoxy), nitro, sulfo, amino, azido, mercapto, carboxy, hydroxy, hydroxyamino and mono (or di) alkylamino (e.g. mono .(or di) methylaraino, mono(or di)ethylamino, mono(or di)propylamino and mono(or di)isopropylamino).

When the above-mentioned acyl group has a functional group such as amino, hydroxy, mercapto and carboxy, the functional group can be protected with a suitable protecting group.

r

Suitable protecting groups for the amino group are e.g. any conventional protecting group, e.g. acyl groups or groups other than acyl groups such as trityl, 2-nitro-phenylthio, 2,4-dinitrophenylthio, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene, 3-hydroxy-4-pyridyl-methylene , l-methoxycarbonyl-2-propylidene, l-ethoxycarbonyl-2-propylidene, 3-ethoxycarbonyl-1-2-butylidene, l-acetyl-2-propylidene, l-benzoyl-2-propylidene, 1-[n-(2-methoxypheny1 )carbamoyl]-2-propylidene, 1- [N-(4-methoxyphenyl)carbamoyl]-2-propylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-dimethyl1-5 -oxocyclohexylidene (among these, 1-methoxycarbonyl-2-propylidene and 2-ethoxycarbonylcyclohexylidene groups may be present as 1-methoxycarbonyl-1-propen-2-yl and 2-ethoxycarbonyl-1-cyclohexenyl, respectively) and mono(or di) silyl; suitable protecting groups for hydroxy or mercapto groups are e.g. any conventional protecting group for hydroxy or mercapto groups, e.g. acyl groups or groups other than acyl groups such as benzyl, trityl, methoxymethyl, 2-nitro-phenylthio and 2,4-dinitrophenylthio; and suitable protecting groups for the carboxy group are e.g. any conventional protecting group, which is used to protect a carboxy group, and as examples of compounds with such protected carboxy groups lower alkyl esters (e.g. methyl esters, ethyl esters, propyl esters, butyl esters, 1-cyclopropyl esters and tert.- butyl esters), mono(or di- or tri-)halo(lower) alkyl esters (e.g. chloromethyl esters, 2,2,2-trichloroethyl esters and 3,3-dibromopropyl esters), aryl esters (e.g. phenyl esters, nitrophenyl esters and indanyl esters), ar(lower) alkyl esters (e.g. benzyl esters, diphenyl methyl esters, triphenyl methyl esters, p-nitrobenzyl esters and p-bromobenzyl esters) and tri(lower) alkyl silyl esters (e.g. trimethylsilyl esters and triethyl silyl esters).

As protecting groups for the amino group, which is different from an acyl group, which is indicated above for explanation of the term "substituted amino", the same amino-amino protecting groups as those indicated above as protecting groups for the amino radical in the acyl group can also be indicated.

The following are examples of particularly suitable acyl groups: 1) lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, butoxycarbonyl and tert.butoxycarbonyl), 2) phenyl(lower) alkoxycarbonyl (e.g. benzyloxycarbonyl and phenethyloxycarbonyl),

3) phenylcarbamoyl,

4) phenylglyoxyloyl,

5) lower alkoxyphenylglyoxyloyl (e.g. 2-[2-(or -3- or -4-)-methoxyphenyl]glyoxyloyl and 2-[2-(or -3- or -4-)ethoxyphenyl]-glyoxyloyl),

6) phenylthiocarbonyl,

7) cyano(lower)alkanoyl (e.g. 2-cyanoacetyl, 3-cyanopropionyl and

4-cyanobutyryl),

8) lower alkylthio(lower)alkanoyl (e.g. 2-methylthioacetyl,

2-methylthiobutyryl, 2-ethylthioacetyl and 3-methylthiopropionyl),

9) lower alkenylthio(lower)alkanoyl (e.g. 2-allylthioacetyl and

3- allylthiopropiohyl),

10) phenylthio(lower)alkanoyl (e.g. 2-phenylthioacetyl and 3-phenylthiopropionyl), 11) phenoxy(lower)alkanoyl (e.g. 2-phenoxyacetyl, 3-phenoxy-propionyl and 4-phenoxybutyryl),

12) phenyl (lower) alkanoyl (e.g. 2-phenylacetyl, 3-phenylpropionyl

and 4-phenylbutyryl),

13) halophenyl(lower)alkanoyl (e.g. 2— 12—(or -3- or -4-)

chlorophenyl]acetyl, 2-[2-(or -3- or -4-)bromophenyl]acetyl and 3-[2-(or -3- or -4-)chlorophenyl]propionyl),

14) phenyl- and amino-substituted lower alkanoyl (e.g. phenylglycyl

and 3-amino-3-phenylpropionyl),

15) phenyl and lower alkoxycarbonylamino substituted lower

alkanoyl (e.g. N-methoxycarbonylphenylglycyl, N-ethoxycarbonylphenylglycyl, N-(1-cyclopropylethoxy)carbonylphenylglycyl, N-tert.-butoxycarbonylphenylglycyl and 2-(1-cyclopropylethoxy)carbonylamino-3-phenylpropionyl),

16) phenyl- and trihalo(lower) alkoxycarbonylamino-substituted

lower alkanoyl (e.g. N-trichloroethoxycarbonylphenylglycyl, 3-trichloroethoxycarbonylamino-3-phenylpropionyl and N-tribromomethoxycarbonylphenylglycyl),

17) phenyl- and nitrophenoxy (lower) alkanoylamino substituted lower

alkanoyl (eg N-[2-[2-(or -3- or -4-)nitrophenoxy]acetyl]-phenylglycyl),

18) phenyl- and thiadiazolylthio(lower)alkanoylamino substituted

lower alkanoyl (e.g. N-(1,3,4-thiadiazol-2-yl)thioacetylphenyl-glycyl and 2-[3-(1,3,4-thiadiazol-2-yl)thiopropionyl]amino-3- phenylpropionyl) , 19) hydroxyphenyl- and amino-substituted lower alkanoyl (e.g. 2-amino-2-[2-(or -3- or -4-)hydroxyphenyl]acetyl and 2-amino-3- [2-(or -3- or.-4-)hydroxyphenyl]propionyl), 20) hydroxyphenyl- and lower alkoxycarbonylamino substituted lower

alkanoyl (eg 2-methoxycarbonylamino-2-[2-(or -3- or -4-)-hydroxyphenyl]acetyl, 2-(1-cyclopropylethoxy)carbonylamino-2-[2-(or -3- or -4-)hydroxyphenyl]acetyl and 2-tert.butoxycarbonylamino-2-[2-(or -3- or -4-)hydroxyphenyl]acetyl),

21) lower alkoxyphenyl- and amino-substituted lower alkanoyl

(e.g. 2-amino-2-[2-(or -3- or -4-)methoxyphenyl]acetyl and 2-amino-3-[2-(or -3- or -4-)methoxyphenyl]acetyl ),

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 and 2-tert.butoxycarbonylamino-2-[2-(or -3- or -4-)methoxyphenyl]acetyl),

23) lower alkylthiophenyl- and amino-substituted lower alkanoyl

(e.g. 2-amino-2-[2-(or -3- or -4-)methylthiophenyl]acetyl and 2-amino-3-[2-(or -3- or -4-)ethylthiophenyl]propionyl ),

24) lower alkylthiophenyl- and lower alkoxycarbonylamino-substituted lower alkanoyl (e.g. 2-methoxycarbonylamino-2-[2-(or -3- or -4-)methylthiophenyl]acetyl, 2-(1-cyclopropylethoxy)-carbonylamino- 2-[2-(or -3- or -4-)methylthiophenyl]acetyl, 2-tert-butoxycarbonylamino-2-[2-(or -3- or -4-)methylthiophenyl]-

acetyl and 2-tert.butoxycarbonylamino-3-[2-(or -3- or -4-)-ethylthiophenyl]propionyl),

25) lower alkylsulfinylphenyl- and amino-substituted lower alkanoyl

(e.g. 2-amino-2-[2-(or -3- or -4-)methylsulfinylphenyl]-

acetyl and 2-amino-3-[2-(or -3- or -4-)ethylsulfinylphenyl]-propionyl),

26) lower alkylsulfinylphenyl- and lower alkoxycarbonylamino-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 and 2-tert.butoxycarbonylamino-2 -[2-(or -3- or -4-)-methylsulfinylphenyl]acetyl),

27) carboxy(lower) alkoxyphenyl)- and amino-substituted lower

alkano<r>yl (e.g. 2-amino-2-[2-(or -3- or -4-)carboxymethoxy-phenyl]-acetyl and 2-amino-3-[2-(or -3- or -4-)carboxy-methoxyphenyl]propionyl),

28) lower alkoxycarbonyl(lower) alkoxyphenyl- and lower alkoxycarbonylamino-substituted lower alkanoyl (e.g. 2-methoxycarbonyl-amino-2-[ 2-(or *-3- or -4-) methoxycarbonylmethoxy phenyl ]acetyl, 3-(1 -cyclopropylethoxy)carbonylamino-3-[2-(or -3- or -4-)ethoxycarbonyl]propionyl and 2-tert-butoxycarbonylamino-2-[2-(or -3- or -4-)tert-butoxycarbonylmethoxyphenyl] acetyl), 29) lower alkanesulfonamidophenyl- and lower alkoxycarbonylamino-substituted lower alkanoyl (e.g. 2-methoxycarbonylamino-2-[2-(or -3- or -4-)methanesulfonamidophenyl]acetyl, 3-(1-cyclopropylethoxy) carbonylamino-3-[2-(or -3- or -4-)ethanesulfonamido-phenyl]propionyl and 2-tert.butoxycarbonylamino-2-[2-(or -3- or

-4-)methanesulfonamidophenyl]acetyl),

30) dihydrophenyl- and amino-substituted lower alkanoyl (e.g. 2-amino-2-(2,5-dihydrophenyl)acetyl and 2-amino-3-(2,5-dihydrophenyl)-propionyl), 31) dihydrophenyl- and lower alkoxycarbonylamino-substituted lower alkanoyl (e.g. 2-methoxycarbonylamino-2-(2,5-dihydrophenyl)acetyl, 2-(1-cyclopropylethoxy)carbonylamino-2-(2,5-dihydrophenyl)acetyl, 2-tert.butoxycarbonylamino- 2-(2,5-dihydrophenyl)acetyl and 2-tert.-butoxycarbonylamino-3-(2,5-dihydrophenyl)propionyl), 32) phenyl- and azido-substituted lower alkanoyl (e.g. 2-azido-2-phenylacetyl and 3-azido-3-phenylpropionyl), 33) phenyl- and hydroxy-substituted lower alkanoyl (e.g. 2-hydroxy-2-phenylacetyl and 2-hydroxy-3-phenylpropionyl),

34) phenyl- and lower alkanoyloxy-substituted lower alkanoyl

(e.g. 2-formyloxy-2-phenylacetyl, 2-acetoxy-2-phenylacetyl and

3-propionyloxy-3-phenylpropionyl),

35) phenyl- and pyridylcarbonyloxy-substituted lower alkanoyl (e.g. 2-nicotinoyloxy-2-phenylacetyl and 2-isonicotinoyloxy-2-phenylacetyl), 36) phenyl- and sulfo-substituted lower alkanoyl (e.g. 2-phenyl-2-sulfoacetyl and 3-phenyl-3-sulfopropionyl),

37) phenyl- and indanyloxycarbonyl-substituted lower alkanoyl

(e.g. 2-(5-indanyloxy)carbonyl-2-phenylacetyl and 3-(5-indanyloxy)carbonyl-3-phenylacetyl),

38) thienyl(lower)alkanoyl (e.g. 2-(2-thienyl)acetyl and 3-(2-thienyl)propionyl), 39) thienyl- and amino-substituted lower alkanoyl (e.g. 2- amino-2-(2-thienyl)acetyl and 2-amino-3-(2-thienyl)propionyl), 40) thienyl- and lower alkoxycarbonylamino-substituted lower alkanoyl (e.g. 2-methoxycarbonylamino-2-(2-thienyl) acetyl, 2-(1-cyclopropylethoxy)carbonylamino-2-(2-thienyl)acetyl, 2-tert-butoxycarbonylamino-2-(2-thienyl)acetyl and 3-tert-butoxycarbonylamino-3-(2-thienyl)propionyl ), 41) thienyl- and hydroxy-substituted lower alkanoyl (e.g. 2-hydroxy-2-(2-thienyl)acetyl and 3-hydroxy-3-(2-thienyl)propionyl), 42) dihydropyranyl^and amino-substituted lower alkanoyl (e.g. 2-amino-2-(5,6-dihydro-2H-pyran-3-yl)acetyl and 2-amino-3-(5,6-dihydro-2H-pyran-3-yl)propionyl ), 43) dihydropyranyl- and lower alkoxycarbonylamino-substituted lower alkanoyl (e.g. 2-methoxycarbonylamino-2-(5,6-dihydro-2H-pyran-3-yl)acetyl, 2-(1-cyclopropylethoxy)carbonylamino-2- (5,6-dihydro-2H-pyran-3-yl)acetyl, 2-tert.but oxycarbonylamino-2-(5,6-dihydro-2H-pyran-3-yl)acetyl and 2-tert.butoxycarbonylamino-3-(5,6-dihydro-2H-pyran-3-yl)propionyl), 44) pyridyl substituted lower alkanoyl (e.g. 2-(3-pyridyl)acetyl and 3-(3-pyridyl)propionyl), 45) thiadiazolyl(lower)alkanoyl (e.g. 2-(1,2,5-thiadiazol-3-yl)-acetyl, 2 -(1,3,4-thiadiazol-2-yl)acetyl and 3-(1,2,5-thiadiazol-3-yl)-propionyl), 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 and 2-(5-ethyl-1,3 ,4-thiadiazol-2-yloxy)propionyl), 47) thiadiazolylthio(lower)alkanoyl (e.g. 2-(1,3,4-thiadiazol-2-ylthio)acetyl, 2-(1,2,5- thiadiazol-3-ylthio)acetyl and 3-(1,3,4-thiadiazol-2-ylthio)propionyl), 48) tetrazolyl(lower)alkanoyl (e.g. 2-(1H-tetrazol-1-yl)acetyl , 3-(1H-tetrazol-1-yl)-propionyl and 4-(1H-tetrazol-1-yl)butyryl), 49) 3-halophenyl-5-lower alkylisoxazol-4-ylcarbonyl (e.g. 3- [ 2-(or -3- or -4-)chlorophenyl]-5-methylisoxazol-4-ylcarbonyl and 3-[2-(or -3- or -4-)bromophenyl]-5-ethylisoxazol-4-yl- carbonyl), 50) halobenzotriazolyl(lower)alkanoyl (e.g. 2-[4-(or -5-or -6- or -7-)chloro-1H-benzotriazol-1-yl]acetyl, 2-[4 - (or -5- or -6- or -7-)bromo-1H-benzotriazol-1-yl]acetyl and 3-t 4 —

(or -5- or 6- or 7-)fluoro-2H-benzotriazol-2-ylJpropionyl), 51) sydnonyl(lower)alkanoyl (e.g. 2-(sydnon-3-yl)acetyl and

3-(sydnon-3-yl)propionyl),

52) phthaloyl,

53) lower alkanoylaminobenzenesulfonyl (e.g. 2-(or -3- or -4-)acetamidobenzenesulfonyl and 2-(or -3- or -4-)propionamido-benzenesulfonyl) and 54) phenyl- and halophenoxy-substituted lower alkanoyl (f .ex.

2-phenyl-2-[2-(or -3- or -4-)chlorophenoxy]acetyl and 2-phenyl-2-[2-(or -3- or -4-)bromophenoxy]acetyl).

The term "protected amino" in the context of R 1 and acylamino with a protected amino group for R 1c is, for example, acylamino and amino groups, which are substituted with amino protecting groups other than acyl groups listed above.

The term "protected hydroxy" in the context of acylamino with a protected hydroxy group is e.g. hydroxy, which is protected with the same conventional protecting groups for hydroxy, as indicated above.

lb lb The designation "acylamino" in the context of R , R' acylamino with a protected amino group for R lc , acylamino with amino for R"*"^, acylamino with a protected hydroxy group for R"*"e and acylamino with hydroxy for R ^ , is e.g. the same acylamino groups, which are listed above.

The term "protected carboxy group" in connection with R<2>

and R a is e.g. ester, acid amide and acid anhydride groups.

Suitable esters are e.g. silyl esters, aliphatic esters and

esters containing an aromatic or heterocyclic ring.

Suitable silyl esters are e.g. tri(lower)alkylsilyl esters

(eg trimethylsilyl and triethylsilyl esters).

Suitable aliphatic esters are e.g. saturated or unsaturated, lower or higher alkyl esters, which may be branched, or which may contain a cyclic ring, such as lower or higher aliphatic esters, e.g. lower alkyl esters (e.g. methyl, ethyl, propyl, isopropyl, 1-cyclopropylethyl, butyl and tert.butyl esters),

higher alkyl esters (e.g. octyl, nonyl and undecyl esters), lower alkenyl esters (e.g. vinyl, 1-propenyl, allyl and 3-butenyl esters),

lower alkynyl esters (e.g. 3-butynyl and 4-pentynyl esters),

lower or higher cycloalkyl esters (e.g. cyclopentyl, cyclohexyl and cycloheptyl esters), and lower or higher aliphatic esters containing a nitrogen, sulfur or oxygen atom, e.g. lower alkoxy (lower) alkyl esters (e.g. methoxymethyl-, ethoxyethyl-

r

and methoxyethyl esters), lower alkylthio(lower) alkyl esters (e.g. methylthiomethyl, ethylthioethyl and methylthiopropyl esters), di(lower) alkylaminoesters (e.g. dimethylamino, diethylamino and dipropylaminoesters), lower alkylideneaminoesters (f .eg ethylideneamino, propylideneamino and isopropylideneamino esters) and lower alkylsulfenyl (lower) alkyl esters (eg methylsulfenylmethyl and ethylsulfenylmethyl esters).

Suitable esters containing an aromatic ring are e.g. aryl esters (e.g. phenyl, xylyl, tolyl, naphthyl, indanyl and dihydroanthryl esters), ar(lower)alkyl esters (e.g. benzyl and phenethyl esters), aryloxy(lower)alkyl esters (e.g. phenoxymethyl, phenoxyethyl and phenoxypropyl esters), arylthio(lower)alkyl esters (e.g. phenylthiomethyl, phenylthioethyl and phenylthiopropyl esters), arylsulfenyl (lower)alkyl esters (e.g. phenylsulfenylmethyl and phenylsulfenylethyl esters), aryloxy(lower)alkylesters ( e.g. benzoylmethyl and toluoyl ethyl esters) and -arylamino esters (e.g. phthalimido esters).

Suitable esters containing a heterocyclic ring are e.g. heterocyclic esters and heterocyclic lower alkyl esters.

Suitable heterocyclic esters are e.g. saturated or unsaturated, condensed or uncondensed 3- - 8-membered heterocyclic esters containing 1-4 heteroatoms such as oxygen, sulfur and nitrogen

(eg pyridyl, piperidino, 2-pyridon-1-yl, tetrahydropyranyl, quinolyl and pyrazolyl esters). Suitable heterocyclic lower alkyl esters are e.g. with saturated or unsaturated, condensed or uncondensed .3- - 8-membered heterocyclic groups containing 1-4 heteroatoms such as oxygen, sulfur and nitrogen (e.g. pyridyl, piperidino, 2-pyridon-1-yl, tetrahydropyranyl, quinolyl and pyrazolyl ) substituted lower alkyl esters (e.g. methyl-, ethyl-

and propyl esters).

The silyl esters, the aliphatic esters and the esters containing an aromatic or heterocyclic ring, which are indicated above, may have 1 - 10 suitable substituents such as lower alkyl (eg methyl, ethyl, propyl, isopropyl, butyl, and tert.butyl), lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert.butoxy), lower alkylthio (e.g. methylthio, ethylthio and propylthio), lower alkylsulfinyl (e.g. methylsulfinyl, ethylsulfinyl and propylsulfinyl), lower alkanesulfony1 (e.g. methanesulfony: and ethanesulfonyl), phenylazo, halogen (e.g. chlorine, bromine and fluorine), cyano and nitro, and as examples of this can be cited mono(or di-or rt<r>i) halogeno(lower)alkyl esters (e.g. chloromethyl-, bromomethyl-, dichloromethyl-, 2,2,2-trichloroethyl and 2,2,2-tribromomethyl esters), cyano-(lower)alkyl esters (e.g. cyanomethyl- and cyanoethyl esters), mono (or di-, tri-, tetra- or penta)halophenyl esters (e.g. 4-chlorophenyl-, 3,5-dibromophenyl-, 2,4,5-trichlorophenyl-, 2,4,6- trichlorophenyl and pentachlorophenyl esters e), lower alkanesulfonylphenyl esters (e.g. 4-methanesulfonylphenyl and 2-ethanesulfonylphenyl esters),

2-(or 3- or 4-)phenylazophenyl esters, mono(or di- or tri)-nitrophenyl esters (e.g. 4-nitrophenyl-, 2,4-dinitrophenyl- and 3,4,5-trinitrophenyl esters), mono( or di-, tri-, tetra- or penta)-halophenyl(lower) alkyl esters (e.g. 2-chlorobenzyl-, 2,4-dibromo-benzyl-, 3,4,5-trichlorobenzyl- and pentachlorobenzyl esters), mono (or di- or tri)nitrophenyl (lower) alkyl esters (e.g. 2-nitro-benzyl-, 2,4-dinitrobenzyl- and 3,4,5-trinitrobenzyl esters), mono (or di- or.tri)( lower)Alkoxyphenyl(lower)alkyl esters (e.g. 2-methoxybenzyl-, 3,4-dimethoxybenzyl- and 3,4,5-trimethoxybenzyl-esters), hydroxyesters and di(lower)alkylphenyl(lower)alkylesters (e.g. .3,5-dimethyl-4-hydroxybenzyl- and 3,5-di-tert.butyl-4-hydroxybenzyl esters).

