NO750390L - - Google Patents

Description

Process for the preparation of penam and cefam derivatives.

The present invention relates to a method for the production of antibacterially active penam and cefam derivatives, and the method is illustrated in the following reaction core:

1 2

In the stated formulas R denotes optionally substituted anno, R denotes optionally protected carboxy, R denotes lower alkyl, R 4 denotes the residue of a thiol compound HR 4 , R 5 denotes amino or the residue of an amine, X denotes -S- or t Y denotes the residue

-s-,

of a nucleophile, Z denotes a group, which can be converted into a nucleophile residue, R'^" denotes protected amino, R""'" denotes acylamino, R' . denotes protected carboxy, Y<1> denotes halogen or the residue of a nucleophile, Z" denotes halogen, Z" denotes an acid residue, and A denotes a group of the general formula

where R 3 and Y have the meaning indicated above.

The compounds with the general formula II, which are used as starting materials in the method according to the present invention can be prepared by the reaction of the corresponding 2-methyl-2-lower alkyl-6r-substituted penam-3-carboxylic acid-1-oxide compound with the corresponding thiol compound, and the compounds of the general formula III, which are used as starting materials, can be prepared by the reaction of the corresponding compounds of the formula II with ammonia or the corresponding amine

In the description, the term "substituted amino" in connection with R"^ denotes suitable substituted amino groups, for example suitable substituted amino groups such as hydrazino, mono(or di)-(lower)-alkylamino, mono(or di)-(lower)alkenylamino, lower alkyldenamino, ar(lower)alkyldenamino, acylamino and amino groups, which are substituted with amino protecting groups other than acyl groups; suitable lower alkyl groups in mono(or di)-(lower)alkylamino are, for example, methyl, ethyl, propyl, isopropyl and butyl;

suitable lower alkenyl groups in mono(or di)-(lower)-alkenylamino are, for example, allyl and 2-butenyl;

suitable lower alkylidene groups in lower alkylideneamino are, for example, ethylidene, propylidene and butylidene;

suitable ar(lower)alkylidene groups in ar(lower)alkylidene are .benzylidene and phenylethylidene;

suitable acyl groups in the acylamino groups are carbamoyl, aliphatic acyl groups and acyl groups containing an aromatic or heterocyclic ring;

suitable aliphatic acyl groups are saturated or unsaturated, lower or higher alkanoyl groups, which may be branched or contain a cyclic ring, for example lower or higher aliphatic acyl groups such as lower alkanoyl (for example formyl, acetyl, propi^nyl, butyryl, isobutyryl, valeryl ( for example cyclopentanecarbonyl, cyclohexanecarbonyl and cycloheptanecarbonyl), lower or higher cycloalkyl(lower)alkanoyl (for example cyclopentylacetyl, cyclohexylacetyl, cycloheptylacetyl, cyclohexylpropionyl and cycloheptylpropionyl), lower or higher cycloalkadienecarbonyl (for example dihydrobenzoyl), lower or higher cycloalkadienyl(lower) alkanoyl (eg dihydro-phenylacetyl, dihydrophenylpropionyl), and lower or higher a liphatic acyl groups containing an oxygen or sulfur atom, for example lower alkoxy(lower)alkanoyl (for example methoxyacetyl, ethoxyacetyl and methoxypropionyl), lower alkylthio(lower)alkanoyl (for example methylthioacetyl, ethylthioacetyl and methylthiopropionyl), lower alkenylthio(lower )alkanoyl (for example, allylthioacetyl and allylthiopropionyl), lower or higher cycloalkylthio(lower)alkanoyl (for example, cyclopentylthioacetyl, cyclohexylthiopropionyl, cycloheptylthioacetyl), lower or higher cycloalkoxy(lower)alkanoyl (for example, cyclopentyloxyacetyl and cyclohexyloxypropionyl), lower or higher cycloalkanedienyloxy (lower)alkanoyl (for example dihydrophenoxyacetyl , dihydrophenoxypropionyl), lower or higher cycloalkahdienylthio(lower)alkanoyl (for example dihydrophenylthio-acetyl and dihydrophenylthiopropionyl), lower alkoxycarbonyl (for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butox ycarbonyl and tert.-butoxycarbonyl), lower or higher cycloalkyloxycarbonyl (for example cyclopentyloxycarbonyl, cyclohexyloxycarbonyl and cycloheptyloxycarbonyl), lower or higher cycloalkanedienyloxycarbonyl (for example dihydrophenoxycarbonyl);

suitable acyl groups containing an aromatic ring such as benzene and naphthalene are for example arylcarbamoyl (for example phenylcarbamoyl), aryloyl (for example benzoyl, toluoyl, naphthoyl, 9-methylnaphthoyl, phthaloyl, benzenesulfonyl, tetrahydronaphthoyl, indan-carbonyl), ar(lower )alkanoyl (for example phenylacetyl, phenylpropio-

nyl, phenylbutyryl, tolylacetyl, xylylacetyl, naphthylacetyl, tetra-hydronaphthylacetyl and indanylacetyl), and the carbon atom in the alkyl group 1 the indicated ar(lower)alkanoyl groups can be replaced with an oxygen or sulfur atom or a carbonyl group, for example aryloxy (plaver) alkanoyl (for example phenoxyacetyl, phenoxypropionyl, phenoxybutyryl, xylyloxyacetyl) , aryloxycarbonyl (for example phenoxycarbonyl, xylyloxycarbonyl, naphthyloxycarbonyl and indanyloxycarbonyl) , ar(lower) alkoxycarbonyl (for example benzyloxycarbonyl and phenylethyloxycarbonyl), arylthio( lower)alkanoyl (eg phenylthioacetyl and phenylthiopropionyl), arylglyoxyloyl (eg phenylglyoxyloyl);