Suitable acid amides are e.g. N-methyl acid amides and N-ethyl acid amides), N,N-di(lower)alkyl acid amides (e.g. N,N-dimethyl acid amides, N,N-diethyl acid amides and N-methyl-N-ethyl acid amides), N-phenyl acid amides or an acid amide with pyrazole, imidazole and 4-lower alkylimidazoles (e.g. 4-methylimidazole and 4-ethylimidazole).

Suitable acid anhydrides are e.g. an acid anhydride with a di(lower)alkyl phosphate (e.g., dimethyl phosphate and diethyl phosphate), dibenzyl phosphate, phosphoric acid halide (e.g., phosphoric acid chloride and phosphoric acid bromide), di(lower)alkyl phosphite (e.g., dimethyl phosphite and diethyl phosphite), sulfuric acid, thiosulphuric acid , sulfuric acid, lower alkyl carbonate (e.g. methyl carbonate and ethyl carbonate), azoimide, hydrohalic acid (e.g. hydrochloric and hydrobromic acid),

saturated or unsaturated lower aliphatic carboxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutanoic acid, crotonic acid, valeric acid and propionic acid), saturated or unsaturated halogen(lower)-aliphatic carboxylic acid (e.g. chloroacetic acid, 3-chloro-2 -pentenoic acid and

3-bromo-2-butenoic acid), substituted lower aliphatic carboxylic acid (e.g. phenylacetic acid, phenoxyacetic acid, furanacetic acid and thiopheneacetic acid), aromatic carboxylic acid (e.g. benzoic acid) or a symmetrical acid anhydride.

3 5 6 The designation "lower alkyl" in connection with R , R and R

r

denotes an alkyl chain, which may be linear, branched or cyclic, and which may contain 1-6 carbon atoms, such as methyl, ethyl,

propyl, isopropyl, butyl, tert.butyl and cyclohexyl.

The term "aryl" in connection with R 4 indicates e.g. phenyl and naphthyl.

In the present description, the term "lower" denotes a carbon chain containing 1-6 carbon atoms, and the term "higher" denotes a carbon chain containing 7-16 carbon atoms, which may be branched or contain a cyclic ring.

The compounds with the general formula I mentioned here can be prepared by reacting a starting compound with the general formula II with a Lewis acid.

Suitable Lewis acids for this reaction are e.g. boron halides (e.g. boron trichloride, boron tribromide and boron trifluoride), titanium halides (e.g. titanium tetrachloride and titanium tetrabromide), zirconium halides (e.g. zirconium tetrachloride and zirconium tetrabromide), tin(IV) halides (e.g. tin (IV) chloride and stannous (IV) bromide), antimony halides (e.g. antimony trichloride and antimony pentachloride), bismuth chloride, aluminum halides (e.g. aluminum chloride and aluminum bromide), zinc chloride, iron (III) chloride, toluenesulfonic acid, polyphosphoric acid ester , sulfuric acid, trichloroacetic acid, trifluoroacetic acid, zinc sulphate and iron (III) sulphate.

The reaction is usually carried out in the presence of a solvent. Suitable solvents for use in the method according to the present invention include any solvent which does not have an adverse influence on the turnover, e.g. methylene chloride, chloroform, benzene, tetrahydrofuran, dimethylformamide and carbon disulfide.

The reaction temperature is not particularly limited, and the reaction can usually be carried out under mild conditions such as during cooling or at room temperature.

In the process according to the present invention, the compound in question with the general formula I is sometimes obtained in the form of a mixture of the 2-cepheme compound and the 3-cepheme compound and/or the 3-cepheme stereoisomers in the 2-position of the cephem ring, and if necessary these can mixtures are resolved using conventional methods such as recrystallization.

The present invention encompasses the cases where the carboxy group is converted to a protected carboxy group, a protected carboxy group is converted to another protected carboxy group or to a free carboxy group, and a protected amino group is converted to a free amino group during the reaction or during treatment after the reaction.

When the compound in question with the general formula I is used in the subsequent step, it can be used before or after isolation and/or purification, i.e. the compound can be used in the form of a mixture of the 2-cephem compound and the 3-cephem compound and/or 3- cephem stereoisomers in the 2-position of the cephem ring.

The compound in question with the general formula I can be prepared by reduction of the compound in question with the general formula ia. The reduction is carried out under such conditions,

0 r

that the group -S- can be converted into the group -S-.

The reduction in this reaction is carried out in the usual way, such as using stannous chloride or a metal thiosulphate (e.g. sodium thiosulphate or potassium thiosulphate) or a combination of

an acid chloride' and the specified tin (II) chloride or metal thiosulphate;

phosphorus trichloride, phosphorus pentachloride, silicon trichloride and the method described in "Japanese patent official gazette" no. 21111/1972 can also be used.

The reaction is usually carried out in a solvent, which does not have an adverse influence on the reaction, e.g. dimethylformamide, acetonitrile, acetic acid ester, tetrahydrofuran, chloroform, methylene chloride or dioxane.

The reaction temperature is not limited, and it can be appropriately selected taking into account the compound of the general formula Ia and the reduction method used in the reaction.

The present invention encompasses the cases where the carboxy group is converted to a protected carboxy group, a protected carboxy group is converted to another protected carboxy group or to a free carboxy group, and a protected amino group is changed to a free amino group during the reaction or after the reaction.

The subject compound of the general formula Ia can be prepared by subjecting the compound of the general formula Ib to an elimination reaction for the protecting group of the amino group, and the subject compound of the general formula Ig can be prepared by subjecting the compound of the general formula If to an elimination reaction for the protecting group for the amino group.

The elimination reaction is carried out in a conventional manner such as by hydrolysis, using an acid, treatment with hydrazine. or reduction. These methods can be selected depending on the nature of the protecting groups to be removed. When the protecting group is an acyl group, it can also be eliminated by treatment with an iminohalogenating agent and then with an iminoesterifying agent, if necessary followed by hydrolysis.

r

The elimination reaction with acid is one of the most used methods for the elimination of protecting groups such as benzyloxycarbonyl, substituted benzyloxycarbonyl, alkoxycarbonyl, substituted alkoxycarbonyl, aralkyloxycarbonyl, adamantyloxycarbonyl, trityl, substituted phenylthio, substituted aralkylidene, substituted alkylidene and substituted cycloalkylidene. Suitable acids are e.g. formic acid, trifluoroacetic acid, benzenesulfonic acid and p-toluenesulfonic acid,

and the most suitable acid is an acid which can be easily distilled off under reduced pressure, e.g. formic acid and trifluoroacetic acid. The acid suitable for the reaction can be chosen taking into account the protecting group to be eliminated and other factors. When the elimination reaction is carried out with acid, it is carried out in the presence or absence of a solvent. Suitable solvents include a hydrophilic organic solvent, water or a mixed solvent thereof. The elimination reaction with hydrazine is usually used to eliminate e.g. phthaloyl. The reduction is usually used to eliminate e.g. trichloroethoxycarbonyl, benzyloxycarbonyl, substituted benzyloxycarbonyl and 2-pyridylmethoxycarbonyl. The reduction applicable to the elimination reaction according to the present invention is e.g. reduction with a metal (eg tin, zinc and iron) or a combination of a metallic compound (eg chromium(II) chloride and chromium(II) acetate)

and an organic or inorganic acid (eg, acetic acid, propionic acid, and hydrochloric acid) and reduction in the presence of a metallic catalyst to catalytic reduction. The metallic catalyst for catalytic reduction is e.g. Raney nickel, platinum oxide, palladium/charcoal and other conventional catalysts.

The trifluoroacetyl protecting group can usually be eliminated by treatment with water in the presence or absence of base, and halogen-substituted alkoxycarbonyl and 8-quinolyloxycarbonyl are usually eliminated by treatment with a heavy metal such as copper and zinc.

When the protecting group is acyl, the acyl group can be eliminated by reaction with an iminohalogenating agent and then with an iminophorethering agent, if necessary followed by hydrolysis.

Suitable iminohalogenating agents are e.g. phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride and phosgene. The reaction temperature for imino-halogenation is not limited, and the reaction proceeds satisfactorily at room temperature or at a lower temperature. Suitable iminophoretic agents, with which the resulting product from the iminohalogenation reaction is reacted, are e.g. an alcohol such as an alkanol (e.g. methanol, ethanol, propanol, isopropanol, butanol and tert.butanol) or a corresponding alkanol with alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy and butoxy) as substituent or substituents in the alkyl group and a metal alkoxide such as an alkali metal alkoxide (e.g. sodium alkoxide and potassium alkoxide)

or alkaline earth metal alkoxide (eg, calcium alkoxide and barium alkoxide), each of which is derived from the alcohol. The reaction temperature for the iminophoresis is not limited either, and the reaction proceeds satisfactorily at room temperature or at a lower temperature. The reaction product thus obtained can, if necessary,

Hydrolysis proceeds satisfactorily by pouring the reaction mixture into water or a mixture of water and a hydrophilic solvent such as methanol or ethanol. During the hydrolysis, the water may contain a base such as an alkali metal bicarbonate or a trialkylamine or an acid such as dilute hydrochloric acid or acetic acid. When the protecting group is acyl, the acyl group can also be eliminated by hydrolysis as indicated above or using another conventional hydrolysis method.

The reaction temperature is not limited and can be suitably chosen taking into account the protecting group for the amino group and the above-mentioned elimination reaction, and the reaction is preferably carried out under mild conditions such as during cooling or by slight heating.

The present invention covers the cases where a protected carboxy group is converted into another protected carboxy group or into a free carboxy group during the reaction or after the reaction.

They thus produced connections with the general

formula Ic and lg. can, using a conventional method, if necessary, be converted into a desired acid addition salt thereof.

The compounds in question with the general formula Id

can be prepared by reacting the compound of the general formula Icells a salt thereof with an acylating agent.

Suitable salts of the compound with the general formula Ia are e.g. organic acid salts (eg acetates, maleates, tartrates, benzene sulphonates and toluene sulphonates) and inorganic acid salts (eg hydrochlorides, sulphates and phosphates).

As examples of acylating agents for the reaction, an aliphatic, aromatic and heterocyclic carboxylic acid and a corresponding sulphonic acid, carboxylic acid esters, carbamic acid and thioic acid and reactive derivatives of the above-mentioned acids can be mentioned.

Examples of reactive derivatives include an acid anhydride, an activated amide, an activated ester, an isocyanate and an isothiocyanate, and examples of this include an acid azide, a mixed acid anhydride with an acid such as a dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid , a halogenated phosphoric acid, a dialkyl phosphoric acid, sulfuric acid, thiosulphuric acid,

a hydrohalic acid (e.g. hydrochloric acid), sulfuric acid, a mono-alkyl carbonate, an aliphatic carboxylic acid (e.g. acetic acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid and trichloroacetic acid), an aromatic carboxylic acid (e.g. benzoic acid) , or a symmetrical acid anhydride, an acid amide with pyrazole, imidazole, a 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole, an ester (e.g. cyanomethyl ester, methoxymethyl ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentacldrphenyl ester, methanesulfonyl phenyl ester, phenyl azophenyl ester, phenyl thio ester, p-nitrophenyl thio ester, p-cresyl thio ester, carboxymethyl thio ester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thio ester or an ester with N,N-dimethylhydroxylamine, l-hydroxy-2-( 1H)-pyridone, N-hydroxysuccinimide or N-hydroxyphthalimide).

The reactive derivatives listed above have been chosen taking into account the nature of the acid used. In the acylation reaction, when free acid is used, a condensing agent such as N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4-diethylamino-cyclohexyl)-carbodiimide, N-cyclohexyl-N'-(4-diethylamino-cyclohexyl)-carbodiimide, N ,N<1->diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, N,N'-carbonyldi-(2-methylimidazole), pentamethylketene-N-cyclohexylimide, diphenylketene-N-cyclohexylimine, Alkoxyacetylene, 1-Alkoxyl-1-chloroethylene, trialkylphosphite, ethyl polyphosphate, isopropylpolyphosphate, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine, 2-ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5-

(m-sulfophenyl)isoxazolium hydroxide intramolecular salt, (chloromethylene)dimethylammonium chloride, 2,2,4,4,6,6-hexachloro-2,2,4,4,6,6-hexahydro-1,3,5 ,2,4,6-triazatriphosphorine or a mixed condensing agent such as triphenylphosphine and a carbon tetrahalide (e.g. carbon tetrachloride and carbon tetrabromide) or a halogen

r

(e.g. chlorine and bromine).

As examples of an acyl group, which can be introduced into the amino group in connection with the formula Ie using the above-

for specified acylating agents, a group dehydroxylated from an aliphatic, aromatic or heterocyclic carboxylic acid and the corresponding sulfonic acid, carboxylic acid ester, carbamic acid or thio acid may be specified, and specified more precisely, the acyl group may be the same acyl group as specified for the acyl group in the acylamino group in context with R"<*>".

The acylation is usually carried out in a solvent, which does not have an adverse influence on the turnover, e.g. water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethane dichloride, tetrahydrofuran, ethyl acetate, dimethylformamide and pyridine, and the above-mentioned hydrophilic solvent together with water can be used as a mixed solvent.

The acylation can be carried out in the presence of a base such as an inorganic base (eg an alkali metal hydrogen carbonate) and an organic base such as a trialkylamine (eg trimethylamine, triethylamine and tributylamine), N-methylmorpholine, N-methylpiperidine, N,N -dialkylaniline (e.g. N,N-dimethylaniline and N,N-diethylaniline), N,N-dialkylbenzylamine (e.g. N,N-dimethylbenzylamine and N,N-diethylbenzylamine), pyridine, picoline, lutidine, 1,5-diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2,2,2joctane and 1,8-diazabicyclo[5,4,0]undecene-7.

During the turnover, it can also be used as a solvent

a liquid base or a liquid condensing agent.

The reaction temperature is not limited, and the reaction can be carried out under cooling or at room temperature.

The present invention covers the cases where a free carboxy group is converted into a protected carboxy group, and. a protected carboxy group is converted to another protected carboxy group or to a free carboxy group During the reaction or after the reaction.

The subject compound of the general formula le can be prepared by reacting the compound of the general formula Id with a trialkyloxonium haloborate or an iminohalogenating agent and an iminophorethering agent, and then reacting the resulting compound with an acylating agent, if necessary followed by hydrolysis.

Suitable trialkyloxonium haloborates are e.g. trimethyloxonium chloroborate, trimethyloxonium fluoroborate and triethyloxonium fluoroborate.

Suitable iminohalogenating agents are e.g. phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride and phosgene.

Suitable iminophoretic agents, with which the product obtained from the imino-halogenation is reacted, are e.g. an alcohol such as an alkanol (e.g. methanol, ethanol, propanol, isopropanol, butanol and tert.butanol) or a corresponding alkanol with alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy and butoxy) as substituent or substituents at the alkyl group and a metal alkoxide such as an alkali metal alkoxide (eg sodium alkoxide and potassium alkoxide) or an alkaline earth metal alkoxide (eg calcium alkoxide and barium alkoxide), which is derived from such an alcohol.

These reactions are usually carried out in a solvent, which does not have an adverse influence on the reactions, e.g. chloroform, methylene chloride, tetrahydrofuran and dioxane.

The reaction temperature is not particularly limited, and the reactions are often carried out at room temperature or during cooling.

The acylation reaction can be carried out under similar conditions as described for the acylation of the compound of the general formula Ic.

The reaction product thus obtained is hydrolysed if necessary.

The hydrolysis proceeds satisfactorily by pouring the reaction mixture into water or a mixture of water and a hydrophilic solvent such as methanol and ethanol. During the hydrolysis, the water may contain a base such as an alkali metal hydrogen carbonate or a trialkylamine or an acid such as dilute hydrochloric acid or acetic acid.

In the reactions indicated above, the acylamino group R lb in the compound with the general formula Id is converted into another acylamino group R' lb in the compound with the general formula le which is derived from the acylating agent.

The present invention includes those cases where a

free carboxy group is converted into a protected carboxy group, and a protected carboxy group is converted into another protected carboxy group or into a free carboxy group during the reactions or after the reactions.

r

The subject compound of the general formula li

can be prepared by subjecting the compound of the general formula Ih to the elimination reaction of the protecting group of the hydroxy group.

The elimination reaction is carried out in a conventional manner such as using an acid or a base or by reduction.

These methods are chosen depending on the nature of the protecting groups that are to be eliminated. The elimination reaction with acid is one of the most frequently used methods for eliminating protecting groups such as benzyloxycarbonyl, substituted benzyloxycarbonyl, alkoxycarbonyl, substituted alkoxycarbonyl, aralkyloxycarbonyl, adamantyloxycarbonyl, trityl and substituted phenylthio. Suitable acids are e.g. formic acid, trifluoroacetic acid, benzenesulfonic acid and p-toluenesulfonic acid, and a particularly suitable acid is an acid which can easily be distilled off under reduced pressure, e.g. formic acid and trifluoroacetic acid. The acid suitable for turnover can be selected taking into account the protecting group to be eliminated and other factors. The elimination reaction with acid can be carried out in the presence of a solvent such as a hydrophilic organic solvent, water or a mixed solvent thereof.

The elimination reaction with base is used for elimination

of an acyl group. Suitable bases are e.g. an inorganic base such as an alkali metal (e.g. sodium or potassium), an alkaline earth metal (e.g. magnesium and calcium), a hydroxide, carbonate or bicarbonate thereof or an organic base such as a trialkylamine (e.g. trimethylamine. and triethylamine), picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2,2,2]-octane and 1,8- diazabicyclo[5,4,0]undecene-7. The elimination reaction with base is often carried out in water or a hydrophilic organic solvent or a mixed solvent thereof.

The reduction is usually used when eliminating e.g. trichloroethoxycarbonyl, benzyloxycarbonyl, substituted benzyloxycarbonyl and 2-pyridylmethoxycarbonyl.

A reduction method that can be used for the elimination reaction according to the present invention is, e.g. reduction using a metal (e.g. tin, zinc and iron) or a combination of a metallic compound (e.g. chromium(II) chloride and chromium(II) acetate) and an organic or inorganic acid (e.g. eg acetic acid, propionic acid and hydrochloric acid) and reduction in the presence of a metallic catalyst to catalytic reduction. A metallic catalyst for catalytic reduction is e.g. Raney nickel, platinum oxide, palladium/charcoal and other conventional catalysts. The protecting group trifluoroacety1 can usually be eliminated by treatment with water in the presence or absence of base, and halogen-substituted alkoxycarbonyl and 8-quinolyloxycarbonyl can usually be eliminated by treatment with a heavy metal such as copper and zinc.

When the protecting group is trifluoroacetyl, it can be eliminated by treatment with water or water in the presence of a base, and when the protecting group is halogen-substituted alkoxycarbonyl or 8-quinolyloxycarbonyl, it can be eliminated by treatment with a heavy metal such as copper and lead.

When the protecting group is acyl, the acyl group can be eliminated using the above-described hydrolysis or by another conventional hydrolysis.

The reaction temperature is not limited and can be suitably chosen taking into account the protecting group for the hydroxy group and the elimination method, and the reaction is preferably carried out under mild conditions such as during cooling or by slight heating.

The present invention covers the cases where a protected carboxy group is converted into another protected carboxy group or into a free carboxy group during the reaction or after the reaction.

The present invention also covers those cases where the compound of the general formula Ih further carries one or more protected amino groups, protected carboxy groups and/or protected mercapto groups in the acylamino group in the 7-position of the cephem ring, and these groups are converted into corresponding free groups during the reaction.

The subject compound of the general formula Ik can be prepared by subjecting the compound of the general formula Ij to the elimination reaction of the protecting group of the carboxy group.

In the elimination reaction, all conventional methods for elimination reactions can be used, all conventional methods used for the elimination of carboxy protecting groups, e.g. reduction and hydrolysis. When the protected group is an active ester, an active amide or an acid anhydride, they can be eliminated by hydrolysis, usually under mild hydrolysis conditions such as the use of water. Reduction can be used to eliminate e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester and benzyl ester. The elimination reaction with an acid can be used to eliminate protecting groups from compounds such as p-methoxybenzyl esters, tert-butyl esters, tert-pentyl esters, trityl esters, diphenylmethyl esters, bis(methoxyphenyl)methyl esters, 3,4-dimethoxybenzyl esters and 1-cyclopropyl ethyl esters. The elimination reaction with an anhydrous basic catalyst can be used to eliminate protecting groups from compounds such as ethynyl esters and 4-hydroxy-3,5-di-(tert.butyl)benzyl esters. The reduction, which can be used for the elimination reaction according to the present invention, is e.g. reduction using a combination of a metal (e.g. zinc and zinc amalgam) or a chromium salt compound (e.g. chromium(II) chloride and chromium(II) acetate) and an organic or inorganic acid (e.g. acetic acid, propionic acid and hydrochloric acid), and reduction in the presence of a metallic catalyst. The metallic catalysts for catalytic reduction are e.g. platinum catalysts (e.g. platinum wire, platinum sponge, platinum black and colloidal platinum), palladium catalysts (e.g. palladium sponge, palladium black, palladium oxide, palladium on barium sulphate, palladium on barium carbonate, palladium on charcoal, palladium on silica gel and colloidal palladium) and nickel catalysts (e.g. eg reduced nickel, nickel oxide, Raney nickel and Urushibara nickel). Suitable acids for use in the elimination reaction are e.g. formic acid, trihaloacetic acids (eg trichloroacetic acid and trifluoroacetic acid), hydrochloric acid, hydrofluoric acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid and mixtures of hydrochloric acid and acetic acid. Suitable anhydrous basic catalysts for the elimination reaction are e.g. sodium thiophenolate and (CH^)2LiCu. When the protecting group is eliminated by treatment with water or a liquid acid, the reaction can be carried out without a solvent.

In this reaction, any solvent can be used, which does not have an adverse effect on the reaction, e.g. dimethylformamide, methylene chloride, chloroform, tetrahydrofuran, acetone, methanol and ethanol.

The reaction temperature is not particularly limited, and it is appropriately chosen taking into account the starting compound and the elimination method used.

The present invention covers the cases where a protected carboxy group, hydroxy group, mercapto group or amino group, which is found in the starting compound, is converted into a free carboxy group, hydroxy group, mercapto group or amino group, respectively. during the turnover or after the turnover. The thus obtained compound with the general formula Ik can, if necessary, be converted into a desired metal salt thereof (e.g. sodium

and potassium salt) or an organic base salt thereof.

The compound in question with the general formula Im can be prepared by reacting the compound with the general formula II or a salt thereof with a lower alkanone of the general formula R^-CO-R^, where R^ and R^ each denote lower alkyl.

Suitable salts of the compound of the general formula II

is e.g. organic acid salts (e.g. acetates, maleates,

tartrates, benzenesulphonates and toluenesulphonates) and inorganic acid salts (e.g. hydrochlorides, sulphates and phosphates).

Suitable lower alkanones with the general formula R 5 -CO-R 6 are e.g. acetone, 2-butanone, 2-pentanone and 3-hexanone.

The turnover can preferably be carried out in the presence of a base, e.g. an inorganic base such as an alkali metal (eg lithium, sodium and potassium) and an alkaline earth metal (eg magnesium and calcium) and a corresponding hydroxide, carbonate or bicarbonate and an organic base such as a tertiary amine (eg . trimethylamine, triethylamine, . ,0]non-5-ene, 1,4-diazabicyclo[2,2,2]octane and 1,8-diazabicyclo[5,4,0]undecene-7) and a quaternary ammonium hydroxide compound.

The reaction can be carried out with or without a solvent.

Suitable solvents are e.g. solvents that do not have an adverse effect on turnover, e.g. dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, tetramethylurea, tetrahydrofuran, methylene chloride, dioxane, glyme, diglyme, acetonitrile and phosphate buffers. The reaction temperature is not particularly limited,

and the turnover proceeds satisfactorily at room temperature or during cooling and can be accelerated by heating.

The present invention covers the cases where a free carboxy group is converted into a protected carboxy group, and a protected carboxy group is converted into another protected carboxy group or into a free carboxy group during the reaction or after the reaction.

The compound in question with the general formula Im can be converted into a desired acid salt, e.g. an organic acid salt (e.g. acetate, maleate, tartrate, benzenesulfonate and toluenesulfonate) and a

r

inorganic acid salt (e.g. hydrochloride, sulphate and phosphate).

The present invention encompasses the cases where the 2-cephem compound, the 3-cephem compound and 3-cephem stereoisomers in the 2-position in the 3-cephem ring are sometimes converted during one of the above-mentioned reactions by an alternative method or after the reaction.

When the subject compound of the general formula I has one or more free carboxy groups, it can be converted into a metal salt (e.g. sodium, potassium and magnesium salt) or an organic amine salt (e.g. . methylamine, diethylamine, trimethylamine, triethylamine, aniline, pyridine, picoline and N,N'-dibenzylethylenediamine salt), and when the compound in question with the general formula I has one or more free amino groups, it can be used by a conventional method is converted to an inorganic acid salt (e.g. hydrochloride and sulfate) or an organic acid salt (e.g. acetate, maleate and tartrate).

The compounds of formula I produced by the method according to the present invention have antimicrobial action against various pathogenic microorganisms and can be used for the treatment of diseases caused by such microorganisms in humans and animals.

The antimicrobial activity of some representative compounds prepared by the method of the present invention is listed below. The MIC values (µg/ml) against Staphylococcus aureus 209-P JC-1 and Bacillus subtilis ATCC-66 33 for compounds of the general formula I are given below.

Procedure for the determination of antimicrobial activity

in vitro:

The antimicrobial activity in vitro is determined by it

double agar plate dilution procedure described below.

A thread full of a culture, which has grown overnight,

of each test strain in Trypticase soy nutrient fluid (10 p viable cells per ml) is plated on heart infusion agar (HI agar) containing graded concentrations of antibiotics, and the

minimal inhibitory concentration (MIC) is given in ug/ml after incubation at 37°C for 20 hours. 1) 2-methyl-7-[N-[2-(1,3,4-thiadiazol-2-ylthio)acetyl]phenylglycyl]-amino-3-cephem-4-carboxylic acid, Staphylococcus aureus: 1.56 Bacillus subtilis : 3.13 2) 2-methyl-7-[2-hydroxy-2-(2-thienyl)acetamido]-3-cephem-4-carboxylic acid,

Staphylococcus aureus: 0.78; Bacillus subtilis: 0.78

3) 2-methyl-7-[2-(5-indanyloxy)carbonyl-2-phenylacetamido]-3-cephem-4-carboxylic acid,

Staphylococcus aureus: 1.56; Bacillus subtilis: 6.25.

4) 2-methyl-7-(2-isonicotinoyloxy-2-phenylacetamido)-3-cephem-4-carboxylic acid,

Staphylococcus aureus: 0.39; Bacillus subtilis: 0.78.

5) 2-methyl-7-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylic acid, Staphylococcus aureus: 0.78; Bacillus subtilis: 0.39 6) 2-methyl-7-[2-(3-chlorophenyl)acetamido]-3-cephem-4-carboxylic acid, Staphylococcus aureus: 0.1; Bacillus subtilis: 0.2. 7) 2-methyl-7-(2-hydroxy-2-phenylacetamido)-3-cephem-4-carboxylic acid, Staphylococcus aureus: 0.78; Bacillus subtilis: 0.39 8) 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid, Staphylococcus aureus: 0.78; Bacillus subtilis: 0.2. 9) 2-methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylic acid, Staphylococcus aureus: 0.2; Bacillus subtilis: 0.2. 10) 2-methyl-7-(2-azido-2-phenylacetamido)-3-cephem-4-carboxylic acid, Staphylococcus aureus: 1.56; Bacillus subtilis: 0.39. 11) 2-methyl-7-[2-(1,3,4-thiadiazol-2-ylthio)acetamido]-3-cephem-4-carboxylic acid,

Staphylococcus aureus: 1.56; Bacillus subtilis: 0.78.

12) 2-methyl-7-[2-(1,2,5-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylic acid,

Staphylococcus aureus: 3.13; Bacillus subtilis: 1.56.

13) 2-methyl-7-(2-cyanoacetamido)-3-cephem-4-carboxylic acid, Staphylococcus aureus: 3.13; Bacillus subtilis: 3.13 14) 2-methyl-7-[2-(allylthio)acetamido]-3-cephem-4-carboxylic acid, Staphylococcus aureus: 1.56; Bacillus subtilis: 1.56. 15) ,2-methyl-7-[2-(3-pyridyl)acetamido]-3-cephem-4-carboxylic acid, Staphylococcus aureus: 3.13; Bacillus subtilis: 0.78. 16) 2*-methyl-7-[2-amino-2-(methylthiophenyl)acetamido]-3-cephem-4-carboxylic acid,

Staphylococcus aureus: 3.13; Bacillus subtilis: 6.25.

The compounds of the general formula I produced by the method according to the present invention can be formulated for administration in any conventional way in analogy with other antibiotic substances.

Thus, a preparation containing a compound of the general formula I can be used in the form of pharmaceutical preparations, e.g. in solid, semi-solid or liquid form, containing the active compound of the general formula I in admixture with a pharmaceutical or inorganic carrier or excipient, suitable for external or parenteral use. The active ingredient can e.g. are compounded with usual carriers for tablets, pills, capsules, suppositories, solutions, emulsions, aqueous suspensions or other suitable forms. Glucose, lactose, acacia gum, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silicon dioxide, potato starch, urea and other carriers can be used as carriers.

which are usually used for the production of preparations in solid, semi-solid or liquid form, and the preparations may further contain excipients, stabilizers, thickeners and colourings. The preparations may also contain preservatives or bacteriostatic agents, whereby the active substances in the preparations retain their activity.

Compounds of the general formula I are used in the preparations in an amount sufficient to induce the desired therapeutic effect on the bacterially infected process or condition.

Since the dosage or the therapeutically effective amount of the compound varies and also depends on the age and condition of each patient being treated, for the treatment of diseases against which the compound of the general formula I is active, a daily dose of about 0.5 - 6 g of the active ingredient per day, preferably 1 - 2 g per day and night.

The method according to the invention is explained in more detail by the following examples:

Reaction:

Example 1 a

A solution of 3.4 g of aluminum bromide in 20 ml of dry dichloromethane is added dropwise at -10°C over 10 minutes to a solution of 4.6 g of 2-methyl-2,3-methylene-6-(2-phenylacetamido) -penam-3-carboxylic acid-2,2,2-trichloroethyl ester in 30 ml of dry dichloromethane. After the addition, the reaction mixture is stirred for 4.5 hours at room temperature and washed three times with 30 ml of 2% hydrochloric acid with a saturated aqueous sodium bicarbonate solution and with a saturated aqueous sodium chloride solution in the specified order. After drying over magnesium sulfate, the solvent is distilled off, and the residue is washed with ether and collected by filtration, whereby 3.3 g of 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid-2,2,2- trichloroethyl ester. The compound is recrystallized from ethanol,

whereby crystals with a melting point of 175-178°C are obtained.

Example 2 a

A solution of 0.4 g of aluminum bromide in 5 ml of dry dichloromethane is added dropwise under ice-cooling to a suspension of 0.46 g of 2-methyl-2,3-methylene-6-{2-(1H-tetrazol-1-yl)acetamido }penam-3-carboxylic acid-2,2,2-trichloroethyl ester in 10 ml of dry dichloromethane. After stirring for 4 hours at room temperature, the reaction mixture is washed three times with 2% hydrochloric acid, with a saturated aqueous sodium bicarbonate solution and with a saturated aqueous sodium chloride solution in the specified order and is then dried over magnesium sulfate. After drying, the solvent is distilled off, and the residue is crystallized from ethanol, whereby 0.24 g of 2-methyl-7-{2-(1H-tetrazol-1-yl)acetamido}-3-cephem-4-carboxylic acid-2,2 ,2-trichloroethyl ester with melting point 168-170°C.

Example 3a

0.19 g of titanium tetrachloride is added to a solution of 0.46 g of 2-methyl-2,3-methylene-6-(2-phenylacetamido)penam-3-carboxylic acid-2,2,2-trichloroethyl ester in 5 ml of dry dichloromethane, and the mixture is stirred. for 2.5 hours. After the reaction, the reaction mixture is washed three times with 2% hydrochloric acid, with a saturated aqueous sodium hydrogen carbonate solution and with a saturated aqueous sodium chloride solution in the specified order and is then dried over magnesium sulfate. After distilling off the solvent, the residue (0.43 g) is purified by column chromatography on 10 g of silica gel using chloroform as developing agent, whereby 0.1 g of 2-methyl-7-(2-phenylacetamido)-2-cephem-4- carboxylic acid 2,2,2-trichloroethyl ester with melting point 136-137°C.

Example 4 a

2.66 g of aluminum chloride are added under ice-cooling to a solution of 9.2 g of 2-methyl-2,3-methylene-6-(2-phenylacetamido)penam-3-carboxylic acid-2,2,2-trichloroethyl ester in 100 ml of dry dichloromethane,

and the mixture is stirred for 7 hours at room temperature. After the reaction, the reaction mixture is washed three times with 2% hydrochloric acid, with a saturated aqueous sodium bicarbonate solution and with a saturated aqueous sodium chloride solution in the specified order and is then dried over magnesium sulfate. After drying, the solvent is distilled off, and the residue is purified using column chromatography on 200 g of silica gel using chloroform as developing agent, whereby 2.4 g of 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid is obtained 2,2,2-trichloroethyl ester with melting point 175-178°C.

Example 5 a

A solution of 0.58 g of 2-methyl-2,3-methylene-6-(benzyloxycarboxamido)penam-3-carboxylic acid-2,2,2-trichloroethyl ester in 10 ml of dry dichloromethane is added dropwise at a temperature between -15 and

-12°C to a solution of 0.5 g of aluminum bromide in 10 ml of dry dichloromethane, and the mixture is stirred for 20 minutes at the same temperature and then for 1.5 hours at room temperature. After the reaction, the reaction mixture is washed with 5% hydrochloric acid, with water, with 5% aqueous sodium bicarbonate solution and with water in the specified order and dried, and the solvent is distilled off, whereby an oily product is obtained. The oily product dissolves in

ethanol and allowed to stand, after which precipitated crystals are collected by filtration and dried, whereby 2-methyl-7-benzyloxycarboxamido-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 143-144°C is obtained.

Example 6 a

A solution of 3.4 g of 2-methyl-2,3-methylene-6-[2-(3-chlorophenyl)acetamido]penam-3-carboxylic acid-2,2,2-trichloroethyl ester in 50 ml of dry dichloromethane is added dropwise at -15°C to a solution of 2.8 g of aluminum bromide in 20 ml of dry dichloromethane, and the mixture is stirred for 3 hours at room temperature. After the reaction, the reaction mixture is washed with 5% hydrochloric acid, with water, with 5% aqueous sodium bicarbonate solution and with water in the specified order and is then dried. After distilling off the solvent, the residue is crystallized from ether, whereby 2.9 g of 2-methyl-7-[2-(3-chlorophenyl)acetamido]-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 144-145.5°C (decomposition).

Example 7 a

A solution of 1.74 g of 2-methyl-2,3-methylene-6-[2-(2-thienyl)-acetamido]penam-3-carboxylic acid-2,2,2-trichloroethyl ester in 20 ml of dry dichloromethane is added dropwise at -15°C to a solution of 2.14 g of aluminum bromide in 10 ml of dry dichloromethane, and the mixture is stirred for 4 hours at room temperature. After the reaction, the reaction mixture is washed with 5% hydrochloric acid, with water, with 5% aqueous sodium bicarbonate solution and with water in the specified order and is then dried. After distilling off the solvent, the resulting powder is recrystallized from ethanol, whereby 1.46 g of 2-methyl-7-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylic acid-2,2,2-- trichloroethyl ester with melting point 161-162°C (decomposition).

Example 8 a

A solution of 16.5 g of 2-methyl-2,3-methylene-6-[2-(1,2,5-thiadiazol-3-yl)acetamido]penam-3-carboxylic acid 2,2,2-trichloroethyl ester in 100 ml of dry dichloromethane is added drop by drop below -10°C to a solution of 17.5 g of aluminum bromide in 100 ml of dichloromethane. The mixture is then stirred for 2 hours at a temperature below 0°C and further stirred for 2 hours at room temperature. After the reaction, the reaction mixture is washed twice with 100 ml of 2% hydrochloric acid, with a saturated aqueous sodium hydrogen carbonate solution and with a saturated aqueous sodium chloride solution in the specified order and is then dried over magnesium sulfate. After drying, the solvent is distilled off, which gives 13.2 g of powdered 2-methyl-7-[2-(1,2,5-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylic acid-2,2, 2-trichloroethyl ester with melting point 180-185°C (decomposition).

■ r

Example 9 a

A solution of 2.1 g of 2-methyl-2,3-methylene-6-(2-phenoxyacetamido)-penam-3-carboxylic acid methyl ester in 11 ml of dry dichloromethane is added dropwise over the course of 8 minutes at -10°C to a solution of 2.32 g of aluminum bromide in 23 ml of dry dichloromethane, and the reaction temperature is raised little by little to room temperature, after which the mixture is stirred for 4.4 hours at room temperature. After the reaction, the reaction mixture is poured into 150 ml of ice water, and the dichloromethane phase is separated, after which the aqueous phase is extracted once with chloroform. The combined dichloromethane and chloroform extract is washed with water, with 2% hydrochloric acid, with water, with a dilute aqueous sodium bicarbonate solution and with water in the order indicated and then dried over magnesium sulfate. After distilling off the solvent, the yellow oil produced is purified by column chromatography on 15 g of silica gel using chloroform as a developing agent, whereby 0.7 g of 2-methyl-7-(2-phenoxyacetamido)-3-cephem-4- carboxylic acid methyl ester in the form of an orange oil with IR absorption spectrum (chloroform): 3400, 1785, 1726 and 1689 cm"<1>.

Example 10 a

A solution of 1.39 g of 2-methyl-2,3-methylene-6-(2-phenoxyacetamido)penam-3-carboxylic acid-2,2,2-trichloroethyl ester in 7 ml of dry dichloromethane is added dropwise over 10 minutes at -10°C to a solution of 1.16 g of aluminum bromide in 12 ml of dry dichloromethane, and the reaction temperature is raised little by little to room temperature, after which the mixture is stirred for 4 hours at room temperature. After the reaction, the reaction mixture is poured into 70 ml of ice water, and the dichloromethane phase is separated, after which the aqueous phase is extracted once with chloroform. The combined dichloromethane and chloroform phase is washed with water, with 2% hydrochloric acid, with water, with a dilute aqueous sodium bicarbonate solution and with water in the order indicated and then dried over magnesium sulfate. After distilling off the solvent, the product is recrystallized

light brown oil (1.2 g) by adding ether and a small amount of isopropyl ether. The crystals are collected by filtration, after which they are washed with isopropyl ether and recrystallized from a mixture of benzene and isopropyl ether (1:3), whereby 0.9 g of 2-methyl-7-(2-phenoxyacetamido)-3-cephem-4- carboxylic acid 2,2,2-trichloroethyl ester in the form of colorless granules with a melting point of 118-120 oC.

Example 11 a

A solution of 0.9.2 g of 2-methyl-2,3-methylene-6-(2-phenyl-acetamido)-penam-3-carboxylic acid-2,2,2-trichloroethyl ester in 5 ml

dry dichloromethane is added dropwise at -10°Ci during approx. 5 minutes to a solution of 0.8 g of aluminum bromide in 10 ml of dry dichloromethane, and the mixture is stirred for 2 hours at room temperature. The reaction mixture is washed, after the reaction has ended, with 2% hydrochloric acid, with an aqueous sodium bicarbonate solution and with a saturated aqueous sodium chloride solution in the order indicated and then dried over magnesium sulfate, after which the solvent is distilled off under reduced pressure. The resulting crystals are washed with ether and dried, whereby 0.74 g of 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 175-178°C is obtained . The residue obtained by concentrating the ether washing solution is purified by column chromatography on silica gel, whereby 0.05 g of 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 118-120°C, which is a stereoisomer in the 2-position of the previously prepared 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 175- 178°C and 0.05 g

2-methyl-7-(2-phenylacetamido)-2-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 136-137°C. The produced 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 118-120°C is recrystallized from benzene, whereby crystals with melting point 120-123° are obtained C.

Example 12 a

A solution of 1.7 g of aluminum bromide in 40 ml of carbon disulfide is added dropwise with stirring at room temperature to a suspension of 0.66 g of 2-methyl-2,3-methylene-6-(2-phenylacetamido)penam-3-carboxylic acid in 70 ml of carbon disulfide, and the mixture is stirred for 20 hours at the same temperature. After the reaction has ended, the reaction mixture is poured into 200 ml of 5% hydrochloric acid, and the hydrochloric acid phase is separated and then extracted with ethyl acetate. The extract is washed with water and dried, after which the solvent is distilled off. The residue is recrystallized from acetonitrile, whereby 0.33 g of 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid with melting point 109°C (decomposition) is obtained. \

The following compounds are produced during use

of one with the method in the examples "la-12a analogous method.