suitable acyl groups containing a heterocyclic ring

is, for example, heterocyclic carbonyl or heterocyclic-lower alkanoyl; the heterocyclic group in the heterocyclic carbonyl group or heterocyclic-lower alkanoyl group may be saturated or unsaturated, monocyclic or polycyclic, and it may contain at least one heteroatom, such as oxygen, sulfur or nitrogen such as unsaturated 3-8 membered heteromonocyclic rings containing a sulfur atom (for example thienyl), unsaturated fused heterocyclic rings containing a sulfur atom (for example benzothienyl), unsaturated 3-8 membered heteromonocyclic rings containing an oxygen atom (for example furyl, 2(or 4)pyranyl or 5,6-dihydro -2H-pyran-3-yl), unsaturated 3 - 8-membered heteromonocyclic rings containing 1-4 nitrogen atoms (eg 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 rings containing 1-2 nitrogen atoms (for example pyrrolidinyl, imidazolidinyl, piperidine o and piperadinyl), unsaturated fused heterocyclic rings containing 1-3 nitrogen atoms such as indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, 1(or 2)H-indazolyl and 1(or 2)H-benzotriazolyl), unsaturated 3 - 8-membered heteromonocyclic rings containing 1 or more oxygen atoms and 1 - 3 nitrogen atoms (for example oxazolyl, isoxazolyl and oxadiazolyl), saturated 3 - 8-membered heteromonocyclic rings containing 1 or 2 oxygen atoms and 1 or 2 nitrogen atoms (for for example sydnonyl), unsaturated 3 - 8 membered heteromonocyclic rings containing a sulfur atom and 1 - 3 nitrogen atoms (for example thiazolyl and thiadiazolyl), unsaturated condensed heterocyclic rings containing an oxygen atom and 1 - 2 nitrogen atoms (for example benzoxazolyl..and

benzoxadiazolyl), unsaturated fused heterocyclic rings containing a sulfur atom and 1 or 2 nitrogen atoms (for example, benzothiazolyl and benzothiadiazolyl);

the carbon atom in the lower alkyl groups in the indicated heterocyclic-lower alkanoyl groups can be replaced by an oxygen or sulfur atom, for example heterocyclic lower alkylcarbonyl, heterocyclic oxycarbonyl, heterocyclic oxy(lower)alkanoyl and heterocyclic thio(lower)alkanoyl;

the carbamoyl groups, the aliphatic acyl groups and the acyl groups containing an aromatic or heterocyclic ring may contain 1-10 suitable substituents such as lower alkyl (for example methyl, ethyl, propyl and isopropyl), lower alkenyl (for example allyl, 1-propenyl), lower or higher cycloalkyl (for example cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl), lower alkoxy (for example methoxy, ethoxy, propoxy and isopropoxy), lower alkylthio (for example methylthio and ethylthio), aryl (for example phenyl, xylyl, tolyl and indanyl ), ar(lower)alkyl (for example benzyl and phenylethyl), halogen (for example chlorine, bromine and fluorine), halophenyl (for example chlorophenyl and bromophenyl), halophenoxy (for example chlorophenoxy and bromophenoxy), cyano, lower alkylsulfinyl (for for example methylsulfinyl and ethylsulfinyl) lower alkanesulfonyl (for example methanesulfonyl and ethanesulfonyl), lower alkoxycarbonyl(lower) alkoxy (for example methoxycarbonyl-methoxy, ethoxycarbonylethoxy, 1-cyc lopropylethoxycarbonylmethoxy and tert.butoxycarbonylmethoxy), nitro, sulfo, amino, azido, mercapto, carboxy, hydroxy, hydroxyamino or mono(or di)alkylamino

(for example mono(or di)methylamino, mono(or di)ethylamino, mono(or di)propylamino and mono(or di)isopropylamino);

when the acyl group contains a functional group such as amino, hydroxy, mercapto or carboxy, the functional group may be protected with a suitable protecting group; suitable protecting groups for the amino group are any common protecting group, for example acyl groups or groups other than acyl groups such as trityl, 2-nitrophenylthio, 2,4-dinitrophenylthio, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene,. 2-hydroxy-1-naphthyimethylene, 3-hydroxy-4-pyridylmethylene, 1-methoxycarbonyl-2-propylidene, 1-ethoxycarbonyl-2-propylidene, 3-ethoxycarbonyl-2-butylidene, 1-acetyl-2-propylidene, 1-benzoyl-2-propylidene, 1-[N-(2-methoxyphenyl)carbamoyl]-2-propylidene, 1-[N-(4-methoxyphenyl)carbamoyl]-2-propylidene, 2-ethoxycarbonylcyclohexylidene, 2- ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene,

3,3-dimethyl-5-oxocyclohexylidene (of which the radicals 1-methoxycarbonyl-2-propylidene and 2-ethoxycarbonylcyclohexylidene can be designated as 1-ethoxycarbonyl-1-propen-2-yl and 2-ethoxycarbonyl-1-cyclohekenyl respectively ), mono- or disilyl;

suitable protecting groups £or hydroxy or mercapto groups are any usual protecting group for hydroxy or mercapto groups, for example acyl groups or groups other than acyl groups, for example benzyl, trityl, methoxymethyl, 2-nitrophenylthio and 2,4-dinitrophenylthio;

suitable protecting groups for the carboxy group can be any common protecting group, which is used to protect a carboxy group such as lower alkyl esters (for example methyl ester, ethyl ester, propyl ester, butyl ester, 1-cyclopropyl ethyl ester and tert.butyl ester), mono (or di or tri) halo(lower) alkyl ester (for example chloromethyl ester, 2,2,2-trichloroethyl ester and 3,3-dibromopropyl ester), aryl ester (for example phenyl ester, nitrophenyl ester and indanyl ester), ar(lower) alkyl ester (for example benzyl ester, diphenylmethyl ester, triphenylmethyl ester, p-nitrobenzyl ester and p-bromobenzyl ester) or tri(lower)alkylsilyl ester (for example trimethylsilyl ester and triethylsilyl ester);

the amino protecting group different from an acyl group, which is indicated in connection with the substituted amino group, is the same as exemplified as the protecting group of the amino radical of the acyl group; particularly suitable acyl groups are:

1) lower alkoxycarbonyl (for example methoxycarbonyl, .ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, butoxycarbonyl and tert.butoxycarbonyl), 2) lower alkylthio(lower)alkanoyl (for example 2-methylthioacetyl, 2-methylthioacetyl, 2-ethylthioacetyl and 3- methylthiopropionyl), 3) lower alkenylthio(lower)alkanoyl (for example 2-allylthioacetyl and-3-allylthiopropionyl), 4) cyano(lower)alkanoyl (for example 2-cyanoacetyl, 3-cyanopropionyl and 4-cyanobutyryl), 5) phenyl (lower)alkanoyl (for example 2-phenylacetyl, 3-phenylpropionyl and 4-phenylbutyryl), 6) phenoxy(lower)alkanoyl (for example 2-phenoxyacetyl,