1) 2-methyl-7-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]amino-3-cephem-4-carboxylic acid with melting point 168-169°C. 2) 2-methyl-7-[2-(1H-tetrazol-1-yl)acetamido]-3-cephem-4-carboxylic acid with melting point 202-203°C (decomposition). 3) 2-methyl-7-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylic acid with melting point 175°C (decomposition). 4) 2-methyl-7-benzyloxycarboxamido-3-cephem-4-carboxylic acid with melting point 167-169°C (decomposition). 5) 2-methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylic acid with melting point 168-171°C (decomposition). 6 ) 2-methyl-7-[2-.(3-chlorophenyl)acetamido]-3-cephem-4-carboxylic acid with melting point 173-174°C (decomposition). 7) 2-methyl-7-[3-(N-tert.butoxycarbonylamino)-3-(2-thienyl)propion-amido]-3-cephem-4-carboxylic acid with melting point 167-170°C (decomposition) .. 8) 2-methyl-7-(2-cyanoacetamido)-3-cephem-4-carboxylic acid with melting point 162-166°C. 9) 2-methyl-7-(3-phenylureido)-3-cephem-4-carboxylic acid with melting point 148-151°C. 10) 2-methyl-7-[2-(1,3,4-thiadiazol-2-ylthio)acetamido]-3-cephem-4-carboxylic acid with melting point 197-199°C. 11) 2-methyl-7-[N-tert.butoxycarbonyl-2-(2-thienyl)glycyl]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 with melting point 113-116°C. 13) 2-methyl-7-[3-(2-chlorophenyl)-5-methylisoxazol-4-yl]carboxamido-3-cephem-4-carboxylic acid with melting point 202-203°C. 14) 2-methyl-7-(2-methylthioacetamido)-3-cephem-4-carboxylic acid with melting point 181-183°C (decomposition). 15) 2-methyl 1-7-(2-allylthioacetamido)-3-cef em-4-carboxylic acid with melting point 121-123°C. 16) 2-methyl-7-(2-formyloxy-2-phenylacetamido)-3-cephem-4-carboxylic acid, powder. 17) 2«-methyl 1-7-(1-cyclopropylethoxy)carboxamido-3-ce f em-4-carboxylic acid with melting point 158.5-160°C (decomposition). 18) 2-methyl-7-[N-(1-cyclopropylethoxy)carbonyl phenylglycyl]amino-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 165-167.5°C. 19) 2-methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 140-142°C. 20) 2-methyl-7-[3-(N-tert.butoxycarbonylamino)-3-(2-thienyl)propion-amido]-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 18 8 -192°C. 21) 2-methyl-7-(2-cyanoacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 160-165°C (decomposition). 22) 2-methyl-7-(3-phenylureido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 172-174°C. 23) 2-methyl-7-[2-(1,3,4-thiadiazol-2-ylthio)acetamido]-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 130-140°C ( cleavage). 24) 2-methyl-7-[N-tert.butoxycarbonyl-2-(2-thienyl)glycyl]amino-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester, powder. 25) 2-methyl-7-[2-(5-methyl-1,3,4-thiadiazol-2-yloxy)acetamido]-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester, amorphous. 26) 2-methyl-7-[3-(2-chlorophenyl)-5-methylisoxazol-4-yl]carboxamido-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester, amorphous. 27) 2-methyl-7-(2-methylthioacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 151-153°C. 28) 2-methyl-7-(2-allylthioacetamido)-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 96°C. 29) 2-methyl-7-(2-formyloxy-2-phenylacetamido)-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester, powder. 30) 2-methyl-7-(1-cyclopropylethoxy)carboxamido-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester, colorless powder. 31) 2-methyl,1-7- [N-tert. butoxycarbonyl-2-(4-hydroxyphenyl)-D-glycyl]amino-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 130-135°C (decomposition). 32) 2-methyl-7-[N-tert.butoxycarbonyl-2-(4-methylthiophenyl)glycyl]-amino;-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 115-120° C. 33) 2-methyl-7-[N-tert.butoxycarbonyl-2-(4-methoxyphenyl)glycyl]-amino-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 92-95°C ( cleavage). 34) 2-methyl-7-[N-tert.butoxycarbonyl-2-(2,5-dihydrophenyl)glycyl]-amino-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 104-111° C (cleavage). 35) 2-methyl-7-(2-sulfo-2-phenylacetamido)-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 150°C (decomposition). 36) 2-methyl-7-[N-(1-cyclopropylethoxy)carbonyl-2-(5,6-dihydro-2H-pyran-3-yl)glycyl]amino-3-cephem-4-carboxylic acid-2,2 ,2-trichloroethyl ester with melting point 118-120°C (decomposition). 37) 2-methyl-7-[N-tert.butoxycarbonyl-2-(4-tert.butoxycarbonyl-1-methoxyphenyl)glycyl]amino-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester, powder. 38) 2-methyl-7-[N-(1,3,4-thiadiazol-2-yl)thiomethylcarbonyl-2-phenylglycyl]amino-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 148 -150°C (decomposition). 39) 2-methyl-7-[N-tert.butoxycarbonyl-2-(4-methylsulfinylphenyl)-glycyl]amino-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 115-125°C. 40) 2-methyl-7-(2-isonicotinoyloxy-2-phenylacetamido)-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 100-115°C (decomposition). 41) 2-methyl-7-[2-(5-indanyl)oxycarbonyl-2-phenylacetamido]-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 165-170°C. 42) 2-methyl-7-[D-2-(4-hydroxyphenyl)glycyl]amino-3-cephem-4-carboxylic acid, powder. 4 3) 2-methyl-7-[2-(5,6-dihydro-2H-pyran-3-yl)glycyl]amino-3-cephem-4-carboxylic acid with melting point 125-128°C (decomposition).- 44) 2-methyl-7-[2-(3-methanesulfonamidophenyl)glycyl]amino-3-cephem-4-carboxylic acid with melting point 192-193°C (decomposition). 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-cef em-4-carboxylic acid with melting point 165-175°C. 47) 2-methyl-7-[2-(4 -methoxyphenyl)glycyl]amino-3-cephem-4-carboxylic acid with melting point 165-168° C. 48) 2-methyl-7-[2-(2,5-dihydrophenyl)glycyl]amino-3-cephem-4- carboxylic acid with melting point 168°C (decomposition). 49) 2-methyl-7-[2-(4-methylsulfinylphenyl)glycyl]amino-3-cephem-4-carboxylic acid, powder. 50) 2-methyl-7-[2 -(5,6-dihydro-2H-pyran-3-yl)acetamido]-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 149.5-150.5°C. 51) 2- methyl-7-[2-(5,6-dihydro-2H-pyran-3-yl)acetamido]-3-cephem-4-carboxylic acid with melting point 172.5-173.5°C (decomposition). 52) 2 -methyl-7-[N-tert.butoxycarbonyl-2-(3-methanesulfonamidophenyl)-glycyl]amino-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester, 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 with melting point 188-189°C (decomposition). 55) 2-methyl-7-(N-tert.butoxycarbonylphenyl-D-glycyl)amino-3-cephem-4-carboxylic acid with melting point 125-127°C (decomposition). 56) 2-methyl-7-(N-[2-(2-nitrophenoxy)acetyl]phenylglycyl)amino-3-cephem-4-carboxylic acid with melting point 135-137°C (decomposition). 57) 2-methyl-7-(N-tert.butoxycarbonylphenyl-D-glycyl)amino-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 115-116°C (decomposition).

Example lb

0.5. ml of phosphorus trichloride is added dropwise under ice-cooling to a solution of 0.72 g of 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester-1-oxide in 5 ml of dimethylformamide, and the mixture is stirred for 1 hour at the same temperature. After the reaction, the reaction mixture is poured into a mixture of 40 ml of ethyl acetate and 40 ml of ice water, and the ethyl acetate phase is separated. The aqueous phase is further extracted with 10 ml of ethyl acetate, and the ethyl acetate phases are combined. The combined solution is washed with 5% hydrochloric acid, with an aqueous sodium bicarbonate solution and with a saturated aqueous sodium chloride solution in the indicated order and dried over magnesium sulfate. The dried solution is treated with activated charcoal, and the solvent is distilled off. The residue is crystallized with a small amount of ether, whereby 0.43 g of 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 175-178°C is obtained.

The following compounds are prepared using a method analogous to the method in example 1b. 1) 2-methyl-7-[2-(1H-tetrazol-1-yl)acetamido]-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 168-170°C. 2) 2-methyl-7-benzyloxycarboxamido-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 143-144°C. 3) 2-methyl-7-[2-(3-chlorophenyl)acetamido]-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 144-145.5°C (decomposition). 4) 2-methyl-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 161-162°C (decomposition). 5) 2-methyl-7-[2-(1,2,5-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 180-185°C ( cleavage). 6) 2-methyl-7-(2-phenoxyacetamido)-3-cephem-4-carboxylic acid methyl ester oil. 7) 2-methyl-7-(2-phenoxyacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 118-120°C. 8) 2-methyl-7-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]amino-3-cephem-4-carboxylic acid with melting point 168-169°C. 9) 2-methyl-7-[2-(1H-tetrazol-1-yl)acetamido]-3-cephem-4-carboxylic acid with melting point 202-203°C (decomposition). 10) 2-methyl-7-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylic acid with melting point \ 15°C (decomposition). 11) 2-methyl-7-benzyloxycarboxamido-3-cephem-4-carboxylic acid with melting point 167-169°C (decomposition). 12) 2-methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylic acid with melting point 168-171°C (decomposition). 13) 2-methyl-7-[2-(3-chlorophenyl)acetamido]-3-cephem-4-carboxylic acid with melting point 173-174°C (decomposition). 14) 2-methyl-7-[3-(N-tert.butoxycarbonylamino)-3-(2-thienyl)-propionamideb]-3-cephem-4-carboxylic acid with melting point 167-170°C (decomposition). 15) 2-methyl-7-(2-cyanoacetamido)-3-cephem-4-carboxylic acid with melting point 162-166°C. 16) 2-methyl-7-(3-phenylureido)-3-cephem-4-carboxylic acid with melting point 148-151°C. 17) 2-methyl-7-[2-(1,3,4-thiadiazol-2-ylthio)acetamido]-3-cephem-4-carboxylic acid with melting point 197-199°C. 18) 2-methyl-7-(N-tert. butoxycarboriyl-2-thienylglycy]}amino-3-cephem-4-carboxylic acid, powder. 19) 2-methyl-7-[2-(5-methyl-1, 3,4-thiadiazol-2-yloxy)acetamido]-3-cephem-4-carboxylic acid with melting point 113-116°C. 20) 2-methyl-7-[3-(2-chlorophenyl)-5-methylisoxazol-4-yl]-carboxamido-3-cephem-4-carboxylic acid with melting point 202-203°C. 21) 2-methyl-7-(2-methylthioacetamido)-3-cephem-4-carboxylic acid with melting point 181-183°C (decomposition). 22) 2-methyl-7-(2-allylthioacetamido)-3-cephem-4-carboxylic acid with melting point 121-123°C. 23) 2'-methyl-7-(2-formyloxy-2-phenylacetamido)-3-cephem-4-carboxylic acid, powder. 24) 2-methyl-7-(1-cyclopropylethoxy)carboxamido-3-cephem-4-carboxylic acid with melting point 158.5-160°C (decomposition). 25) 2-methyl-7-[N-(1-cyclopropylethoxy)carbonyl phenylglycyl]amino-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 165-167.5°C. 26) 2-methyl-?-(2-phenylthioacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 140-142°C. 27) 2-methyl-7-[3-(N-tert.butoxycarbonylamino)-3-(2-thienyl)propion-amido]-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 188- 192°C. 28) 2-methyl-7-(2-cyanoacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester' with melting point 160-165°C (decomposition). 2 9) 2-methyl-7-(3-phenylureido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 172-174°C. 30) 2-methyl-7-[2-(1,3,4-thiadiazol-2-ylthio)acetamido]-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 130-140°C ( cleavage). 31) 2-methyl-7-(N-tert.butoxycarbonyl-2-thienylglycyl)amino-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester, powder. 32) 2-methyl-7-[2-(5-methyl-1,3,4-thiadiazol-2-yloxy)acetamido]-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester, amorphous. 33) 2-methyl-7-[3-(2-chlorophenyl)-5-methylisoxazol-4-yl]carboxamido-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester, amorphous. 34) 2-methyl-7-(2-methylthioacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 151-153°C. 35) 2-methyl-7-(2-allylthioacetamido)-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 96°C. 36) 2-methyl-7-(2-formyloxy-2-phenylacetamido)-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester, powder. 37) 2-methyl-7-(1-cyclopropylethoxy)carboxamido-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 181-183°C. 38) 2-methyl-7-(phenylglycyl)amino-3-cephem-4-carboxylic acid with melting point 168.5-171°C. 39) 2"-methyl-7-[3-amino-3-(2-thienyl) propionamido]-3-cephem-4-carboxylic acid with melting point 218-221°C (decomposition). 40) 2-methyl-7- [2-(2-thienyl)glycyl]amino-3-cephem-4-carboxylic acid with melting point 145-149°C (decomposition). 41) 2-methyl-7-(2-hydroxy-2-phenylacetamido)-3- cephem-4-carboxylic acid with melting point 172-173° C. 42) 2-methyl-7-amino-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester hydrochloride with melting point 185-187° C (decomposition) 4 3) 2-methyl-7-amino-3-cephem-4-carboxylic acid with melting point 220°C (decomposition).

Example lc

A solution of 0.5 g of 2-methyl-7-(1-cyclopropylethoxy)-carboxamido-3-cephem-4-carboxylic acid in 5 ml of formic acid is stirred for 2 hours at room temperature. Under ice-cooling, 20 ml of ether is added to the reaction mixture, and the liquid on top is removed by decantation, which is repeated three times. The precipitate is collected by filtration and washed with ether. The precipitate is added under ice-cooling to a mixture of 5 ml of acetonitrile and 1 ml of water. The mixture is stirred for 1 hour at the same temperature, and the insoluble material is collected by filtration and dried, whereby 0.24 g of 2-methyl-7-amino-3-cephem-4-carboxylic acid with melting point 222°C (decomposition) is obtained .

Example 2c.

0.55 g of pyridine and 1.43 g of phosphorus pentachloride are added in the indicated order while cooling at a temperature between -5 and -10°C to a suspension of 2.14 g of 2-methyl-7-(.2-phenylacetamido)- 3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester in 20 ml of dry dichloromethane, and the mixture is stirred. After dissolution of the starting material, the reaction temperature is raised to room temperature, and it is stirred for 4 hours. 1.47 g absolute methanol is added dropwise to the solution while cooling at a temperature between -10 and -15°C.

The precipitated crystals are collected after stirring for 1 hour at the same temperature and for 1.5 hours at 2-3°C by filtration, washed with a small amount of dichloromethane and ether and dried, whereby 1.26 g of 2-methyl- 7-amino-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester hydrochloride with melting point 185-187°C (decomposition).

Similar results are obtained using the following compounds as starting material instead of 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester.

Example 3c

55 ml of trimethylchlorosilane are added to a suspension of

.18.15 g of 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid in

400 ml of dichloromethane, and the mixture is vortexed for 10 minutes.

41.5 ml of dimethylaniline are added to the mixture, and the mixture is refluxed for 1 hour. After cooling the mixture to a temperature between -30 and -40°C, 16.6 g of phosphorus pentachloride is added to the mixture, and the mixture is stirred for 2 hours at the same temperature, after which 185 ml of methanol is added to the solution, and the mixture is stirred for 1 hour at the same temperature. 250 ml of water is added to the reaction mixture, and the solution is stirred for 30 minutes at a temperature between -10 and 0°C, after which the aqueous phase is separated. The aqueous phase is adjusted at 0-10°C with 1N aqueous sodium hydroxide solution to a pll value of 3-4, and

the precipitated crystals are collected by filtration, washed with water, with acetone and with ether in the order indicated and then dried, whereby 6.9 g of 2-methyl-7-amino-3-cephem-4-carboxylic acid is obtained in the form of white crystals with melting point 222°C (decomposition).

Analogous results are obtained using the following starting compounds instead of 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid.

Example ld

A solution of 1.63 g of N-(1-cyclopropylethoxycarbonyl)-phenylglycine, 0.60 g of triethylamine and 2 drops of dimethylbenzylamine in 10 ml of dry dichloromethane is added dropwise at -10°C to a solution of 0.£7 g of ethyl chloroformate in 15 ml of dry dichloromethane, and the mixture is stirred for 1 hour. The mixture is cooled to a temperature between -10 and 15°C, and a solution of 2.2 g of 2-methyl-7-amino-3-cephem-4-carboxylic acid-2,2 is added dropwise over 10 minutes. 2-trichloroethyl ester hydrochloride and 0.55 g of triethylamine in 20 ml of dry dichloromethane, after which the mixture is stirred for 2.5 hours at the same temperature. After the reaction, the reaction mixture is washed with water containing 2% hydrochloric acid, with a saturated aqueous sodium chloride solution in the order indicated and then dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue is pulverized by adding isopropyl ether, after which the powder is collected by filtration and dried, thereby obtaining 3.0 g of 2-methyl-7-[N-(1-cyclopropylethoxy)carbonyl-phenylglycyl]amino-3 -cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 165-167.5°C.

Example 2d.

A solution of 1.08 g of 2-(1H-tetrazol-1-yl)acetic acid, 0.96 g of triethylamine and 2 drops of dimethylbenzylamine in 10 ml of dry dichloromethane. is added dropwise over 10 minutes at -10°C to a solution of 1.20 g of pivaloyl chloride in 20 ml of dry dichloromethane, and the mixture is stirred for 1 hour at the same temperature. A solution of 3.05 g of 2-methyl-7-amino-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester hydrochloride and 0.8 g of triethylamine in 20 ml is added dropwise to the mixture over the course of 10 minutes dry dichloromethane, and the mixture is stirred for 3 hours. After the reaction, the reaction mixture is washed with water, with 5% hydrochloric acid, with a saturated aqueous sodium bicarbonate solution and with a saturated aqueous sodium chloride solution in the specified order and is then dried over magnesium sulfate. The residue formed is washed after distilling off the solvent with ether and collected by filtration, whereby 2.34 g of 2-methyl-7-[2-(1H-tetrazol-1-yl)acetamido]-3-cephem-4-carboxylic acid is obtained -2,2,2-trichloroethyl ester in the form of colorless crystals with a melting point of 168-170°C.

Example 3d.

3.0 g 2-methyl-7-amino-3-cephem-4-carboxylic acid-2,2,2-

trichloroethyl ester hydrochloride is suspended in 50 ml of dry dichloromethane and dissolved while cooling to -15°C by adding 0.72 g of triethylamine and 1.9 g of dimethylaniline. To the solution is added drop-

show, while stirring and cooling at the same temperature, a solution of 2.0 g of (2-thienyl)-acetyl chloride in 10 ml of dry dichloromethane,

r

and the mixture is stirred for 1.5 hours at the same temperature. The reaction mixture is washed after the reaction with 5% hydrochloric acid,

with water, with 5% aqueous sodium bicarbonate solution and with water in the order indicated and then dried. The residue is dissolved after distilling off the solvent in ether and allowed to stand,

after which the precipitated crystals are collected by filtration and dried, thereby obtaining 3.2 g of 2-methyl-7-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester in form of crystals with melting point 161-162°C (decomposition).

Example 4d.

3.0 g of 2-methyl-7-amino-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester hydrochloride is suspended in 50 ml of dry dichloromethane and then dissolved by cooling to -15°C by adding 0, 72 g of triethylamine and 1.9 g of dimethylaniline. A solution of 2.2 g of phenylthioacetyl chloride in 10 ml of dry dichloromethane is added dropwise while stirring to the mixture, and the mixture is stirred for 1.5 hours at the same temperature. After the reaction, the reaction mixture is washed with 5% hydrochloric acid, with water, with 5% aqueous sodium hydrogen carbonate solution and with water in the specified order and is then dried. After distilling off the solvent, ether is added to the residue, after which the precipitated crystals are collected by filtration and dried, thereby obtaining 3.4 g of 2-methyl-7-(2-phenylthio-acetamido)-3-cephem-4-carboxylic acid-2, 2,2-trichloroethyl ester with melting point 140-142°C.

Example 5d..

A solution of 3.0 g of 2-methyl-7-amino-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester hydrochloride, 0.72 g of triethylamine and 1.9 g of dimethylaniline in 50 ml of dry dichloromethane is placed drop by drop

-15°C during 1.5 hours to a solution of 2.2 g of chloroformic acid benzyl ester in 10 ml of dry dichloromethane, and the mixture is stirred for 1 hour at the same temperature. The reaction mixture is washed after the reaction with 5% hydrochloric acid, with water, with 5% aqueous sodium hydrogen carbonate solution and with water in the specified order and

then dried. After distilling off the solvent, the residue is dissolved in ethanol, after which the precipitated crystals are collected by filtration and dried, whereby 3.2 g of 2-methyl-7-benzyloxy-carboxamido-3-cephem-4-carboxylic acid-2,2,2- trichloroethyl ester with melting point 143-144°C.

r

Example 6d.

A solution of 795 mg of 3-(N-tert.butoxycarbonylamino)-3-(2-thienyl)-propionic acid and 240 mg of triethylamine in 10 ml of dichloromethane is added dropwise under cooling at a temperature between -15 and -10°C during about. 20 minutes to a solution of 330 mg of chloroformate isobutyl ester in 10 ml of dry dichloromethane. The mixture is stirred for a further 1 hour at the same temperature, whereby one solution of the mixed anhydride is obtained. A solution prepared by adding 160 mg of triethylamine and 50 mg of dimethylaniline to a solution of 760 mg of 2-methyl-7-amino-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester hydrochloride in dichloromethane, is added at a temperature between -15 and -10°C to the previously prepared solution of the mixed anhydride, after which the mixture is stirred for 3 hours at the same temperature and for a further 3 hours at room temperature. After the reaction, the dichloromethane is distilled off. The residue is dissolved in 150 ml of ethyl acetate, and the solution is washed with 20 ml of 5% hydrochloric acid, with 5% aqueous sodium hydrogen carbonate solution and with a saturated aqueous sodium chloride solution in the order indicated and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure, whereby 1.17 g of 2-methyl-7-[3-(N-tert-butoxycarbonylamino)-3-(2-thienyl)propionamido]-3-cephem-4-carboxylic acid-2 is obtained ,2,2-trichloroethyl ester with melting point 188-192°C.

Example 7d.

A solution of 0.9 g of triethylamine and 0.15 g of dimethylaniline in 20 ml of dichloromethane is stirred under ice-cooling to a suspension of 3.82 g of 2-methyl-7-amino-3-cephem-4-carboxylic acid-2,2 ,2-trichloroethyl ester hydrochloride in 80 ml of dry dichloromethane. 0.85 g of cyanoacetic acid and 2.25 g of dicyclohexylcarbodiimide are added to the mixture, and the mixture is stirred for 1 hour under ice cooling. 50 ml of 5% hydrochloric acid is added to the mixture, and the mixture is stirred for 30 minutes, after which the organic phase is separated, washed with

5% hydrochloric acid, with a saturated aqueous sodium bicarbonate solution and with a saturated aqueous sodium chloride solution in it

specified order and then dried over magnesium sulphate. The solvent is distilled off, whereby 3.5 g of 2-methyl-7-(2-cyanoacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester is obtained in the form of a colorless powder with a melting point of 160-165 °C.

Example 8d.

3.82 g of 2-methyl-7-amino-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester hydrochloride is suspended in 30 ml of dichloromethane and then dissolved by the addition of 0.9 g of triethylamine and 0.1 g dimethylaniline. 1.2 g of phenyl isocyanate is added to the solution while stirring under ice-cooling, and the mixture is stirred for 5 hours.

10% hydrochloric acid is added to the reaction mixture, and the mixture is stirred for 10 minutes. The reaction mixture is filtered, and the dichloromethane phase is separated from the filtrate, washed with a saturated aqueous sodium bicarbonate solution and with a saturated aqueous sodium chloride solution in the indicated order and dried over magnesium sulfate. The solvent is distilled off, whereby 4.2 g of 2-methyl-7-(3-phenylureido)-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 172-174°C is obtained.

Example 9d.

3.82 g of 2-methyl-7-amino-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester hydrochloride are suspended in 80 ml of dry dichloromethane and dissolved with stirring under ice cooling by adding a solution of 0.9 g triethylamine and 0.15 g dimethylaniline in 20 ml dichloromethane. 1.8 g of (1,3,4-thiadiazol-2-ylthio)acetic acid and 2.25 g of dicyclohexylcarbodiimide are added to the solution while stirring under ice cooling, and the mixture is stirred for 1 hour under ice cooling. 50 ml of 5% hydrochloric acid is added to the reaction mixture, and the mixture is stirred for 30 minutes, after which the organic phase is separated, washed with 5% hydrochloric acid, with; a saturated aqueous sodium bicarbonate solution' and with a saturated aqueous sodium chloride solution in the order indicated and then dried over magnesium sulfate. The solvent is distilled off, whereby 4.5 g of 2-methyl-7-[2-(1,3,4-thiadiazol-2-ylthio)acetamido]-3-cephem-4-carboxylic acid-2,2,2 -trichloroethyl ester in the form of a light brown powder with a melting point of 130-140°C (decomposition).

Example 10d.

930 mg of [N-tert.butoxycarbonyl-2-(2-thienyl)]glycine is added to 15 ml of dry dichloromethane and dissolved by the addition of 360 mg

triethylamine. A solution of 400 mg of pivaloyl chloride in 1 ml of dichloromethane is added dropwise to the solution while stirring and cooling at one temperature between -10 and -15°C, and the mixture is stirred for 2 hours at the same temperature, whereby a solution of

the mixed anhydride. 1.15 g of 2-methyl-7-amino-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester hydrochloride is suspended in 10 ml of dichloromethane and dissolved by stirring for several minutes, after which, while stirring and under ice-cooling 0.64 g of 2,6-lutidine is added. The solution, which is cooled to -10°C, is added at once to the previously prepared solution of the mixed anhydride, and the mixture is stirred for 1.5 hours at -15°C and for 0.5 hour at room temperature. After the reaction, the mixture is concentrated under reduced pressure, and the residue is extracted by adding ethyl acetate and 2-3% sulfuric acid. The ethyl acetate phase is washed with water,

with a saturated aqueous sodium bicarbonate solution and with water in the order indicated and dried over magnesium sulfate. The residue is pulverized after removal of the solvent under reduced pressure by adding a mixture of ether and petroleum ether, collected by filtration and dried, thereby obtaining 1.77 g of 2-methyl-7-(N-tert.butoxycarbonyl-2-thienylglycyl)amino -3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with IR absorption spectrum (Nujol): 3320, 1790, 1740, 1710, 1690, 1680 and 1632 cm"<1>.

Example suffered.

A solution of 2.0 g pivaloyl chloride in 5 ml dichloromethane is added dropwise with stirring and cooling to -15°C to a solution of 3.13 g (5-methyl-1,3,4-thiadiazol-2-yloxy) acetic acid and 1.80 g of triethylamine in 50 ml of dry dichloromethane, and the mixture is stirred for 2 hours at the same temperature, whereby a solution of the mixed anhydride is obtained. 5.75 g of 2-methyl-7-amino-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester hydrochloride is suspended in 40 ml of dichloromethane and dissolved by stirring for 10-20 minutes under ice-cooling after addition of 2.0 g of 2,6-lutidine and then cooled to -15°C, and then this solution was poured at once into the previously prepared solution of the mixed anhydride. The mixture is stirred for 1.5 hours at the same temperature and for 30 minutes at room temperature. After the reaction, the reaction mixture is washed with 5% sulfuric acid, with water, with a saturated aqueous sodium hydrogen carbonate solution and with water in the specified order and dried over magnesium sulfate. The solvent is removed under reduced pressure, thereby obtaining 7.23 g of 2-methyl-7-[2-(5-methyl-1,3,4-thiadiazol-2-yloxy)acetamido]-3-cephem-4-carboxylic acid -2,2,2-trichloroethyl ester in the form of a colorless amorphous substance with an IR absorption spectrum (chloroform): 3420, 1790, 1740, 1700 and 1635 cm"<1>.

* Example 12d.

5 ml of thionyl chloride are added to 855 mg of [3-(2-chlorophenyl)-5-methylisoxazol-4-yl]carboxylic acid, and the mixture is refluxed for 2 hours, after which the thionyl chloride is removed under reduced pressure.

The prepared [3-(2-chlorophenyl)-5-methylisoxazol-4-yl]carbonyl chloride is dissolved in 3-4 ml of dry dichloromethane. 1.15 g of 2-methyl-7-amino-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester hydrochloride is suspended in 10 ml of dichloromethane and dissolved by adding 250 mg of triethylamine and 0.64 g of 2,6 -lutidine, after which the solution is cooled with ice. The previously prepared solution of the acid chloride is added dropwise to the solution, and the mixture is stirred for 1 hour under ice cooling.

After the reaction, the reaction mixture is concentrated under reduced pressure, and the residue is extracted by adding ethyl acetate and 2% sulfuric acid. The extract is washed with water, with a saturated aqueous sodium bicarbonate solution and with water in the order indicated and dried over magnesium sulfate. The solvent is distilled off under reduced pressure, whereby 1.82 g of 2-methyl-7-[3-(2-chlorophenyl)-5-methylisoxazol-4-y1]carboxamido-3-cephem-4-carboxylic acid-2,2 is obtained, 2-trichloroethyl ester in the form of an amorphous substance with an IR absorption spectrum (Nujol): 3340, 1790, 1740 and 1675 cm"<1>.

Example 13d

0.42 g of methylthioacetic acid is added to 5 ml of thionyl chloride, and the mixture is allowed to stand for 40 minutes at room temperature and for 5 minutes at 40-50°C, after which the thionyl chloride is removed under reduced pressure.

5 ml of benzene are added to the residue and then evaporated under reduced pressure, whereby 0.47 g of methylthioacetyl chloride, 0.76 4 g of 2-methyl-7-amino-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester are obtained -hydrochloride is suspended in 8 ml of dichloromethane and dissolved by adding a solution of 0.18 g of triethylamine in 2 ml of dichloromethane and a solution of 0.266 g of dimethylaniline in 2 ml of dichloromethane at -30°C. 0.38 g of the previously prepared methylthioacetyl chloride is added to the solution at -30°C, and the mixture is stirred for 30 minutes at the same temperature, after which the reaction temperature is gradually raised to -10°C over the course of 1 hour with stirring. The reaction mixture is washed according to the setting with 5% hydrochloric acid, with water, with a saturated aqueous sodium bicarbonate solution and with a saturated aqueous sodium chloride solution in the specified order and dried over magnesium sulfate. After distilling off the solvent, the crystalline residue (0.81 g) is recrystallized from ethanol, whereby 0.62 g of 2-methyl-7-[(2-methylthio)acetamido]-3-cephem-4-carboxylic acid-2,2 ,2-trichloroethyl ester in the form of colorless crystal needles with a melting point of 151-153°C.

Example 14d.

A solution of 0.18 g of triethylamine is added to a suspension of 0.764 g of 2-methyl-7-amino-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester hydrochloride in 8 ml of dry dichloromethane at -30°C in 2 ml of dichloromethane and then a solution of 0.27 g of dimethylaniline

in 2 ml of dichloromethane. 0.528 g of allylthioacetic acid is added to 5 ml of thionyl chloride, and the mixture is allowed to stand for 20 minutes at room temperature and for 5 minutes at 50°C, after which the thionyl chloride is removed under reduced pressure, a small amount of benzene is added to the residue and

then evaporated under reduced pressure, whereby 0.527 g of allylthioacetyl chloride is obtained. A solution of 0.452 g of the prepared allylthioacetyl chloride in 3 ml of dichloromethane is placed dropwise at -30°C

during 5 minutes to the previously prepared solution of the 2-methyl-7-amino-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester,

and the mixture is stirred for 1 hour at -20°C. After the reaction, the reaction mixture is washed twice with 5% hydrochloric acid, once with water, twice with a saturated aqueous sodium bicarbonate solution and once with a saturated aqueous sodium chloride solution in the specified order and dried over magnesium sulfate. After distilling off the solvent, the residue (0.82 g) is recrystallized from a mixture of ether and isopropyl ether, whereby 0.71 g of 2-methyl-7-(2-allylthioacetamido)-3-cephem-4-carboxylic acid-2,2 ,2-trichloroethyl ester with melting point 96°C.

Example 15d.

A solution of 0.99 g of dicyclohexylcarbodiimide in 5 ml of tetrahydrofuran is added dropwise with stirring while cooling to

-20°C to a solution of 0.864 g of (2-formyloxy)phenylacetic acid in 15 ml of tetrahydrofuran, and the mixture is stirred for 30 minutes at the

same temperature. To the solution is added dropwise at -20°C a solution prepared by adding 1.5 3 g of 2-methyl,-7-amino-3-

cephem-4-carboxylic acid 2,2,2-trichloroethyl ester hydrochloride and 0.4 g of triethylamine to 20 ml of dichloromethane at -20°C. The reaction temperature of the mixture is gradually raised with stirring to 0°C over the course of 1.5 hours. The reaction mixture is stirred for a further 1.5 hours at 0°C, after which the precipitate is filtered off, and the filtrate is concentrated to dryness under reduced pressure. A small amount of ethyl acetate is added to the residue, after which insoluble material is filtered off, and the filtrate is washed with 5% hydrochloric acid, with water, with a saturated aqueous sodium bicarbonate solution and with a saturated aqueous sodium chloride solution in the specified order and dried over magnesium sulfate. After filtering the solution by passing it through approx. 2 g of silica gel, the solvent is distilled off, after which the residue is pulverized by adding ether, collected by filtration and dried, thereby obtaining 1.72 g of 2-methyl-7-(2-formyl-oxy-2-phenylacetamido)-3-cephem- 4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 142-147°C.

Example 16d.

1.02 g of triethylamine is added to a suspension, which is prepared by suspending 1.92 g of 2-methyl-7-amino-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester hydrochloride in 20 ml of tetrahydrofuran under cooling to -10°C. The mixture is then vigorously stirred. Add dropwise to the solution over approx. 10 minutes a solution of 5.5 millimoles of chloroformic acid-1-cyclopropyl ethyl ester in 20 ml of tetrahydrofuran, and the mixture is stirred for 1.5 hours at the same temperature. After the reaction has ended, the reaction mixture is filtered, and the filtrate is concentrated at room temperature. The residue is dissolved in 30 ml of ethyl acetate, and the solution is washed with 5% hydrochloric acid, with an aqueous sodium bicarbonate solution and with a saturated aqueous sodium chloride solution in the specified order and dried over magnesium sulfate, after which the solvent is distilled off. The residue is pulverized by adding

addition of a small amount of isopropyl ether.

During filtration, a powder is collected, which is dried, whereby

1.4 g of 2-methyl-7-(1-cyclopropylethoxy)carboxamido-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 181-183°C is obtained.

Example 17d.

. A mixture of 0.214 g of 2-methyl-7-amino-3-cephem-4-carboxyl-

acid, 0.40 g of bis(trimethylsilyl)acetamide and 4 ml of dichloromethane are homogenised by stirring for 30-40 minutes at room temperature, and to the solution is added dropwise over approx. 15 minutes while stirring and cooling. a temperature between -15 and -20°C a solution of 0.389 g of the triethylamine salt of the mixed anhydride of 2-sulfo-2-phenylacetic acid with ethoxycarbonic acid in 4 ml of dry dichloromethane, after which the mixture is stirred for 2 hours at a temperature between -10 and - 15°C. After the reaction, the dichloromethane is removed. Ethyl acetate is added to the residue, and the mixture is allowed to stand, after which the precipitate is extracted with water. The extract is washed with ethyl acetate and freeze-dried. The resulting powder is dissolved in a small amount of water, and the solution is adjusted to a pH value of 6-7 by adding sodium bicarbonate. After distilling off the water, the residue is washed with ethanol and pulverized, thereby obtaining 0.1 g of the disodium salt of 2-methyl-7-(2-sulfo-2-phenylacetamido)-3-cephem-4-carboxylic acid with a melting point of 265°C (decomposition ). The compound is treated in a conventional manner, whereby 2-methyl-7-(2-sulfo-2-phenylacetamido)-3-cephem-4-carboxylic acid is obtained, 115°C (bloating), 200-220°C (decomposition).

Example 18d.

A suspension of 6.9 g of 2-methyl-7-amino-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester hydrochloride in 70 ml of dry dichloromethane is homogenized with stirring under ice-cooling by the addition of 1.48 g of triethylamine and 0.44 g of N,N-dimethylaniline and by stirring for 30 minutes at room temperature. A solution of 8.5 g of the triethylamine salt of the mixed anhydride of 2-sulfo-2-phenylacetic acid with ethoxycarbonic acid in 60 ml of dry dichloromethane is added dropwise over approx. 30 minutes with stirring while cooling to a temperature between -20 and -25°C to the previously prepared solution, and the mixture is stirred for 1.5 hours at a temperature between -10 and -15°C and for 1 hour at room temperature. After the reaction, the dichloromethane is removed by low temperature, and the residue is dissolved in ethyl acetate, after which the solution is washed with cold 5% hydrochloric acid and 3 times with water and then dried. The solvent is distilled off at low temperature, whereby 11.5 g of 2-methyl-7-(2-sulfo-2-phenylacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester is obtained in the form of an amorphous product .

Example 19d.

A mixture of 0.805 g of dimethylformamide and 1.55 g of thionyl chloride is heated for 30 minutes at 50°C with sufficient shaking, and then excess thionyl chloride is removed under reduced pressure. The resulting crystals are washed twice with a small amount of absolute ether, after which the ether is removed under reduced pressure. The resulting crystals are dissolved in 40 ml of dry dichloro-

methane, and 0.95 g of thienyl glycolic acid is added to the solution at 0°C. The mixture is cooled to -50°C, and a solution of 1.11 g of triethylamine in 10 ml of dry dichloromethane is added dropwise over 30 minutes to the mixture, after which the mixture is stirred for 30 minutes at the same temperature. A solution prepared by stirring for 12 hours at room temperature of a mixture of 1.075 g of 2-methyl-7-amino-3-cephem-4-carboxylic acid, 2.04 g of bis(triethylsilyl)acetamide and 25 ml of dry dichloromethane. The mixture is stirred for 2 hours at the same temperature and for 1 hour at a temperature between -20 and -30°C.

After the reaction, add 10 ml of water to the reaction mixture at 0°C,

and then the dichloromethane is removed under reduced pressure. 40 ml of water is added to the residue, after which the solution is extracted twice with 50 ml of ethyl acetate. The extract is extracted three times with 50 ml of aqueous sodium bicarbonate solution, and the aqueous extract is washed with 50 ml of ethyl acetate, adjusted to a pH value of 2 with 5% sulfuric acid and extracted three times with 30 ml of ethyl acetate, after which the extract is washed with water and dried. After distilling off the solvent, the residue is pulverized by adding isopropyl ether, whereby 1.32 g of 2-methyl-7-[2-hydroxy-2-(2-thienyl)acetamido]-3-cephem-4-carboxylic acid is obtained in the form of one light yellow powder with melting point 91-96°C (decomposition).

The following compounds are prepared analogously to the method described in the previous examples. 1) 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 175-178°C.. 2) 2-methyl-7-(2-phenylacetamido) )-2-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 136-137°C. 3) 2-methyl-7-[2-(3-chlorophenyl)acetamido]-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 144-144.5°C (decomposition). 4) 2-methyl-7-[2-(1,2,5-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 180-185°C ( cleavage). 5) 2-methyl-7-(2-phenoxyacetamido)-3-cephem-4-carboxylic acid methyl ester in the form of an oil. 6) 2-methyl-7-(2-phenoxyacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 118-120°C. 7) 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester-1-oxide with melting point 173-175°C. 8) 2-methyl-7-[N-(1-cyclopropylethoxy)carbonyl-1-phenylglycyl]amino-3-cephem-4-carboxylic acid with melting point 168-169°C. 9) 2-methyl-7-[2-(1H-tetrazol-1-yl)acetamido]-3-cephem-4-carboxylic acid with melting point 202-203°C (decomposition). 10) 2-methyl-7-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylic acid with melting point 175°C (decomposition). 11) 2-methyl-7-benzyloxycarboxamido-3-cephem-4-carboxylic acid with melting point 167-169°C (decomposition). 12) 2-methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylic acid with melting point 168-171°C (decomposition). 13) 2-methyl-7-[2-(3-chlorophenyl)acetamido]-3-cephem-4-carboxylic acid with melting point 173-174°C (decomposition). 14) 2-methyl-7-[3-(N-tert.butoxycarbonylamino)-3-(2-thienyl)propionamido]-3-cephem-4-carboxylic acid with melting point 167-170°C (decomposition). 15) 2-methyl-7-(2-cyanoacetamido)-3-cephem-4-carboxylic acid with melting point 162-166°C. 16) 2-methyl-7-(3-phenylureido)-3-cephem-4-carboxylic acid with melting point 148-151°C. 17) 2-methyl-7-[2-(1,3,4-thiadiazol-2-ylthio)acetamido]-3-cephem-4-carboxylic acid with melting point 197-199°C. 18) 2-methyl-7-[N-tert.butoxycarbonyl-2-thienylglycyl]amino-3-cephem-4-carboxylic acid in the form of a powder. 19) 2-methyl-7-[2-(5-methyl-1,3,4-thiadiazol-2-yloxy)acetamido]-3-cephem-4-carboxylic acid with melting point 113-116°C.. 20) 2 -methyl-7-[3-(2-chlorophenyl)-5-methylisoxazol-4-yl]carboxamido-3-cephem-4-carboxylic acid with melting point 202-203°C. 21) 2-methyl-7-(2-methylthioacetamido)-3-cephem-4-carboxylic acid with melting point 181-183°C (decomposition). 22) 2<t>methyl-7-(2-allylthioacetamido)-3-cephem-4-carboxylic acid with melting point 121-123°C.