3-phenoxypropionyl, 4-phenoxybutyryl),

7) phenylcarbamoyl,

8) phenylglyoxyloyl,

9) phenylthiocarbonyl,

10) phenyl- and amino-substituted lower alkanoyl (for example phenylglycyl, 3-amino-3-phenylpropionyl), 11) phenyl- and hydroxy-substituted lower alkanoyl (for example 2-hydroxy-2-phenylacetyl and 2-hydroxy-3- phenylpropionyl) , 12) phenyl- and lower alkoxycarbonylamino-substituted lower alkanoyl (for example N-methoxycarbonylphenylglycyl, N-ethoxycarbonyl-phenylglycyl, N-(1-cyclopropylethoxy)carbonylphenylglycyl, N-tert.-butoxycarbonylphenylglycyl and 2-(1-cyclopropylethoxy)carbonylamino- 3- phenylpropionyl), 13) phenyl- and trihalo(lower) alkoxycarbonylamino-substituted lower alkanoyl (for example N-trichloroethoxycarbonylphenylglycyl, 3-trichloroethoxycarbonylamino-3-phenylpropionyl and N-tribroronethoxycarbonylphenylglycyl), 14) phenyl- and lower alkanoyloxy-substituted lower alkanoyl (for for example 2-formyloxy-2-phenylacetyl, 2-acetoxy-2-phenylacetyl, 3- propionyloxy-3-phenylpropionyl), 15) phenyl- and semicarbazono-substituted lower alkanoyl (for example 2-phenyl-2-semicarbazonoacetyl and 2-semi carbazono-3-phenyl-propionyl), 16) halophenylthiocarbamoyl (for example 2-(or 3- or 4-)chlorophenylthiocarbamoyl, 2-(or 3- or 4-)chlorophenylthiocarbamoyl and 2-(or 3- or 4)bromophenylthiocarbamoyl) ,

17) phthaloyl,

18) lower alkanoylaminobenzenesulfonyl (for example 2-(or 3- or 4)acetamidobenzenesulfonyl and 2-(or 3- or 4-)propionamidobenzenesulfonyl), 19) phenyl- and halophenoxy-substituted lower alkanoyl (for example 2-phenyl-2- [2-(or 3- or 4-)chlorophenoxy]acetyl and 2-phenyl-2-[2-(or 3- or 4-)bromophenoxy]acetyl), 20) . halophenyl(lower)alkanoyl (for example 2-[2-(or 3- or 4-)chlorophenyl]acetyl, 2-[2-(or 3- or 4-)bromophenyl]acetyl and 3-[2-(or 3 - or 4-)chlorophenyl]propionyl), 21) phenyl(lower) alkoxycarbonyl (for example benzyloxycarbonyl and phenylethyloxycarbonyl), 22) hydroxyphenyl- and amino-substituted lower alkanoyl (for example 2-amino-2-[2-(or 3- or 4-)hydroxyphenyl]acetyl and 2-amino-3-[2-(or 3- or 4-)hydroxyphenyljpropionyl), 23) hydroxyphenyl- and lower alkoxycarbonylamino substituted

lower alkanoyl (for example, 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),

24) r phenyl- and sulfo-substituted lower alkanoyl (eg

2-phenyl-2-sulfoacetyl and 3-phenyl-3-sulfopropionyl),

25) lower alkoxyphenyl- and amino-substituted lower alkanoyl

(for example 2-amino-3-[2-(or 3- or 4-)methoxyphenyl]acetyl), .

26) lower alkoxyphenyl- and lower alkoxycarbonylamino-substituted lower alkanoyl (for example 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),

27) lower alkylthiophenyl- and amino-substituted lower alkanoyl

(for example 2-amino-2-[2-(or 3- or 4-)methylthiophenyl]acetyl and 2-amino-3-[2-(or 3- or 4-)ethylthiophenyl]propionyl),

28) lower alkylthiophenyl- and lower alkoxycarbonylamino-substituted lower alkanoyl (for example, 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), 29) lower alkylsulfinylphenyl- and amino-substituted lower

alkanoyl (for example 2-amino-2-[2-(or 3- or 4-)methylsulfinyl]-acetyl and 2-amino-3-[2-(or 3- or 4-)ethylsulfinyl]propionyl),

.30) lower alkylsulfinylphenyl- and lower alkoxycarbonylamino-substituted lower alkanoyl (for example, 2-methoxycarbonylamino-2-[2-(or 3- or 4-)methylsulfinyl]acetyl, .2-(1-cyclopropylethoxy)-carbonylamino-3-[2 -(or 3- or 4-)ethylsulfinylphenyl]propionyl and 2-tert.butoxycarbonylamino-2-[2-(or 3- or 4-)methylsulfinyl-phenyl]acetyl), 31) lower alkoxycarbonyl(lower) alkoxyphenyl- and amino-substituted lower alkanoyl (for example 2-amino-2-[2-(or 3- or 4-)-methoxycarbonylmethoxyphenyl]acetyl, 2-amino-3-[2-(or 3- or 4-)-propoxycarbonylmethoxyphenyl]propionyl and 2-amino -2-[2-(or 3-or 4-)tert.butoxycarbonylmethoxyphenyl]acetyl), 32) lower alkoxycarbonyl(lower) alkoxyphenyl- and lower

alkoxycarbonylamino-substituted lower alkanoyl (for example, 2-methoxycarbonylamino-2-[2-(or 3- or 4-)methoxycarbonylmethoxy-

phenyl]acetyl, 2-(1-cyclopropylethyloxy)carbonyl-3-[2-(or 3- or 4-)ethoxycarbonylmethoxyphenyl]propionyl and 2-tert.butoxycarbonylamino-2- [2-(or 3- or 4-)tert .butoxycarbonylmethoxyphenyl]acetyl.