23) 2-methyl-7-(2-formyloxy-2-phenylacetamido)-3-cephem-4-carboxylic acid

1 form of a powder.

24) 2-methyl-7-(1-cyclopropylethoxy)carboxamido-3-cephem-4-carboxylic acid with melting point 158.5-160°C (decomposition). 25) 2-methyl-7-(2-azido-2-phenylacetamido)-3-cephem-4-carboxylic acid with melting point 65-68°C. 26) 2-methyl-7-[N-tert.butoxycarbonyl-2-(4-hydroxyphenyl)-D-glycyl]-amino-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting

point 130-135°C (decomposition).

27) 2-methyl-7-[2-(3-pyridyl)acetamido]-3-cephem-4-carboxylic acid with melting point 147-149°C (decomposition). 2 8) 2-methyl-7-[N-tert.butoxycarbonyl-2-(2,5-dihydrophenyl)glycyl]-amino-3-cephem-4-carboxylic acid with melting point 126-131°C (decomposition). 29) 2-methyl-7-[N-tert-butoxycarbonyl-2-(4-hydroxyphenyl)-D-glycyl]-amino-3-cephem-4-carboxylic acid in the form of a powder. 30) 2-methyl-7-[N-tert.butoxycarbonyl-2-(4-methylthiophenyl)glycyl]-amino-3-cephem-4-carboxylic acid with melting point 110-120°C. 31) 2-methyl-7-[N-tert.butoxycarbonyl-2-(4-methoxyphenyl)glycyl]-amino-3-cephem-4-carboxylic acid with melting point 81-86°C (decomposition). 32) 2-methyl-7-[N-tert.butoxycarbonyl-2-(4-methylthiophenyl)glycyl]-amino-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 115-120°C 33 ) 2-methyl-7-[N-tert.butoxycarbonyl-2-(4-methoxyphenyl)glycyl]amino-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 92-95°C (decomposition) . 34) 2-methyl-7-[N-tert.butoxycarbonyl-2-(2,5-dihydrophenyl)glycyl]-amino-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 104-110° C (cleavage). 35) 2-methyl-7-[N-(1-cyclopropylethoxy)carbonyl-2-(5,6-dihydro-2H-pyran-3-yl)glycyl]amino-3-cephem-4-carboxylic acid-2,2 ,2-trichloroethyl ester with melting point 118-126°C (decomposition). 36) 2-methyl-7-[N-tert.butoxycarbonyl-2-(4-tert.butoxycarbonyl-methoxyphenyl)glycyl]amino-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester in form a<y >a powder. 37) 2-Methyl-7-[N-(1,3,4-thiadiazol-2-yl)thiomethylcarbonyl-2-phenylglycyl]amino-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 148 -150°C (decomposition). 38) 2-methyl-7-[N-tert.butoxycarbonyl-2-(4-methylsulfinylphenyl)-glycyl]amino-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 115-125°C. 39) 2-methyl-7-(2-isonicotinoyloxy-2-phenylacetamido)-3-cephem-4-carboxylic acid with melting point 217-219°C. 40) 2-methyl-7-(2-isonicotinoyloxy-2-phenylacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 100-115°C (decomposition). 41) 2-methyl-7-[2-(5-indanyl)oxycarbonyl-2-phenylacetamido]-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 165-170°C. 42) 2-methyl-7-[N-(1,3,4-thiadiazol-2-yl)thiomethylcarbonyl-2-phenylglycyl]-amino-3-cephem-4-carboxylic acid with melting point 143-145°C (fission). 4 3) 2-methyl-7-[N-tert.butoxycarbonyl-2-(4-tert.butoxycarbonyl-1-methoxyphenyl)glycyl]amino-3-cephem-4-carboxylic acid in the form of a powder. 44) 2-methyl-7-[N-(1-cyclopropylethoxy)carbonyl-2-(5,6-dihydro-2H-pyran-3-yl)glycyl]amino-3-cephem-4-carboxylic acid with melting point 195- 197°C. 45) 2-methyl-7-[2-(1,2,5-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylic acid with melting point 188-190°C (decomposition). 46) 2-methyl-7-[N-tert.butoxycarbonyl-2-(3-methanesulfonamidophenyl)-glycyl]amino-3-cephem-4-carboxylic acid in the form of an oil. 47) 2-methyl-7-[N-tert.butoxycarbonyl-2-(4-methylsulfinylphenyl)-glycyl]amino-3-cephem-4-carboxylic acid with melting point 110-120°C. 48) 2-methyl-7-[2-(5-indenyl)oxycarbonyl-2-phenylacetamido]-3-cephem-4-carboxylic acid, 90-95°C (softening), 150-160°C (decomposition). 49) 2-methyl-7-[2-(5,6-dihydro-2H-pyran-3-yl)acetamido]-3-cefera-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 149.5- 150.5°C. 50) 2-methyl-7-[2-(5,6-dihydro-2H-pyran-3-yl)acetamido]-3-cephem-4-carboxylic acid with melting point 172.5-173.5°C (decomposition) . 51) 2E-methyl-7-[N-tert. butoxycarbonyl-2-(3-methanesulfonamidophenyl)-glycyl]amino-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester in the form of an amorphous product. 52) 2-methyl-7-(4-methoxyphenyl)glyoxylamido-3-cephem-4-carboxylic acid with melting point 188-189°C (decomposition). 5 3) 2-methyl-7-(N-tert.butoxycarbonylphenyl-D-glycyl)amino-3-cephem-4-carboxylic acid with melting point 125-127°C (decomposition). 54) 2-methyl-7-[N-[2-(2-nitrophenoxy)acetyl]phenylglycyl]amino-3-cephem-4-carboxylic acid with melting point 135-136°C (decomposition). 55) 2-methyl-7-(N-tert.butoxycarbonylphenyl-D-glycyl)amino-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 115-116°C (decomposition).

Example le.

0.296 g of pyridine and 0.616 g of phosphorus pentachloride are added in the indicated order while stirring while cooling at -15°C to a solution of 1.12 g of 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid-2 ,2,2-trichloroethyl ester with a melting point of 175-178°C in 20 ml of dry dichloromethane, and the mixture is stirred for 20 minutes at the same temperature and for a further 2 hours at room temperature. 5 ml absolute methanol is added to the mixture while cooling to -15°C,

and then the mixture is stirred for 1 hour at the same temperature.

2.2 g of dimethylaniline and a solution are added dropwise to the mixture

of 0.42 g of 2-thienylacetyl chloride in 5 ml of dry dichloromethane in the indicated order at the same temperature, and then the mixture is stirred for 2.5 hours at the same temperature. The reaction mixture is washed after the reaction with 5% hydrochloric acid, with water, with 5% aqueous

sodium bicarbonate solution and with water in the order indicated and then dried. After concentration of the solution, the oily product formed is crystallized by adding ether, whereby 750 mg of 2-methyl-7-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylic acid-2,2,2- trichloroethyl ester with melting point 161-162 o C r (decomposition).

The following compounds are prepared analogously to the method described in the example above. 1) 2-methyl-7-[2-(3-chlorophenyl)acetamido]-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 144-144.5°C (decomposition). 2) 2-methyl-7-[2-(1,2,5-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 180-185°C ( cleavage). 3) 2-methyl-7-(2-phenoxyacetamido)-3-cephem-4-carboxylic acid methyl ester in the form of an oil. 4) 2-methyl-7-(2-phenoxyacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 118-120°C. 5) 2-methyl-7-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]amino-3-cephem-4-carboxylic acid with melting point 168-169°C. 6) 2-methyl-7-[2-(1H-tetrazol-1-yl)acetamido]-3-cephem-4-carboxylic acid with melting point 202-203°C (decomposition). 7) 2-methyl-7-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylic acid with melting point 175°C (decomposition). 8) 2-methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylic acid with melting point 168-171°C (decomposition). 9) 2-methyl-7-[2-(3-chlorophenyl)acetamido]-3-cephem-4-carboxylic acid with melting point 173-174°C (decomposition). 10) 2-methyl-7-[3-(N-tert.butoxycarbonylamino)-3-(2-thienyl)propion-amido]-3-cephem-4-carboxylic acid with melting point 167-170<Q>C (decomposition) . 11) 2-methyl-7-(2-cyanoacetamido)-3-cephem-4-carboxylic acid with melting point 162-166°C. 12) 2-methyl-7-[2-(1,3,4-thiadiazol-2-ylthio)acetamido]-3-cephem-4-carboxylic acid with melting point 197-199°C. 13) 2-methyl-7-[N-tert.butoxycarbonyl-2-thienylglycyl]amino-3-cephem-4-carboxylic acid in the form of a powder. 14) 2-methyl-7-[2-(5-methyl) -1,3,4-thiadiazol-2-yloxy)acetamido]-3-cephem-4-carboxylic acid with melting point 113-116°C. 15) 2-methyl-7-[3-(2-chlorophenyl)-5-methylisoxazol-4-yl]carboxamido-3-cephem-4-carboxylic acid with melting point 202-203°C. 16) 2r-methyl-7-(2-methylthioacetamido)-3-cephem-4-carboxylic acid with melting point 181-183°C. (fission). 17) 2-methyl-7-(2-allylthioacetamido)-3-cephem-4-carboxylic acid with melting point 121-123°C. 18) 2-methyl-7-(2-azido-2-phenylacetamido)-3-cephem-4-carboxylic acid with melting point 65-68°C. 19) 2-methyl-7-[N-tert.butoxycarbonyl-2-(4-hydroxyphenyl)-D-glycyl]-amino-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 130-135 °C (decomposition). 20) 2-methyl-7-[2-(3-pyridyl)acetamido]-3-cephem-4-carboxylic acid with melting point 147-149°C (decomposition). 21) 2-methyl-7-[N-tert.butoxycarbonyl-2-(2,5-dihydrophenyl)glycyl]-amino-3-cephem-4-carboxylic acid with melting point 126-131°C (decomposition). 22) 2-methyl-7-[N-tert.butoxycarbonyl-2-(4-hydroxyphenyl)-D-glycyl]-amino-3-cephem-4-carboxylic acid in the form of a powder. 2 3) 2-methyl-7-[N-tert.butoxycarbonyl-2-(4-methylthiophenyl)glycyl]-amino-3-cephem-4-carboxylic acid with melting point 110-120°C. 24) 2-methyl-7-[N-tert.butoxycarbonyl-2-(4-methoxyphenyl)glycyl]-.amino-3-cephem-4-carboxylic acid with melting point 81-86°C (decomposition). 25) 2-methyl-7-[N-tert.butoxycarbonyl-2-(4-methylthiophenyl)glycyl]-amino-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 115-120°C. 26) 2-methyl-.7-[N-tert.butoxycarbonyl-2-(4-methoxyphenyl)glycyl]-amino-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 92-95°C (fission). 27) 2-methyl-7-[N-tert.butoxycarbonyl-2-(2,5-dihydrophenyl)glycyl]-amino-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 104-111° C (cleavage). 28) 2-methyl-7-[N-(1-cyclopropylethoxy)carbonyl-2-(5,6-dihydro-2H-pyran-3-yl)glycyl]amino-3-cephem-4-carboxylic acid-2,2 ,2-trichloroethyl ester with melting point 118-126°C (decomposition). 29) 2-methyl-7-[N-tert.butoxycarbonyl-2-(4-tert.butoxycarbonyl-methoxyphenyl)glycyl]amino-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester in the form of a powder . 30) 2-methyl-7-[N-(1,3,4-thiadiazol-2-yl)thiomethylcarbonyl-2-phenylglycyl]amino-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 148 -150°C (decomposition). 31) 2-methyl-7-[N-tert.butoxycarbonyl-2-(4-methylsulfinylphenyl)-glycyl]amino-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 115-125°C. 32) 2-methyl-7-(2-isonicotinoyloxy-2-phenylacetamido)-3-cephem-4-carboxylic acid with melting point 217-219°C. 33) 2-methyl-7-(2-isonicotinoyloxy-2-phenylacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 100-115°C (decomposition). 34) 2-methyl-7-[2-(5-indanyl)oxycarbonyl-2-phenylacetamido]-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 165-170°C. 35) 2-methyl-7-[N-(1,3,4-thiadiazol-2-yl)thiomethylcarbonyl-2-phenylglycyl]amino-3-cephem-4-carboxylic acid with melting point 143-145°C (decomposition). 36) 2-methyl-7-[N-tert.butoxycarbonyl-2-(4-tert.butoxycarbonyl-methoxyphenyl)glycyl]amino-3-cephem-4-carboxylic acid in the form of a powder. 37) 2-methyl-7-[N-(1-cyclopropylethoxy)carbonyl-2-(5,6-dihydro-2H-pyran-3-yl)glycyl]amino-3-cephem-4-carboxylic acid with melting point 195- 197°C. 38) 2-methyl-7-[2-(1,2,5-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylic acid with melting point 188-190°C (decomposition). 39) 2-methyl-7-[N-tert-butoxycarbonyl-2-(3-methanesulfonamidophenyl)-glycyl]amino-3-cephem-4-carboxylic acid in the form of an oil. 40) 2-methyl-7-[N-tert.butoxycarbonyl-2-(4-methylsulfinylphenyl)-glycyl]amino-3-cephem-4-carboxylic acid with melting point 110-120°C. 41) 2-methyl-7-[2-(5-indanyl)oxycarbonyl-2-phenylacetamido]-3-cephem-4-carboxylic acid with melting point 90-95°C (softening), 150-160°C (decomposition). 42) 2-methyl-7-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]amino-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 165-167.5°C. 43) 2-methyl-7-[2-(1H-tetrazol-1-yl)acetamido]-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 168-170°C. 44) 2-methyl-?-(2-phenylthioacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 140-142°C. 45) 2-methyl-7-[' 3-(N-tert. butoxycarbonylamino)-3-(2-thienyl)propionamido]3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 188- 192°C. 46) 2-methyl-7-(2-cyanoacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 160-165°C (decomposition). 4 7) 2-methyl-7-[2-(1,3,4-thiadiazol-2-ylthio)acetamido]-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 130-140°C (fission) . 48) 2-methyl-7-(N-tert.butoxycarbonyl-2-thienylglycyl)amino-.3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester in the form of a powder. 49) 2-methyl-7-[2-(5-methyl-1,3,4-thiadiazol-2-yloxy)acetamido]-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester in the form of colorless crystals. 50) 2-methyl-7-[3-(2-chlorophenyl-5-methylisoxazol-4-yl]carboxamido-S-cef em-4-carboxylic acid-2 , 2 , 2-trichloroethyl ester in the form of an amorphous substance. 51) 2 -methyl-7-(2-methylthioacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with melting point 151-153°C. 52) 2-methyl-7-(2-allylthioacetamido)-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with melting point 96°C. 53) 2-methyl-7-(2-sulfo-2-phenylacetamido)-3-cephem-4-carboxylic acid with melting point 115°C (bloating, 200-220°C (decomposition). 54) 2-methyl-7- (2-sulfo-2-phenylacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester in the form of an amorphous substance. 55) 2-methyl-7-[2-hydroxy-2-(2-thienyl)acetamido]-3-cephem-4-carboxylic acid with melting point 91-96°C (decomposition). 56) 2-methyl-7-[2-(5,6-dihydro-2H-pyran-3-yl)acetamido]-3-cephem-4-carboxylic acid-2, 2., 2-trichloroethyl ester with melting point 149 , 5 -150.5°C. 57) 2-methyl-7-[2-(5,6-dihydro-2H-pyran-3-yl)acetamido]-3-cephem-4-carboxylic acid with melting point 172.5-173.5°C (decomposition) .

Example lf.

A solution of 2.0 g of 2-methyl-7-[N-(1-cyclopropylethoxy)-carbonyl-2-phenylglycyl]amino-3-cephem-4-carboxylic acid in 10 ml of formic acid is stirred for 2.5 hours at room temperature. After the reaction has ended, 30 ml of ether is added to the reaction mixture, and the liquid on top is removed three times by decantation. During filtration, a colorless powder is collected, which is washed with ether. The prepared powder is suspended in a mixture of 15 ml of acetonitrile and 1 ml of water,

and the suspension is stirred for 1.5 hours under ice cooling. The precipitate is collected by filtration and dried, whereby 1.13 g of 2-methyl-7-(2-phenylglycyl)amino-3-cephem-4-carboxylic acid with melting point 168.5-171°C is obtained

Example 2f.

A solution of 310 mg of 2-methyl-7-t3-(tert.butoxycarbonylamino)-3-(2-thienyl)propionamido]-3-cephem-4-carboxylic acid in 1.5 ml of formic acid is stirred for 4 hours at room temperature. After the reaction has ended, the solvent is distilled off from the reaction mixture and the residue is pulverized by treatment with ethyl acetate.

The yellow powder produced in this way is suspended in a mixture

of 10 ml of acetonitrile and 3 ml of water, and the suspension is stirred for 1 hour. The precipitate is collected by filtration and dried, whereby 180 mg of 2-methyl-7-[3-amino-3-(2-thienyl)propionamido]-3-cephem-4-carboxylic acid with melting point 218-221°C (decomposition) is obtained .

Example 3f.

A solution of 2.34 g of 2-methyl-7-[N-(tert-butoxycarbonyl)-2-(2-thienyl)glycyl]amino-3-cephem-4-carboxylic acid in 10 ml of formic acid is stirred for 4 hours at room temperature. After the reaction has ended, the solvent is distilled off from the reaction mixture under reduced pressure, and the residue is pulverized by treatment with ethyl acetate. The powder (1.79 g) is dissolved in 40 ml of water, and the solution is stirred for 30 minutes and then filtered. The filtrate is freeze-dried, whereby 1.5 g of 2-methyl-7-L2-(2-thienyl)glycyl]amino-3-cephem-4-carboxylic acid with a melting point of 145-149°C is obtained.

Example 4f.

A solution of 2.0 g of 2-methyl-7-[D-N-(tert-butoxycarbonyl)-2-(4-hydroxyphenyl)glycyl]amino-3-cephem-4-carboxylic acid in 40 ml of formic acid is stirred for 5 hours at room temperature . After the reaction has ended, the reaction mixture is concentrated under reduced pressure, and the residue is dissolved in a mixture of water and ethyl acetate. The aqueous phase is separated and freeze-dried, whereby 1.38 g of 2-methyl-7-[D-2-(4-hydroxyphenyl)glycyl]amino-3-cephem-4-carboxylic acid is obtained in powder form with an NMR spectrum (D20+ DC1, t): 8.60 (3H, d, J=7.0 Hz), 6.1-6.7 (1H, m), 4.95 (1H, d, J=4.5 Hz), 4.62 (1H, s), 4.11 (1H, d, J=4.5 Hz), 3.40 (1H, d, J=6Hz), 2.93 (2H, d, J = 8, 5 Hz) and 2.48 (2H, d, J = 8.5 Hz).

Example 5f.

A mixture of 3.0 g of 2-methyl-7-[N-(Cl-cyclopropylethoxy)-carbonyl-2-(5,6-dihydro-2H-pyran-3-yl)glycyl]amino-r3-cephem-4 -carboxylic acid and 20 ml of formic acid are stirred for 3 hours at room temperature. After the reaction has ended, the formic acid is removed from the reaction mixture under reduced pressure at room temperature. The residue is pulverized with acetonitrile, and the powder is collected by filtration. The powder is washed with acetonitrile and with water in the indicated order and dried, whereby 2.20 g of 2-methyl-7-[2-(5,6-dihydro-2H-pyran-3-yl)-glycyl]amino- 3-cephem-4-carboxylic acid with melting point 125-128°C.

(fission) .

Example 6f.

A solution of 2.5 g of 2-methyl-7-[N-(tert-butoxycarbonyl)-2-(3-methanesulfonamidophenyl)glycyl]amino-3-cephem-4-carboxylic acid in 45 ml of formic acid is stirred for 4 hours at 8 -15°C. After the reaction has ended, the formic acid is removed under reduced pressure at 30°C from the reaction mixture. The residue is pulverized by adding ethyl acetate, and the powder is collected by filtration and dissolved in 70 ml of water. Ethyl acetate is added to the solution, after which the mixture is shaken, and the aqueous phase is separated. The aqueous phase is treated with activated charcoal and freeze-dried. 15 ml of methanol and 3 ml of water are added to the residue, and the mixture is stirred for 30 minutes at room temperature, filtered and dried, whereby 1.2 g of 2-methyl-7-[2-(3-methanesulfonamidophenyl)glycyl]amino is obtained -3-cephem-4-carboxylic acid in the form of a powder with a melting point of 192-193°C (decomposition).

Example 7f.

A solution of 3.0 g of 2-methyl-7-[N-(tert.butoxycarbonyl)-2-(4-"tert.butoxycarbonylmethoxyphenyl)glycyl]amino-3-cephem-4-carboxylic acid in 50 ml of formic acid is stirred in 3 hours at 45°C. After the reaction has ended, the formic acid is removed from the reaction mixture under reduced pressure, after which 20 ml of acetonitrile is added to the residue, and the residue is pulverized by adding 2 ml of water while stirring. The powder is collected by filtration, washed with acetonitrile and dried, which gives 1.81 g of 2-methyl-7-[2-(4-carboxymethoxy-phenyl)glycyl]-amino-3-cephem-4-carboxylic acid in the form of a powder with NMR spectrum (D20 + DC1, x): 8 .51 and 8.60 (3H, 2d, J=7.5 Hz), 6.3

(1H, m), 5.20 (2H, s), 4.95 (1H, d, J=4.5Hz), 4.69 (1H, s), 4.15 and 4.32 (1H, 2d , J=4.5 Hz), 3.20 and 3.32 (1H, 2s), 2.90 (2H, d,

J=9Hz) and 2.46 (2H, d, J=9Hz).

Example 8f.

A solution of 3.0 g of 2-methyl-7-[N-(tert.butoxycarbonyl)-2-(4-methylthiophenyl)glycyl]amino-3-cephem-4-carboxylic acid in 100 ml of formic acid is stirred for 1 hour at room temperature under anhydrous conditions. After the reaction has ended, the solvent is removed under reduced pressure from the reaction mixture, and the residue is dissolved in a mixture of water and ethyl acetate, after which the aqueous phase is separated. The aqueous phase is washed with ethyl acetate, and the organic solvent is completely removed under reduced pressure. The insoluble material is collected by filtration and freeze-dried, whereby 1.2 g of 2-methyl-7-[2-(4-methylthiophenyl) glycyl]amino-3-cephem-4-carboxylic acid is obtained in the form of a white powder with melting point 165-175°C.

Example 9f.<:>'

A solution of 3.80 g of 2-methyl-7-[N-(tert-butoxycarbonyl)-2-(4-methoxyphenyl)glycyl]amino-3-cephem-4-carboxylic acid in 20 ml of formic acid is stirred for 4.5 hours at room temperature. After the reaction has ended, the formic acid is removed under reduced pressure at a temperature below 35°C from the reaction mixture, and the residue is pulverized by adding acetonitrile, after which the powder is collected by filtration, whereby 2.9 g of powder is obtained. The powder (2.6 g) is suspended in 50 ml of acetonitrile. To the suspension is added 1.5 ml of water, after which the mixture is stirred for 1 hour at room temperature. The precipitate is collected by filtration and dried, whereby 2.15 g of 2-methyl-7-[2-(4-methoxyphenyl)glycyl]amino-3-cephem-4-carboxylic acid with melting point 165-168°C (decomposition) is obtained.

Example 10f.

A mixture of 317 mg of 2-methyl-7-[N-(tert-butoxycarbonyl)-2-(1,4-cyclohexadienyl)glycyl]amino-3-cephem-4-carboxylic acid and 3.17 ml of formic acid is stirred for 4 hours at room temperature. After the reaction has ended, the formic acid is removed under reduced pressure from the reaction mixture, and the residue is pulverized by adding ether. The powder is collected by filtration and dissolved in 27 ml of 95% aqueous acetonitrile solution, and then the solution is stirred for 1 hour. The precipitate is collected by filtration and dried, whereby 200 mg of 2-.methyl-7-[ 2-(1, 4-cyclohexadienyl) glycyl ] amino-3-cephem-4-carboxylic acid is obtained in the form of white crystals with a melting point of 168°C (fission).

Example llf.

A solution of 2.9 g of 2-methyl-7-[N-(tert.butoxycarbonyl)-2-(4-methylsulfinylphenyl)glycyl]amino-3-cephem-4-carboxylic acid in 7.5 ml of formic acid is stirred for 1 hour at room temperature under anhydrous conditions. After the reaction has ended, the solvent is removed under reduced pressure from the reaction mixture, and the residue is dissolved in a small amount of water, after which acetonitrile is added to the solution, and the precipitated crystals are collected by filtration. The crystals are dissolved in water, and the solution is freeze-dried, whereby

1.5 g of 2-methyl-7-[2-(4-methylsulfinylphenyl)glycyl]amino-3-cephem-4-carboxylic acid is obtained in the form of a powder with a melting point of 178-180°C (decomposition).

Example lg.

1 drop of a 1% solution of phenolphthalein in 95% ethanol is added to a solution of 0.43 g of 2-methyl-7-(D-2-phenyl-2-formyloxy-acetamido)-3-cephem-4- carboxylic acid in a mixture of 5 ml of water and 7 ml of methanol. Every time the red color of the phenolphthalein disappears, aqueous sodium hydroxide solution is added dropwise to the solution under ice-cooling. This is repeated until the 2-methyl-7-(D-2-phenyl-2-formyloxy-acetamido)-3-cephem-4-carboxylic acid can no longer be observed in the reaction mixture, and the solution is adjusted to a pH value of 3 with 10% hydrochloric acid. The methanol is removed under reduced pressure from the reaction mixture, and the precipitated gummy material is extracted 4 times with 10 ml of ethyl acetate. The extracts are collected, and the combined solution is dried over magnesium sulfate, after which the solvent is removed under reduced pressure. The residue is treated with isopropyl ether, whereby 0.29 g of 2-methyl-7-(D-2-phenyl-2-hydroxy-acetamido)-3-cephem-4-carboxylic acid is obtained in the form of a powder with a melting point of 172-173° C (cleavage).

The following compound is prepared in an analogous manner. 2-Methyl-7-[2-(2-thienyl)-2-hydroxyacetamido]-3-cephem-4-carboxylic acid with melting point 91-96°C (decomposition).

Example lh.

3.0 g of zinc powder are added with stirring at 5°C to a solution of 2.95 g of 2-methyl-7-[N-(1-cyclopropylethoxy)carbonyl-phenylglycyl]-amino-3-cephem-4-carboxylic acid-2 ,2,2-trichloroethyl ester in a mixture of 12.5 ml of anhydrous dimethylformamide and 3.75 ml of acetic acid, and the mixture is stirred for 1.5 hours. After the reaction, the zinc powder is filtered off, which is washed with 2 ml of dimethylformamide. The filtrate and washing liquids are collected, and the combined solution is extracted by

be poured into a mixture of 50 ml ethyl acetate, 50 ml ice water and 3 ml 10% hydrochloric acid. The aqueous phase is further extracted with 20 ml of ethyl acetate. The extracts are collected, washed three times with 20 ml of water and once with a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. After drying, the solvent is distilled off, and the residue formed is washed with ether and dried, whereby 2.01 g of 2-methyl-7-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]-

amino-3-cephem-4-carboxylic acid in the form of colorless crystals with a melting point of 168-169°C.

Example 2h.

Add 2.4 g of zinc powder under ice-cooling and stirring

a solution of 2.0 g of 2-methyl-7-[2-(1H-tetrazol-1-yl)acetamido]-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester in a mixture of 10 ml of anhydrous dimethylformamide and 3 ml acetic acid, and the mixture is stirred for 1.5 hours at the same temperature. After the reaction, the zinc powder is filtered off, and the filtrate is extracted by pouring it into a mixture of 50 ml ethyl acetate, ice water and 5 ml 10% hydrochloric acid. The aqueous phase is further extracted with 10 ml of ethyl acetate and the ethyl acetate extracts are collected, washed twice with water and dried over magnesium sulfate. After distilling off the solvent, the residue is crystallized by adding a small amount of ether, whereby 0.97 g of 2-methyl-7-[2-(1H-tetrazol-1-yl)acetamido]-3-cephem-4-carboxylic acid is obtained in form of colorless crystals with melting point 202-203°C (decomposition).

Example 3h.

3 ml of acetic acid and 2.4 g of zinc powder are added with stirring under ice cooling to a solution of 1.8 g of 2-methyl-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid-2, 2,2-trichloroethyl ester in 10 ml of anhydrous dimethylformamide, and the mixture is stirred for 1 hour at the same temperature. After the reaction, the zinc powder is filtered off,

and the filtrate is extracted by pouring it into a mixture of 50 ml of 5% hydrochloric acid and 40 ml of ethyl acetate. The ethyl acetate phase is washed with water and dried. After distilling off the solvent, the residue is dissolved in ether and allowed to stand, after which the precipitated crystals are collected by filtration and dried, whereby 1.2 g of 2-methyl-7-[2-(2-thienyl)acetamido]-3-cephem- 4-carboxylic acid with melting point 175°C (decomposition) ...

Example 4h.

3 ml of acetic acid and 2.4 g of zinc powder are added with stirring and ice-cooling to a solution of 1.9 g of 2-methyl-7-benzyloxycarboxamido-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester in 10 ml of anhydrous dimethylformamide , and the mixture is stirred for 1 hour at the same temperature. After the reaction, the zinc powder is filtered off, and the filtrate is poured into a mixture of 50 ml of 5% hydrochloric acid and 40 ml of ethyl acetate and extracted. The extract is washed with water and then dried. After distilling off the solvent, the residue is crystallized by adding ether, whereby 1.13 g of 2-methyl-7-benzyloxycarboxamido-3-cephem-4-carboxylic acid is obtained in the form of colorless crystals with a melting point of 167-169°C (decomposition).

Example 5h.

4.5 ml of acetic acid and 3.6 g of zinc powder are put under

stirring under ice-cooling to a solution of 2.79 g of 2-methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester in 15 ml of anhydrous dimethylformamide, and the mixture is stirred for 2 hours at the same temperature. After the reaction, the zinc powder is filtered off, and the filtrate is poured into a mixture of 75 ml of 5% hydrochloric acid and 50 ml of ethyl acetate and extracted. The extract is washed with water and dried. After distilling off the solvent, the residue is crystallized by adding ether, whereby 2.0 g of 2-methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylic acid is obtained in the form of colorless crystals with a melting point of 168-171°C (fission).

Example 6h.

4.1 ml of acetic acid and 3.4 g of zinc powder are put under

stirring under ice-cooling to a solution of 2.6 g of 2-methyl-7-12-(3-chlorophenyl)acetamido]-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester in 30 ml of anhydrous dimethylformamide, and the mixture stirred for 1.5 hours at the same temperature. After the reaction, the zinc powder is filtered off, and the filtrate is poured into a mixture of 150 ml of 5% hydrochloric acid and 75 ml of ethyl acetate and then extracted.

The extract is washed with water and dried. After distilling off the solvent, the residue is crystallized by adding acetonitrile. The crystals are collected by filtration, washed with ether and dried, whereby 1.4 g of 2-methyl-7-[2-(3-chlorophenyl)acetamido]-3-cephem-4-carboxylic acid is obtained in the form of colorless crystals with a melting point 173-174°C (decomposition)..

Example 7h.

0.6 g of zinc powder is added while cooling at 0-5°C to a solution of 0.54 g of 2-methyl-7-[3-(N-tert.butoxycarbonylamino)-3-(2-thienyl-propionamido]-3 -cephem-4-carboxylic acid-2,2,2-trichloroethyl ester in a mixture of 3 ml of dimethylformamide and 1 ml of acetic acid, and the mixture is stirred for 2 hours. After the reaction, the zinc powder is filtered off, and the filtrate is poured into a mixture of 50 ml of ethyl acetate and 30 ml of 5% hydrochloric acid and then extracted.The extract is washed with

a saturated aqueous sodium chloride solution and dried over magnesium sulfate, after which the solvent is distilled off, whereby 0.365 g of 2-methyl-7-[3-(N-tert.butoxycarbonylamino)-3-(2-thienyl)-propionamido]-3 is obtained -cephem-4-carboxylic acid with melting point 167-170°C (decomposition).

Example 8h.

Add 4 ml of acetic acid and 3 g of zinc powder while stirring

under ice-cooling to a solution of 3.2 g of 2-methyl-7-(2-cyanoacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester in 15 ml of anhydrous dimethylformamide, and the mixture is stirred for 1 hour at the same temperature. After the reaction, 100 ml of ethyl acetate are added to the reaction mixture. The insoluble material is filtered off, and the filtrate is washed with 5% hydrochloric acid, which is saturated with sodium chloride, and then extracted with a saturated aqueous sodium hydrogen carbonate solution. The extract is acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. After distilling off the solvent, the crystalline residue is recrystallized from a mixture of ethyl acetate and benzene, whereby 2.3 g of 2-methyl-7-(2-cyanoacetamido)-3-cephem-4-carboxylic acid is obtained. with melting point 162-166°C.

Example 9h.

Add 8 ml of acetic acid and 6 g of zinc powder while stirring

under ice-cooling to a solution of 4.1 g of 2-methyl-7-(3-phenylureido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester in 30 ml of anhydrous dimethylformamide, and the mixture is stirred for 1 hour under ice cooling and then for 3.5 hours at room temperature. After the reaction, 10% hydrochloric acid and ethyl acetate are added to the reaction mixture. The insoluble material is filtered off, and the ethyl acetate phase is separated and then extracted with an aqueous sodium bicarbonate solution. The extract is acidified with 10% hydrochloric acid and extracted with ethyl acetate, after which the extract is dried over magnesium sulphate. After distilling off the solvent, the residue is crystallized by adding ether, whereby 1.0 g of 2-methyl-7-(3-phenylureido)-3-cephem-4-carboxylic acid with melting point 148-151°C is obtained.

Example lOh.

Add 8 ml of acetic acid and 6 g of zinc powder while stirring

under ice-cooling to a solution of 4.65 g of 2-methyl-'7-[2-(1,3,4-

thiadiazol-2-ylthio)acetamido]-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester in 30 ml of anhydrous dimethylformamide, and the mixture is stirred for 1 hour at the same temperature. After the reaction, 150 ml of ethyl acetate are added to the reaction mixture. The insoluble material is filtered off, and the filtrate is washed with 5% hydrochloric acid, which is saturated

r

with sodium chloride, and then extracted with an aqueous sodium bicarbonate solution. The extract is acidified with 10% hydrochloric acid and extracted with ethyl acetate, after which the ethyl acetate phase is washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. After distilling off the solvent, the residue is recrystallized from a mixture of ethyl acetate and benzene, whereby 1.5 g of 2-methyl-7-[2-(1,3,4-thiadiazol-2-ylthio)acetamido]-3-cephem- 4-carboxylic acid with melting point 197-199°C.

Example llh.

1.6 ml of acetic acid and 1.2 g of zinc powder are added with stirring under ice cooling to a solution of 1.52 g of 2-methyl-7-[N-tert-butoxycarbonyl-2-(2-thienyl)glycyl]amino-3 -cephem-4-carboxylic acid-2,2,2-trichloroethyl ester in 10 ml of anhydrous dimethylformamide, and the mixture is stirred for 1 hour at the same temperature. After the reaction, the zinc powder is filtered off and the filtrate is poured into an ice-cooled mixture of 2-3% hydrochloric acid and ethyl acetate and then extracted. The extract is washed with water and extracted with an aqueous sodium bicarbonate solution, after which the aqueous phase is acidified by adding 5% sulfuric acid and ethyl acetate and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulphate, after which the solvent is distilled off under reduced pressure. The residue is pulverized by adding isopropyl ether, collected by filtration and dried, whereby 0.7 g of 2-methyl-7-[N-tert.butoxycarbonyl-2-(2-thienyl)glycyl]amino-3-cephem-4- carboxylic acid in the form of an amorphous substance with IR spectrum (Nujol): 3300, 1789, 1725, 1710, 16 90 and 1678 cm"<1>.

Example 12h.

8 ml of acetic acid and 6 g of zinc powder are added under ice-cooling to a solution of 6.60 g of 2-methyl-7-[2-(5-methyl-1,3,4-thiadiazol-2-yloxy)acetamido]-3-cephem -4-carboxylic acid-2,2,2-trichloroethyl ester in 40 ml of anhydrous dimethylformamide, and the mixture is stirred for 1.5 hours. After the reaction, the zinc powder is filtered off, and it is washed with dimethylformamide. The filtrate and washing liquids are collected, and the combined solution is poured into an ice-cooled mixture of ethyl acetate and 2-3% hydrochloric acid and then extracted. The extract is extracted with an aqueous sodium bicarbonate solution, and the aqueous solution is acidified with hydrochloric acid and then extracted with ethyl acetate. The aqueous phase is saturated with sodium chloride and then extracted four times with 80 ml of ethyl acetate, after which the two ethyl acetate extracts are combined. After drying the combined extracts over magnesium sulphate, the solvent is distilled off under reduced pressure. The residue is crystallized by adding ether, which gives

2.0 g dimethylformamide adduct of 2-methyl-7-[2-(5-methyl-1,3,4-thiadiazol-2-yloxy)acetamido]-3-cephem-4-carboxylic acid with melting point 113-

116°C.

Example 13h.

0.6 g of zinc powder is added with stirring under ice cooling to a solution of 0.6 g of 2-methyl-7-[3-(2-chlorophenyl)-5-methylisoxazol-4-yl]carboxamido-3-cephem-4- carboxylic acid 2,2,2-trichloroethyl ester in a mixture of 5 ml of anhydrous dimethylformamide and 0.8 ml of acetic acid,

and the mixture is stirred for 40 minutes at the same temperature. After the reaction, the zinc powder is filtered off, and it is washed with dimethylformamide. The filtrate and washing liquids are collected, and the combined solution is poured into an ice-cooled mixture of ethyl acetate and 2-3% hydrochloric acid and then extracted with ethyl acetate. The extract is extracted with an aqueous sodium bicarbonate solution, and the aqueous phase is acidified with 10% sulfuric acid and then extracted with ethyl acetate, after which the extract is washed with water and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the oily component is crystallized by adding ether, and the crystals are collected by filtration and then washed with ether, whereby 0.2 g of 2-methyl-7-[3-(2-chlorophenyl)-5 is obtained - methylisoxazol-4-yl]carboxamido-3-cephem-4-carboxylic acid with melting point 2O2-2.03°C.

Example 14h.

0.48 g of 2-methyl-7-(2-methylthioacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester, 0.48 ml of glacial acetic acid and 0.48 g of zinc powder are added to 5 ml of anhydrous dimethylformamide, and the mixture is stirred for 1 hour under ice cooling. After the reaction, the zinc powder is filtered off. The filtrate is poured into a mixture of 10 ml of 3% hydrochloric acid and

10 ml of ethyl acetate, and the ethyl acetate phase is separated. The aqueous phase is extracted a further three times with 10 ml of ethyl acetate. The ethyl acetate fractions are collected. The combined extract is washed with a saturated aqueous sodium chloride solution and dried over magnesium sulphate, after which the solvent is distilled off under reduced pressure.

The residue formed is crystallized by adding ether, and the crystals are collected by filtration and washed with ether, whereby

0.29 g of 2-methyl-7-(2-methylthioacetamido)-3-cephem-4-carboxylic acid with melting point 181-183°C (decomposition) is obtained.

Example 15h.

5.55 g of zinc powder is added to a solution of 5.55 g of 2-methyl r 7-(2-allylthioacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester in 55.5 ml of anhydrous dimethylformamide, and then 5.5 ml of acetic acid is added dropwise to the solution, after which the mixture is stirred for 1 hour. After the reaction, the zinc powder is filtered off,

and it is washed with ethyl acetate. The filtrate and washing liquids are collected, after which the solution is poured into a mixture of 250 ml of 5% hydrochloric acid and 100 ml of ethyl acetate and then extracted. The aqueous phase is extracted twice more with ethyl acetate. The ethyl acetate phases are collected, and the combined ethyl acetate phases are washed with a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solution is then concentrated under reduced pressure, until the solution has a volume of approx. 40 ml. The precipitated crystals are collected by filtration, washed with isopropyl ether and dried, whereby 3.69 g of 2-methyl-7-(2-allylthioacetamido)-3-cephem-4-carboxylic acid is obtained in the form of colorless crystals with a melting point of 121-123° C. The filtrate is further concentrated, and the crystals produced are washed with isopropyl ether and dried, whereby 0.75 g of 2-methyl-7-(2-allylthioacetamido)-3-cephem-4-carboxylic acid is obtained.

Example 16h.

1.58 g of 2-methyl-7-(2-formyloxy-2-phenylacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester, 1.5 g of zinc powder and 1.5 ml of glacial acetic acid are added to 15 ml of anhydrous dimethylformamide, and the mixture is stirred for 1 hour under ice cooling. After the reaction, the zinc powder is filtered off, and the filtrate is poured into a mixture of 30 ml of 5% hydrochloric acid and 30 ml of ethyl acetate and then extracted. The aqueous phase is extracted a further two times with 30 ml of ethyl acetate. The ethyl acetate fractions are collected, and the combined solution is washed with 5% hydrochloric acid and with water and then dried over magnesium sulfate. After off-

distillation of the solvent under reduced pressure, the residue is pulverized by addition of isopropyl ether followed by filtration

and drying, whereby 1.0 g of 2-methyl-7-(2-formyloxy-2-phenylacetamido)-3-cephem-4-carboxylic acid is obtained in the form of an amorphous substance with an IR absorption spectrum (Nujol): 3280, 1787, 1720 and 1678 cm"<1>.

Example 17h.