33) phenyl- and thiadiazolylthio(lower)alkanoylamino substituted

lower alkanoyl (for example N-(1,3,4-thiadiazol-2-yl)thioacetylphenyl-glycyl, 2-[3-(1,3,4-thiadiazol-2-yl)thiopropionyl]amino-3-phenylpro- pionyl),

34) phenyl- and indanyloxycarbonyl-substituted lower alkanoyl

(for example 2-phenyl-2-indanyloxycarbonylacetyl and 3-phenyl-2-indanyloxycarbonylpropionyl),

35) dihydrophenyl- and amino-substituted lower alkanoyl (for example 2-amino-2-(2,5-dihydrophenyl)acetyl, 2-amino-3-(2,5-dihydrophenyl)propionyl), 36) dihydrophenyl- and lower alkoxycarbonylamino-substituted lower alkanoyl (for example 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), 37) 3-halophenyl-5-lower alkylisoxazol-4-yl-carbonyl (for

example 3-[2-(or 3- or 4-)chlorophenyl]-5-methylisoxazol-4-ylcarbonyl and 3-[2-(or 3- or 4-)bromophenyl]-5-ethylisoxazol-4-yl -bonyl),

38) thienyl(lower)alkanoyl (for example 2-(2-thienyl)acetyl and

3-(2-thienyl)propionyl),

39) thienyl- and amino-substituted lower alkanoyl (eg

.2-amino-2-(2-thienyl)acetyl and 2-amino-3-(2-thienyl)propionyl),

40) thienyl- and lower alkoxycarbonylamino-substituted lower

alkanoyl (for example 2-methoxycarbonylamino-2-(2-thienyl)acetyl, 2-(1-cyclopropylethoxy)carbonylamino-2-(2-thienyl)acetyl, 2-tert.-butoxycarbonylamino-2-(2-thienyl)acetyl , 2-tert.butoxycarbonylamino-3-(2-thienyl)propionyl),

41) tetrazolyl(lower)alkanoyl (for example 2-(1H-tetrazol-1-yl)acetyl, 3-(1H-tetrazol-1-yl)propionyl) and 4-(1H-tetrazol-1-yl)-butyryl ), 42) thiadiazolyl(lower)alkanoyl (for example 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), 43) thiadiazolylthio(lower)alkanoyl (for example 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),

44) halogenzotriazolyl(lower)alkanoyl (for example 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-[4-(or 5- or 6- or 7-)fluoro-2H-benzotriazol-2-yl]propionyl), 45) lower alkylthiadiazolyloxy(lower)alkanoyl (for example 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), 46) dihydropyranyl- and amino-substituted lower alkanoyl (for example 2-amino-2-(5,6-dihydro-2H-pyran- 3-yl)acetyl and 2-amino-3-(5,6-dihydro-2H-pyran-3-yl)propionyl), 47) dihydropyranyl- and lower alkoxycarbonylamino-substituted lower alkanoyl (for example 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.butoxycarbonylamino-2 -(5,6-dihydro-2H-pyran-3-yl)acetyl and 2-tert.butoxycarbonylamino-3-(5,6-dihydro-2H-pyran-3-yl)propionyl) and 48) sydnonyl(lower)alkanoyl (eg 2-(sydnon-3-yl)-acetyl and 3-(sydnon-3-yl)propionyl).

The term "protected amino" for R'<1> includes acylamino and amino substituted with amino protecting groups other than the acyl groups as indicated above.

The term "acylamino" in conjunction with R"^ denotes acylamino as indicated above.

The term "a protected carboxy group" in connection with

2 2

R and R* denote, for example, the ester, the acid amide, the acid anhydride and the salt;

suitable esters are, for example, silyl esters, aliphatic esters and esters containing an aromatic or heterocyclic ring;

suitable silyl esters are, for example, tri(lower) alkyl silyl esters (trimethylsilyl and triethylsilyl esters);

suitable aliphatic esters are for example saturated or unsaturated, lower or higher alkyl esters, which may be branched, or which may contain a cyclic ring, for example lower or higher aliphatic esters such as lower alkyl esters (for example methyl-, ethyl-, propyl- , isopropyl, 1-cyclopropylethyl, butyl and tert.butyl esters), higher alkyl esters (for example octyl, nonyl and undecyl esters), lower alkenyl esters (for example vinyl, 1-propenyl, allyl and 3-butenyl esters), lower alkynyl esters (for example 3-bu-

thynyl and 4-pentynyl esters), lower or higher cycloalkyl esters (for example cyclopentyl, cyclohexyl and cycloheptyl esters) and lower or higher aliphatic esters containing a nitrogen, sulfur or oxygen atom such as lower alkoxy (lower) alkyl esters

r

(for example methoxymethyl, ethoxyethyl and methoxyethyl esters),

lower alkylthio(lower)alkyl esters (for example, methylthiomethyl, ethylthioethyl, and methylthiopropyl esters), di(lower)alkylaminoesters (for example, dimethylamino, diethylamino, and dipropylaminoesters), lower alkylideneaminoesters (for example, ethylideneamino, propylideneamino, and isopropylaminoesters) , lower alkylsulfenyl(lower) alkyl esters (eg methylsulfenylmethyl and ethylsulfenylmethyl esters);

suitable esters containing an aromatic ring are for example aryl esters (for example phenyl, xylyl, tolyl, naphthyl, indanyl and dihydroanthryl esters), ar(lower) alkyl esters (for example benzyl

and phenylethyl esters), aryloxy(lower)alkyl esters (for example phenoxymethyl, phenoxyethyl and phenoxypropyl esters), arylthio(lower)alkyl esters (for example phenylthiomethyl, phenylthioethyl and phenylthiopropyl esters), arylsulfenyl (lower)alkyl esters (for example phenylsulfenyl methyl and phenylsulfenyl ethyl esters), aryl(lower) alkyl esters (eg benzoyl methyl and toluoyl ethyl esters) and arylamino esters (eg phthalimido esters);

suitable esters containing a heterocyclic ring are, for example, heterocyclic esters and heterocyclic lower alkyl esters;

suitable heterocyclic esters are, for example, saturated or unsaturated, condensed or uncondensed. 3 - 8-membered heterocyclic esters containing 1 - .4 heteroatoms, for example oxygen, sulfur

and nitrogen atoms (for example, pyridyl, piperidino, 2-pyridon-1-yl, tetrahydropyranyl, quinolyl, and pyrazolyl esters);

suitable heterocyclic lower alkyl esters are, for example, saturated or unsaturated, fused or unfused 3-8 membered heterocyclic rings, containing 1-4 heteroatoms such as oxygen, sulfur and nitrogen (for example pyridyl-, piperidino-, 2-pyridone-1- yl, tetrahydropyranyl, quinolyl and pyrazolyl esters), substituted lower alkyl esters (eg methyl, ethyl and propyl esters);

Silyl esters, the aliphatic esters and esters containing an aromatic or heterocyclic ring may have 1 - 10 suitable substituents such as lower alkyl (for example methyl, ethyl, propyl, isopropyl, butyl and tert.butyl), lower alkoxy (for example methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert.butoxy), lower alkylthio

(for example methylthio, ethylthio and propylthio), lower alkylsulfinyl (for example methylsulfinyl, ethylsulfinyl and propylsulfinyl), lower alkanesulfonyl (for example methanesulfonyl and ethanesulfonyl), phenylazo, halogen (for example chlorine, bromine and fluorine)., cyano, nitro, mono(or di- or tri-)halo(lower) alkyl esters (for example chloromethyl-, bromo-, dichloromethyl-, 2 , 2 , 2^trio.chloroethyl- and 2 , 2 ,2-tribromomethyl-esters), cyano(lower)alkyl esters (for example cyanomethyl and cyanoethyl esters), mono(or di- or tri- or tetra- or penta)halophenyl esters (for example 4-chlorophenyl-, 3,5-dibromophenyl-, 2, 4,5-trichlorophenyl-, 2,4,6-trichlorophenyl- and pentachlorophenyl esters), lower alkanesulfonylphenyl esters (for example 4-methanesulfonylphenyl and 2-ethanesulfonylphenyl esters), 2-(or 3- or 4-)phenylazophenyl esters, mono( or di or tri)nitrophenyl esters (for example 4-nitrophenyl-, 2,4-dinitrophenyl- and 3,4,5-trinitrophenyl esters), mono(or di or tri or tetra or penta)halo nphenyl (lower) alkyl esters (for example 2-chlorobenzyl, 2,4-dibromobenzyl, 3,4,5-trichlorobenzyl and pentachlorobenzyl esters), mono(or di or tri)nitrophenyl (lower) alkyl esters (for example 2- nitrobenzyl-, 2,4-dinitrobenzyl- and 3,4,5-trinitrobenzyl esters), mono(or di or tri)(lower) alkoxyphenyl-(lower) alkyl esters (for example 2-methoxybenzyl-, 3,4-dimethoxy-benzyl - and 3,4,5-trimethoxybenzyl esters), hydroxy- and di(lower)alkyl-phenyl(lower)alkyl esters (for example 3,5-dimethyl-4-hydroxybenzyl-

and 3,5-di-tert-butyl-4-hydroxybenzyl esters);

suitable acid amides are for example N-(lower)alkyl acid amides (for example N-methyl acid amide and N-ethyl acid amide), N,N-di(lower)alkyl acid amides (for example N,N-dimethyl acid amide, N,N-diethyl acid amide and N -methyl-N-ethyl acid amide), N-phenyl acid amide or an acid amide with pyrazole, imidazole or 4-lower alkylimidazole (for example 4-methylimidazole and 4-ethylamidazole);

suitable acid anhydrides are, for example, an acid anhydride with a di(lower) alkyl phosphate - (for example dimethyl phosphate and diethyl phosphate), dibenzyl phosphate, phosphoric acid halide (for example phosphoric acid chloride and phosphoric acid bromide), di(lower) alkyl phosphite (for example dimethyl phosphite and diethyl phosphite ), sulfuric acid, thiosulphuric acid, sulfuric acid, lower alkyl carbonate (for example, methyl carbonate and ethyl carbonate), azoimide, halogen acids (for example, hydrochloric and bromic acid), saturated or unsaturated lower aliphatic carboxylic acid (for example, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutanoic acid, crotonic acid, valeric acid and propionic acid), saturated or unsaturated halogen (lower) aliphatic carboxylic acid

(for example chloroacetic acid, 3-chloro-2-pentenoic acid and 3-bromo-2-butenoic acid), substituted lower aliphatic carboxylic acid (for example phenylacetic acid, phenoxyacetic acid, furanacetic acid and thiophenacetic acid

re), aromatic carboxylic acid (eg benzoic acid) or a symmetrical acid anhydride; and

suitable acid salts, for example an acid salt with a metal (sodium, potassium and magnesium) or an organic amine (for example methylamine, diethylamine, trimethylamine, aniline, pyridine, picoline and N,N'-dibenzyl-ethylenediamine).

The term "lower alkyl" in connection with R 3 denotes a straight branched or cyclic alkyl group with 1-6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and cyclohexyl.

The term "residue of a thiol compound HR^" in connection with R 4 means the residue obtained by omitting the hydrogen atom from a thiol compound HR^;

suitable residues of thiol compounds are, for example, a substituted or unsubstituted aliphatic thiol, aromatic thiol or heterocyclic thiol compound;

suitable aliphatic thio groups are for example lower alkylthio (for example methylthio, ethylthio, propylthio, isopropylthio, butylthio and iso-butylthio), lower alkenylthio (for example vinylthio, 1-isopropenylthio and 3-butenylthio);

suitable substituted aliphatic thio groups are for example lower alkoxy(lower)alkylthio (for example methoxymethylthio and ethoxymethylthio), ar(lower)alkylthio (for example benzylthio, phenylethylthio and xylylmethylthio), halophenyl(lower)alkylthio (for example 4-chlorobenzylthio and 4-bromobenzylthio), nitrophenyl(lower)alkylthio (e.g. 4-nitro benzylthio), mono(or di)lower alkoxyphenyl(lower)alkylthio (e.g. 4-methoxybenzylthio, 2,4-dimethoxybenzylthio), halogen- and lower alkoxy-substituted phenyl (lower)alkylthio (eg 2-chloro-4-methoxybenzylthio); suitable aromatic thio groups are for example arylthio (for example phenylthio, xylylthio, tolylthio and naphthylthio), suitable substituted aromatic thio groups are for example mono(or di)halophenylthio (for example chlorophenylthio, bromophenylthio and dichlorophenylthio), nitrophenylthio, mono(or di) lower alkoxyphenylthio (for example methoxyphenylthio and dimethoxyphenylthio), or halogen- cg nitro-substituted phenyl-

thio (eg chloronitrophenylthio);