1.2 g of zinc powder is added under ice cooling to a solution of 0.92 g of 2-methyl-7-(1-cyclopropylethoxy)carboxamido-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester in a mixture of 5 ml dimethylformamide and 1.5 ml of acetic acid, and the mixture is stirred for 1.5 hours at the same temperature. After the reaction, the zinc powder is filtered off,

and it is washed with 2 ml of dimethylformamide. The dimethylformamide phase is poured

in a mixture of 30 ml ethyl acetate, 30 ml water and 2 ml 10% saline

acid and extracted. The dimethylformamide phase is further extracted

with 10 ml of ethyl acetate. The ethyl acetate extracts are collected, washed with water and with a saturated aqueous sodium chloride solution in the specified order and dried over magnesium sulfate, after which the solvent is distilled off. The residue is pulverized using a small amount of ether, whereby 0.45 g of 2-methyl-7-(1-cyclopropylethoxy)-carboxamido-3-cephem-4-carboxylic acid with melting point 158.5-160°C (decomposition) is obtained .

Example 18h.

1 ml of acetic acid and 2.0 g of zinc powder are added under ice-cooling to a solution of 1.53 g of 2-methyl-7-amino-3-cephem-4-carboxylic acid-.2,2,2-trichloroethyl ester hydrochloride in 10 ml of dimethylformamide , and the mixture is stirred for 1 hour at a temperature between -5 and 0°C, after which the reaction mixture is filtered. The filtered zinc powder is washed with dimethylformamide, and the filtrate and washing liquids are collected, after which a few ml of water are added to the solution. The precipitated crystals are collected by filtration and dissolved in a small amount of aqueous sodium bicarbonate solution, after which insoluble material is filtered off. The filtrate is adjusted with

10% hydrochloric acid at a pH value of 4, and the precipitated crystals are collected by filtration, washed with water and with acetone, and dried, whereby 0.38 g of 2-methyl-7-amino-3-cephem-4 is obtained -carboxylic acid with melting point 222°C (decomposition).

Example 19h.

2.4 g of zinc powder are added under ice-cooling to a solution

of 1.85 g of 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester in a mixture of 10 ml of dimethylformamide and 3 ml of acetic acid, and the mixture is stirred for 2 hours , after which the reaction mixture is filtered. The filtrate is poured into a mixture of 50 ml ethyl acetate, 50 ml ice water and 2 ml 10% hydrochloric acid, and then the ethyl acetate phase is separated. The aqueous phase is further extracted with 10 ml of ethyl acetate. The ethyl acetate fractions are collected, and the combined solution is washed with water and then with a saturated aqueous sodium chloride solution and dried over magnesium sulfate, after which the solvent is distilled off. The residue is crystallized by adding a small amount of acetonitrile, and the precipitated crystals are collected by filtration and dried, whereby 1.2 g of 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid is obtained in the form of colorless crystals with melting point 109°C (decomposition).

Example 20h.

0.9 g of zinc powder is added under ice cooling to a solution of 0.69 g of 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester with a melting point of 120-130 °C in a mixture of 5 ml of dimethylformamide and 1 ml of acetic acid, and the mixture is stirred for 1.5 hours, followed by filtration of the reaction mixture, after which the filtered zinc is washed with a small amount of dimethylformamide. The filtrate and washing liquids are collected, and the combined solution is poured

in a mixture of 30 ml ethyl acetate, 30 ml water and 2 ml 10% hydrochloric acid, after which the ethyl acetate phase is separated. The aqueous phase is further extracted with 10 ml of ethyl acetate. The ethyl acetate fractions are collected, and the combined solution is washed with water and with a saturated aqueous sodium chloride solution in the order indicated and dried over magnesium sulfate, after which the solvent is distilled off. The residue is crystallized by adding a small amount of acetonitrile, and the precipitated crystals are collected by filtration and dried, whereby 0.34 g of 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid with a melting point of 121° is obtained C, which is an isomer in the 2-position of 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid with melting point 109°C (decomposition), which was prepared in example 19h.

Example 21h.

1.8 g of zinc powder is added under ice cooling to a solution of 1.0 g of 2-methyl-7-(2-phenylacetamido)-2-cephem-4-carboxylic acid-2,2,2-

trichloroethyl ester in a mixture of 7.5 ml of dimethylformamide and 2.5 ml of acetic acid, and the mixture is stirred for 1.5 hours followed by filtration of the reaction mixture, and the filtered zinc is washed with 2 ml of dimethylformamide. The filtrate and washing liquids are collected, and the combined solution is poured into a mixture of 30 ml ethyl acetate, 30 ml ice water and 2 ml 10% hydrochloric acid, after which the ethyl acetate phase

be divorced. The aqueous phase is further extracted with 10 ml of ethyl acetate. The ethyl acetate fractions are collected, and the combined solution is washed with water and with a saturated aqueous sodium chloride solution in the order indicated and dried over magnesium sulfate, after which the solvent is distilled off. The residue is crystallized by adding a small amount of ether, after which the precipitated crystals are collected by filtration and dried, whereby 0.45 g of 2-methyl-7-(2-phenylacetamido)-2-cephem-4-carboxylic acid is obtained in the form of colorless crystals with melting point 204°C.

The following compounds are prepared using a method which is analogous to the method used in the above-mentioned examples. 1) 2-methyl-7-(phenylglycyl)amino-3-cephem-4-carboxylic acid with melting point 168.5-171°C. 2) 2-methyl-7-[3-amino-3-(2-thienyl).propionamido]-3-cef em-4-carboxylic acid with melting point 218-221°C (decomposition). 3) 2-methyl-7-[(2-thienyl)glycyl]amino-3-cephem-4-carboxylic acid with melting point 145-149°C (decomposition). 4) 2-methyl-7-(2-hydroxy-2-phenylacetamido)-3-cephem-4-carboxylic acid with melting point 172-173°C. 5) 2-methyl-7-[N-tert.butoxycarbonyl-2-(2,5-dihydrophenyl)glycyl]-amino-3-cephem-4-carboxylic acid with melting point 126-131°C (decomposition). 6) 2-methyl-7-[N-tert.butoxycarbonyl-2-(4-hydroxyphenyl)-D-glycyl]-amino-3-cephem-4-carboxylic acid in the form of a powder. 7) 2-methyl-7-[N-tert.butoxycarbonyl-2-(4-methylthiophenyl)glycyl]-amino-3-cephem-4-carboxylic acid with melting point 110-120°C. 8) 2-methyl-7-[N-tert.butoxycarbonyl-2-(4-methoxyphenyl)glycyl]-amino-3-cephem-4-carboxylic acid with melting point 81-86°C (decomposition). 9) 2-methyl-7-(2-sulfo-2-phenylacetamido)-3-cephem-4-carboxylic acid with melting point 115°C (bloating), 200-220°C (decomposition). 10) 2-methyl-7-(2-azido-2-phenylacetamido)-3-cephem-4-carboxylic acid with melting point 65-68°C. 11) 2-methyl-7-[2-(3-pyridyl)acetamido]-3-cephem-4-carboxylic acid with melting point 147-149°C (decomposition). 12) 2-methyl-7-[2-hydroxy-2-(2-thienyl)acetamido]-3-cephem-4-carboxylic acid with melting point 91-96°C (decomposition). 13) 2-methyl-7-[N-(1,3,4-thiadiazol-2-yl)thiomethylcarbonyl-2-phenylglycyl]amino-3-cephem-4-carboxylic acid with melting point 14 3-145°C.

(fission).

14) 2-methyl-7-tN-tert.butoxycarbonyl-2-(4-tert.butoxycarbonyl-1-methoxyphenyl)glycyl]amino-3-cephem-4-carboxylic acid in the form of a powder. 15) 2-methyl-7-[N-(1-cyclopropylethoxy)carbonyl-2-(5,6-dihydro-2H-pyran-3-yl)glycyl]amino-3-cephem-4-carboxylic acid with melting point 195- 197°C. 16) 2-methyl-7-[2-(1,2,5-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylic acid with melting point 188-190°C (decomposition). 17) 2-methyl-7-[N-tert.butoxycarbonyl-2-(3-methanesulfonamidophenyl)-glycyl]amino-3-cephem-4-carboxylic acid in the form of an oil. 18) 2-methyl-7-[N-tert.butoxycarbonyl-2-(4-methylsulfinylphenyl)-glycyl]amino-3-cephem-4-carboxylic acid with melting point 110-120°C. 19) 2-methyl-7-[2-(5-indanyl)oxycarbonyl-2-phenylacetamido]-3-cephem-4-carboxylic acid with melting point 90-95°C (softening), 150-160°C (decomposition). 20) 2-methyl-7-(2-isonicotinoyloxy-2-phenylacetamido)-3-cephem-4-carboxylic acid with melting point 217-219°C. 21) 2-methyl-7-[D-2-(4-hydroxyphenyl)glycyl]amino-3-cephem-4-carboxylic acid in the form of a powder. 22) 2-methyl-7-[2-(5,6-dihydro-2H-pyran-3-yl)glycyl]amino-3-cephem-4-carboxylic acid with melting point 125-128°C (decomposition). 23) 2-methyl-7-[2-(3-methanesulfonamidophenyl)glycyl]amino-3-cephem-4-carboxylic acid with melting point 192-193°C (decomposition). 2 4) 2-'methyl-7-[2-(4-carboxymethoxyphenyl)glycyl]amino-3-ce fem-4-carboxylic acid in the form of a powder. 25) 2-methyl-7-[2-(4-methylthiophenyl)glycyl]amino-3-cephem-4-carboxylic acid with melting point 165-175°C. 26) 2-methyl-7-[2-(4-methoxyphenyl)glycyl]amino-3-cephem-4-carboxylic acid with melting point 165-168°C. 2 7) 2c-methyl-7-[2-(2,5-dihydrophenyl)glycyl]amino-3-ce f em-4-carboxylic acid with melting point 168°C (decomposition). 28) 2-methyl-7-[2-(4-methylsulfinylphenyl)glycyl]amino-3-cephem-4-carboxylic acid in the form of a powder. 29) 2-methyl-7-[2-(5,6-dihydro-2H-pyran-3-yl)acetamido]-3-cephem-4-carboxylic acid with melting point 172.5-173.5°C (decomposition) . 30) 2-methyl-7-(4-methoxyphenyl)glyoxylamido-3-cephem-4-carboxylic acid with melting point 188-189°C (decomposition). 31) 2-methyl-7-(N-tert.butoxycarbonylphenyl-D-glycyl)amino-3-cephem-4-carboxylic acid with melting point 125-127°C (decomposition). 32) 2-methyl-7-N-[2-(2-nitrophenoxy)acetyl phenylglycyl]amino-3-cephem-4-carboxylic acid with melting point 135-137°C (decomposition).

Example li

A suspension of 1.0 g of 2-methyl-7-(2-phenylglycyl)amino-3-cephem-4-carboxylic acid in 10 ml of water is adjusted to a pH value of 8.8 by the dropwise addition of 10% sodium hydroxide solution . 10 ml of acetone is added to the suspension, and the mixture is stirred for 24 hours in an ice bath. The acetone is removed under reduced pressure, and then the aqueous phase is adjusted to a pH value of 3.5 with 10% hydrochloric acid, and then it is extracted three times with 20 ml of ethyl acetate. The residue produced by distilling off the ethyl acetate is dissolved in a small amount of acetone, and then a small amount of insoluble material is filtered off. A large amount of ether is added to the filtrate, and then the precipitate is collected by filtration, whereby 0.30 g of 2-methyl-7-(2,2-dimethyl-4-phenyl-5-oxoimidazolidin-1-yl)-3- cephem-4-carboxylic acid with melting point 160-162°C (decomposition).

Claims (4)

1. Analogy method for the manufacture of pharmaceutical active compounds of the general formula I 1 2 where R denotes amino or substituted amino, R denotes carboxy or protected carboxy, and R denotes lower alkyl, or salts thereof, characterized by ata) a compound of the general formula Ia 12 3 where R , R and R each have the above meaning, is reduced, or b) for making connections with the general formula Ic where R 2 and R 3 each have the above meaning or salts thereof, a compound of the general formula Ib 2 3 let. where R and R each have the meaning given above, and R denotes protected amino, is subjected to elimination reaction for the protecting group of the amino group, or c) for making connections with the general formula Id 2 3 where R denotes acylamino, and R and R each have the meaning given above, or salts thereof, a compound of the general formula Ic 2 3 where R and R have the meaning stated above, or a salt thereof is reacted with an acylating agent, ord) to produce compounds with the general formula le 11d 2 3 where R denotes acylamino, and R and R each have the above meaning or salts thereof, a compound of the general formula Id lb 2 3 where R , R , and R each have the meaning given above, is reacted with a trialkyloxonium haloborate or an iminohalogenating agent and an iminophoretic agent, after which the resulting compound is reacted with an acylating agent, if necessary followed by hydrolysis, or e) for making connections with the general formula lg where R <lc> ^ denotes acylamino with an amino group, and R <2> and R"^ each have the above meaning, or salts thereof, a compound of the general formula If 2 3 le where R and R have the meaning given above, and R denotes acylamino with protected amino, subject to an elimination reaction for the protecting group for the amino group, or f) for the preparation of compounds of the general formula li lf. 23 where R denotes acylamino with a hydroxy group, and R and R each has the above meaning, or salts thereof, a compound of the general formula Ih 2 3 le where R and R each have the meaning given above, and R denotes acylamino with a protected hydroxy group, is subjected to an elimination reaction for the protecting group for the hydroxy group, or g) to. making connections with the general formula Ik where R 1 and R 3 each have the above meaning, or salts thereof, a compound of the general formula Ij where R 1 and R 3 each have the meaning indicated above, and R<2a> denotes protected carboxy, is subjected to an elimination reaction for the protecting group of the carboxy group, orh) for the preparation of compounds with the general 2 3 .4 where R and R each have the above meaning, R denotes - 5 6 aryl, and R and R each denote lower alkyl, or salts thereof, a compound of the general formula II 2 3 4 where R , R and R each have the meaning indicated above, or a salt thereof is reacted with a lower alkanone with the general formula R^-CO-R^, where R^ and R ^ h <y> are have the meaning indicated above. 2. Method according to claim 1, characterized in that compounds are produced, where R<1> is amino, 2,2-di(lower)alkyl-4-aryl-5-oxoimidazolidin-1-yl or acylamino, R 2 is carboxy or protected carboxy, and 3 R is lower, alkyl. 3. Method according to claim 2, characterized in that compounds are produced, where R <1> is amino, 2,2-di(lower)alkyl-4-phenyl-5-oxoimidazolidin-1-yl, lower alkyloxycarbonylamino, phenyl(lower)alkylcarbonylamino, 3-phenylureido, lower oxyphenylglyoxylamido, cyano(lower) -alkanoylamino, lower alkylthio(lower)alkanoylamino, lower alkenyl-thio(lower)alkanoylamino, phenylthio(lower)alkanoylamino, phenoxy-(lower)alkanoylamino, phenyl(lower)alkanoylamino, halophenyl-(lower)alkanoylamino, phenyl- and amino-substituted lower alkanoylamino, phenyl- and lower alkoxycarbonylamino-substituted lower alkanoylamino, phenyl- and nitrophenoxy(lower)alkanoylamino-substituted lower alkanoylamino, phenyl- and thiadiazolylthio(lower)-alkanoylamino-substituted lower alkanoylamino, hydroxyphenyl- and amino-substituted lower alkanoylamino, hydroxyphenyl- and lower alkoxycarbonylamino-substituted lower alkanoylamino, Lower Alkoxyphenyl- and Amino-Substituted Lower Alkanoylamino, Lower Alkoxyphenyl- and Lower Alkoxycarbonylamino-Substituted Lower Alkanoylamino, Lower Alkylthiophe nyl- and amino-substituted lower alkanoylamino, lower alkylthiophenyl- and lower alkoxycarbonylamino-substituted lower alkanoylamino, lower alkylsulfinylphenyl-and amino-substituted lower alkanoylamino, lower alkylsulfinylphenyl-and lower alkoxycarbonylamino-substituted lower alkanoylamino, carboxy(lower) alkoxyphenyl- and amino-substituted lower alkanoylamino, lower alkoxycarbonyl(lower) alkoxyphenyl - and lower alkoxycarbonylamino-substituted lower alkanoylamino, lower alkanesulfonamidophenyl- and lower alkoxycarbonylamino-substituted lower alkanoylamino, dihydrophenyl- and amino-substituted lower alkanoylamino, dihydrophenyl- and lower alkoxycarbonylamino-substituted lower alkanoylamino, phenyl- and azido-substituted lower alkanoylamino, phenyl- and hydroxy-substituted lower alkanoylamino, phenyl- and lower alkanoyloxy-substituted lower alkanoylamino, phenyl- and pyridylcarbonyloxy-substituted lower alkanoylamino, phenyl- and sulfo-substituted lower alkanoylamino, phenyl- and indanyloxycarbon yl-substituted lower alkanoylamino, thienyl(lower)alkanoylamino, thienyl- and amino-substituted lower alkanoylamino, thienyl- and lower alkoxycarbonylamino-substituted lower alkanoylamino, thienyl- and hydroxy-substituted lower alkanoylamino, dihydropyranyl(lower)-alkanoylamino,. dihydropyranyl- and amino-substituted lower alkanoylamino, dihydropyranyl- and lower alkoxycarbonylamino-substituted lower alkanoylamino, pyridyl(lower)alkanoylamino, thiadiazolyl-(lower)alkanoylamino, lower alkylthiadiazolyloxy(lower)alkanoylamino, thiadiazolylthio(lower)alkanoylamino, tetrazolyl(lower)alkanoylamino or halophenyl- and lower alkyl-substituted isoxazolylcarboxamido, R 2 is carboxy, lower alkoxycarbonyl or trihalogen (lower) alkoxycarbonyl, ,_ and R <3> is lower alkyl or salts thereof. 4. Method according to claim 1, characterized in that compounds are produced where R <1> is amino, 2,2-dimethyl-4-phenyl-5-oxoimidazolidin-1-yl, (1-cyclopropylethoxy)carboxamido, benzyloxycarboxamido, 3-phenylureido, 2-(4-methoxyphenyl)glyoxylamido, 2- cyanoacetamido, 2^ methylthioacetamido, 2-(allylthio)acetamido, 2-(phenylthio)acetamido, 2-phenoxyacetamido, 2-phenylacetamido, 2-(3-chlorophenyl)acetamido, phenylglycylamino, N-(1-cyclopropylethoxy)carbonylphenylglycylamino, N-tert.butoxycarbonylphenylglycylamino, N-[2-(2-nitrophenoxy)acetyl]-phenylglycylamino, N-(1,3,4-thiadiazol-2-ylthio)acetylphenylglycyl, 2-amino-2-(4-hydroxyphenyl)acetamido, 2-tert.butoxycarbonylamino-2-(4-hydroxyphenyl)acetamido, 2-amino-2-(4-methoxyphenyl)acetamido, 2-tert.butoxycarbonylamino-2-( 4-Methoxyphenyl)acetamido, 2-amino-2-(4-methylthiophenyl)acetamido, 2-tert.butoxycarbonylamino-2-(4-methylthiophenyl)acetamido, 2-amino-2-(4-methylsulfinylphenyl)acetamido, 2-tert. .butoxycarbonylamino-2-(4-methylsulfinylphenyl)acetamido, 2-amino-2-(4-carboxymethoxyphenyl)acetamido, 2-tert.butoxycarbonylamino-2-(4-tert.butoxycarbonylmethoxyphenyl)acetamido, 2-tert.butoxycarbonylamino-2 -(3-methanesulfonamidophenyl)acetamido, 2-amino-2-(2,5-dihydrophenyl)acetamido, 2-tert. butoxycarbonylamino-2-(2,5-dihydrophenyl)acetamido, 2-azido-2-phenylacetamido, 2-hydroxy-2- phenylacetamido, 2-formyloxy-2-phenylacetamido, 2-isonicotinoyloxy-2-phenylacetamido, 2-sulfo-2-phenylacetamido, 2-(5-indanyloxy)carbonyl-2-phenylacetamido, 2-(2-thienyl)acetamido, 2- amino-2-(2-thienyl)-acetamido, 2-tert.butoxycarbonylamino-2-(2-thienyl)acetamido, 3-amino-3-(2-thienyl)propionamido, 3-tert.butoxycarbonylamino-3-(2 -thienyl)-propionamido, 2-hydroxy-2-(2-thienyl)acetamido, 2-(5,6-dihydro-2H-pyran-3-yl)acetamido, 2-amino-2-(5,6-dihydro -2H-pyran-3-yl)acetamido, 2-(1-cyclopropylethoxy)carbonylamino-2-(5,6-dihydro-2H-pyran-3-yl)acetamido, 2-tert.butoxycarbonylamino-2-(5, 6-dihydro-2H-pyran-3-yl)acetamido, 2-(3-pyridyl)acetamido, 2-(1,2,5-thiadiazol-3-yl)acetamido, 2-(5-methyl-1,3 ,4-thiadiazol-2-yloxy)acetamido, 2-(1,3,4-thiadiazol-2-ylthio)acetamido, 2-(1H-tetrazol-1-yl)acetamido or 3-(2-chlorophenyl)-5 -methylisoxazol-4-ylcarboxamido, R 2 is carboxy, methoxycarbonyl or 2,2,2-trichloroethoxycarbonyl, and R<3> is methyl.