suitable heterocyclic groups in the heterocyclic thio groups may contain at least one heteroatom such as oxygen, nitrogen and sulphur; suitable heterocyclic groups are, for example, unsaturated 3-8-membered heteromonocyclic groups containing a sulfur atom (for example, tienyj.), unsaturated 3-8-membered heteromonocyclic rings containing an oxygen atom (for example, furyl), unsaturated 3-8-membered heteromonocyclic rings containing 1-4 nitrogen atoms (for example pyrrolyl, pyridyl, imidazolyl, triazolyl. and tetrazolyl), saturated 3 - 8 membered heteromonocyclic rings containing 1 - 2 nitrogen atoms (for example pyrrolidinyl, piperazinyl and homo-piperizinyl), unsaturated fused heterocyclic rings containing 1-3 nitrogen atoms (for example quinolyl, isoquinolyl and benzimidazolyl), unsaturated 3-8 membered heteromonocyclic rings

containing an oxygen atom and 1 - 3 nitrogen atoms (for example oxazolyl, oxadiazolyl and oxatriazole), unsaturated 3 - 8 membered heteromonocyclic rings containing a sulfur atom and 1 - 3 nitrogen atoms (for example thiazolyl, thiadiazolyl and thiatriazolyl), unsaturated condensed heterocyclic rings containing an oxygen and nitrogen atom (for example, benzoxazolyl), unsaturated fused heterocyclic rings containing a sulfur and nitrogen atom

(for example benzothiazolyl), and suitable substituted heterocyclic groups in the substituted heterocyclic thio groups are for example the above mentioned heterocyclic groups, which are substituted with 1-6 suitable substituents such as a lower alkyl radical (for example methyl and ethyl), a lower alkoxy radical (for example methoxy and.ethoxy), a halogen atom (for example fluorine, chlorine and bromine), a nitro radical, an aryl radical (for example phenyl, tolyl and xylyl),

a substituted aryl radical (for example chlorophenyl and nitrophenyl) and an ar(lower)alkyl radical (for example benzyl and phenylethyl).

The term "residue of an amine" in connection with R is, for example, the residue of a primary amine (for example, the residue of a primary aliphatic amine and the residue of a primary aromatic amine) or the residue of a secondary amine (for example, the residue of a secondary aliphatic amine, the residue of a secondary aromatic amine and the residue of a secondary cyclic amine);

suitable residues of primary aliphatic amines are for example lower alkylamino (for example methylamino, ethylamino, propylamino, isopropylamino and butylamino), lower or higher cycloalkylamino (for example cyclopentylamino and cyclohexylamino);

suitable residues of primary aromatic amines are for example arylamino (for example anilino), ar(lower)alkylamino (for example benzylamino and phenylethylamino);

suitable residues of secondary aliphatic amines are, for example, di(lower)-alkylamino (for example, dimethylamino, methylethylamino, diethylamino, isopropylamino and dibutylamino);

suitable residues of secondary aromatic amines are for example diarylamino (for example diphenylamino), bis-ar(lower)alkylamino (for example

dibenzylamino and diphenylethylamino); and

suitable residues of secondary cyclic amines are, for example, pyrrolidinyl,

piperidino, morpholino and 4-methylpiperazinyl.

The term "a nucleophile" in the phrase "the residue of a nucleophile" in conjunction with Y and Y<1> is, for example, thiocyanic acid, thiocyanogen, hydrazoic acid, thiourea, aliphatic or aromatic or heterocyclic thiourea, thiosemicarbazide, aliphatic or aromatic or heterocyclic thioamide, aliphatic or aromatic or heterocyclic thiol, aliphatic or aromatic or heterocyclic carboxylic acid, aliphatic or aromatic or heterocyclic thiocarboxylic acid, dithiocarboxylic acid ester, aliphatic or aromatic or heterocyclic dithiocarbamic acid, aliphatic or aromatic or heterocyclic amine, aminobenzoic acid, aminobenzenesulfonic acid, cyanic acid, phthalimide, succinimide, aliphatic or aromatic or heterocyclic alcohol, pyrrole, substituted pyrrole, imidazole, triazole, tetrazole or a salt thereof;

suitable aliphatic thioureas are for example mono(or di or tri)lower alkylthiourea (for example N-methylthiourea N,N,N'-triethylthiourea), mono(or di or tri)lower or higher cycloalkylthiourea (for example.dicyclohexylthiourea) suitable aromatic thioureas are, for example, diarylthiourea (for example, diphenylthiourea), lower alkyl- and aryl-substituted thiourea (for example, N,N-dimethyl-N'-phenylthiourea), di-ar-(lower)alkylthiourea (for example, N,N<1- >dibrnzylthiourea)

and lower alkyl and ar(lower)alkyl substituted thiourea (eg N-ethyl-N'-benzylthiourea);

suitable heterocyclic thioureas are, for example, diheterocyclic thiourea (for example N,N-difuryl and thiourea), lower alkyl and heterocyclic substituted thiourea (for example N-propyl-N<1->pyridylthiourea);

suitable aliphatic thioamides are, for example, thio(lower)alkanamide

(for example, thioacetamide and thiopropionamide);

suitable aromatic thioamides are for example thiobenzamide and thio-ar(lower)alkanamide (for example thiophenylacetamide);

suitable heterocyclic thioamides are, for example, thiopyridinecarboxamide;

suitable aliphatic thiols are for example lower alkanethiol (for example methanethiol, ethanethiol, propanethiol and isobutanethiol), amino(lower)alkanethiol (for example aminoethanethiol) and di(lower)alkylamino(lower)alkanethiol (for example dimethylaminopropanethiol);

suitable aromatic thiols are, for example, thiophenol, aminothiophenol, dinitrothiophenol and phenyl(lower)alkanethiol (for example phenylmethanethiol);

suitable heterocyclic thiols may contain at least one heteroatom such as oxygen, nitrogen and sulfur in the ring;

suitable heterocyclic thiols are, for example, unsaturated 3-8-membered heterocyclic thiols containing 1-4 nitrogen atoms in the ring (for example pyrrolethiol, pyrazolethiol and imidazolethiol), lower alkyl imidazole thiol such as methylimidazolethiol or dihydroimidazolethiol, pyridinethiol, lower alkylpyridinethiol such as methylpyridinethiol, tetrazole thiol and lower alkyl tetrazole thiol such as methyl tetrazole thiol; unsaturated fused-heterocyclic thiol containing 1-3 nitrogen atoms in the ring (for example, indole thiol), unsaturated 3-8 membered heteromonocyclic thiol containing a sulfur atom in the ring (for example, thiophenethiol), unsaturated fused-heterocyclic thiol containing 1-3 sulfur atoms in the ring (for example, thianthrenethiol), unsaturated 3 - 8-membered heterocyclic thiol containing a sulfur atom and 1 - 2 nitrogen atoms in the ring (for example, thiazolethiol, dihydrothiazolethiol, thiadiazolethiol, lower alkylthiadiazolethiol such as methylthiadiazolethiol or lower alkylthiodiazolethiol such as ethylthiothiadiazolethiol, or aminothiadiazolethiol) , unsaturated fused heterocyclic thiol containing, a sulfur atom and 1 - 2 nitrogen atoms in the ring (for example benzothiazole thiol), unsaturated 3 - 8-membered heteromonocyclic thiol containing an oxygen atom in the ring (for example furanthiol), unsaturated fused heterocyclic thiol containing an oxygen atom and 1 - 2 nitrogen atoms in the ring (for example benzocazolethiol ), unsaturated 3-.8-membered heteromonocyclic thiol containing one oxygen atom and 1-2 nitrogen atoms in the ring (for example oxadiazolethiol and lower alkyloxadiazolethiol such as propyloxadiazolethiol);

suitable aliphatic carboxylic acids are, for example, lower aliphatic carboxylic acids (for example, acetic acid and propionic acid);

suitable aromatic carboxylic acids are, for example, benzoic acid;

a suitable heterocyclic acid is, for example, nicotinic acid;

suitable aliphatic thiocarboxylic acids are for example thio(lower)alkanoic acid (for example thioacetic acid);

suitable aromatic thiocarboxylic acids are, for example, thiobenzoic acid; suitable heterocyclic thiocarboxylic acids are, for example, thiopyridine carboxylic acid;

suitable dithiocarboxylic acid esters are, for example, lower alkyldithiocarbonate (for example methyldithiocarbonate and ethyldithiocarbonate) and ar(lower)alkyldithiocarbonate (for example benzyldithiocarbonate);

suitable aliphatic dithiocarbamic acids are, for example, N-(lower)alkyldithiocarbamic acid (for example N-methyldithiocarbamic acid) and N,N-di(lower)alkyldithiocarbamic acid (for example N,N-dimethyldithiocarbamic acid);

suitable aromatic dithiocarbamic acids are, for example, N-phenyldithiocarbamic acid;

suitable heterocyclic dithiocarbamic acids are, for example, piperidino-dithiocarbamic acid and 4-lower(alkyl)-1-piperazinyldithiocarbamic acid (for example, 4-methyl-1-piperazinyldithiocarbamic acid);

suitable aliphatic amines are for example mono(or di)lower alkylamine (for example methylamine and diethylamine);

suitable aromatic amines are, for example, aniline, toluidine, nitroaniline, nitrotoluidine and naphthylamine;

suitable heterocyclic amines are, for example, pyrrolylamine;

suitable aliphatic alcohols are, for example, lower alkanols (eg methanol, ethanol, propanol, isopropanol and butanol);

suitable aromatic alcohols are, for example, phenol, ar(lower)alkanol (for example, benzyl alcohol and phenylethyl alcohol);

suitable substituted pyrroles are, for example, lower alkylpyrrole (eg methylpyrrole and ethylpyrrole); and

suitable salts of nucleophiles are for example a metal salt (for example an antrium salt and a potassium salt).

The term "strong nucleophile" in conjunction with the phrase "residue of a strong nucleophile" in conjunction with Y" means a strong nucleophile obtained by excluding the aliphatic, aromatic or heterocyclic carboxylic acid and the aliphatic, aromatic or heterocyclic alcohol from the above nucleophile; a particularly suitable residue of a strong nucleophile is:

1) thiocyanate,

2) lower alkanoylthio (for example acetylthio, propionylthio and butyrylthio),

3) piperidinothiocarbonylthio,

4) lower alkyl substituted thiadiazolthio (for example 5-methyl-1,3,4-thiadiazol-2-ylthio and 5-ethyl-1,3,4-thiadiazol-2-ylthio), 5) lower alkyl substituted imidazolylthio (for example 1 -methylimidazol-2-ylthio and l-ethylimidazol-2-ylthio), 6) lower alkyl substituted tetrazolylthio (for example 1-methyl-lH-tetrazol-5-ylthio and l-ethyl-lH-tetrazol-2-ylthio) ,

7) benzothiazolylthio,

8) pyridylthio,

9) arylamino (for example aniline) and

10) azide.

The term "halogen" in conjunction with Y' and Z' means chlorine,

bromine and fluorine.

The term "a group which can be converted into the residue of a nucleophile" in connection with Z means a group which can be converted into the residue of a nucleophile by the reaction with a nucleophile;

a suitable group which can be converted into the residue of a nucleophile is, for example, the residue of an acid, for example halogen (for example chlorine, bromine and fluorine), and acyloxy (for example methanesulfonyloxy, benzenesulfonyloxy and toluenesulfonyloxy).

The term "residue of an acid" in conjunction with Z" denotes a group obtained by omitting a hydrogen atom from an acid, for example halogen (for example chlorine, bromine and fluorine) and acyloxy (for example methanesulfonyloxy, benzenesulfonyloxy and toluenesulfonyloxy).

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

The specified compound of formula Ia can be prepared by

to react the compound of formula II, the compound of formula III, the compound of formula IV or the compound of formula V with a nucleophile.

Suitable nucleophiles that can be used in this reaction

are, for example, thiocyanic acid, thiocyanogen, hydrazoic acid, thiourea, aliphatic or aromatic or heterocyclic thiourea, thiosemicarbazide, aliphatic or aromatic or heterocyclic thioamide, aliphatic or aromatic or heterocyclic thiol, aliphatic or aromatic or heterocyclic thiocarboxylic acid, dithiocarboxylic acid ester, aliphatic or aromatic or heterocyclic dithiocarbamic acid, aliphatic or aromatic or heterocyclic amine, aminobenzoic acid, ami-

nobenzenesulfonic acid, cyanic acid, phthalimide, succinimide and aliphatic or aromatic or heterocyclic alcohol, pyrrole, substituted pyrrole, imidazole, triazole and tetrazole or a salt thereof;

suitable aliphatic thioureas are for example mono(or di or tri)lower alkylthiourea (for example N-methylthiourea and N,N,N'-triethylthiourea) and mono(or di or tri)lower or higher cycloalkylthiourea (for example dicyclohexylthiourea); suitable aromatic thioureas are, for example, diarylthiourea (for example, diphenylthiourea), lower alkyl- and aryl-substituted thiourea (for example, N,N-dimethyl-N'-phenylthiourea), di-ar(lower)alkylthiourea (for example, N,N-dibenzylthiourea) and lower alkyl and ar(lower)alkyl substituted thiourea (eg N-ethyl-N'-benzylthiourea);

suitable heterocyclic thioureas are, for example, di-heterocyclic thiourea (eg N,N-difuryl) and lower alkyl and heterocyclic substituted thiourea (eg N-propyl-N'-pyridylthiourea);

suitable aliphatic thioamides are for example thio(lower)alkanamide (for example thioacetamide and thiopropionamide);

suitable aromatic thioamides are for example thiobenzamide and thio-ar(lower)alkanamide (for example thiophenylacetamide);

suitable heterocyclic thioamides are, for example, thiopyridinecarboxamide; suitable aliphatic thiols are for example lower alkanethiol (for example methanethiol, ethanethiol, propanethiol, isobutanethiol), amino(lower)alkanethiol (for example aminoethanethiol) and di(lower)alkylamino(lower alkanethiol (for example dimethylaminopropanethiol);

suitable aromatic thiols are, for example, thiophenol, aminothiophenol, dinitrothiophenol and phenyl(lower)alkanethiol (eg phenylmethanethiol); suitable heterocyclic thiols may contain at least one heteroatom such as an oxygen, nitrogen or sulfur atom in the ring.

Suitable heterocyclic thiols are, for example, unsaturated 3-8-membered heterocyclic thiol containing 1-4 nitrogen atoms in the ring (for example pyrrole thiol, pyrazole thiol, imidazole thiol, lower alkylimidazole thiol such as methylimidazole thiol or dihydroimidazole thiol, pyridine thiol, lower alkylpyridine thiol such as methylpyridine thiol or tetrazol thiol and lower alkyl tetrazol thiol such as methyl tetrazol thiol), unsaturated fused heterocyclic thiol containing 1-3 nitrogen atoms in the ring (for example indole thiol), unsaturated 3-8 membered heteromonocyclic thiol containing a sulfur atom in the ring (for example thiophenethiol), unsaturated fused heterocyclic thiol thiol containing 1-3 sulfur atoms in the ring (eg thiantrenethiol), unsaturated

3- 8-membered heterocyclic thiol containing a sulfur atom and 1 -

2 nitrogen atoms in the ring (for example thiazole thiol, dihydrothiazole thiol,

thiadiazolethiol, lower alkylthiadiazolethiol such as methylthiadiazolethiol or lower alkylthiothiadiazolethiol such as ethylthiothiadiazolethiol or aminothiadiazolethiol), unsaturated condensed heterocyclic thiol containing a sulfur atom and 1 - 2 nitrogen atoms in the ring (for example benzothiadiazolethiol), unsaturated 3 - 8 membered heteromonocyclic thiol containing an oxygen atom in the ring (for example, furanthiol), unsaturated fused heterocyclic thiol containing an oxygen atom and 1 - 2 nitrogen atoms in the ring (for example, benzoxazole thiol), unsaturated 3-8 membered heteromonocyclic thiol containing an oxygen atom and 1 - 2 nitrogen atoms in the ring (eg oxadiazole thiol bg lower alkyl oxadiazole thiol such as propyl oxadiazole thiol); suitable aliphatic thiocarboxylic acids are, for example, thio(lower)alkanoic acid (for example, thioedic acid);

suitable aromatic thiocarboxylic acids are, for example, thiobenzoic acid;

suitable heterocyclic thiocarboxylic acids are, for example, thiopyridine carboxylic acid;

suitable dithiocarboxylic acid esters are, for example, lower alkyldithiocarbonate (for example methyldithiocarbonate and ethyldithiocarbonate) and ar(lower)alkyldithiocarbonate (for example benzyldithiocarbonate);

suitable aliphatic dithiocarbamic acids are, for example, N-(lower)alkyldithiocarbamic acid (for example N-methyldithiocarbamic acid) and N,N-di-(lower)alkyldithiocarbamic acid' (for example N,N-dimethyldithiocarbamic acid);

suitable aromatic dithiocarbamic acids are, for example, N-phenyldithiocarbamic acid;

suitable heterocyclic dithiocarbamic acids are for example piperidinodithiocarbamic acid and 4-lower (alkyl)-1-piperadinyldithiocarbamic acid (for example 4-methyl-1-piperadinyldithiocarbamic acid)j suitable aliphatic amines are for example mono(or di)lower alkylamine (for example methylamine and diethylamine);

suitable aromatic amines are, for example, aniline, toluidine, nitroaniline, nitrotoluidine and naphthylamine;

suitable heterocyclic amines are, for example, pyrrolylamine;

suitable aliphatic alcohols are, for example, lower alkanol (eg methanol, ethanol, propanol, isopropanol and butanol);

suitable aromatic alcohols are for example phenol, ar(lower)alkanol (for example phenylethyl alcohol);

suitable substituted pyrroles are for example lower alkylpyrrole (for example methylpyrrole ethylpyrrole);

suitable salts of the nucleophile are, for example, metal salts (for example the sodium salt and the potassium salt).

The reaction is usually carried out in the presence of a solvent such as water, a lower alcohol, chloroform, acetic acid, methylene chloride, acetone, acetonitrile, formamide, tetrahydrofuran, dioxane or any solvent which does not have an adverse effect on the reaction.

When the compound of formula II is used as starting material by the reaction is preferably carried out in the presence of an agent which can remove the thiol compound HR^, for example a Lewis acid (for

(e.g. sulfuric acid, benzenesulfonic acid, toluenesulfonic acid, polyphosphoric acid, aluminum chloride, titanium chloride and boron fluoride), cupric oxide, silver nitrate, silver fluoride, silver oxide, silver carbonate, mercuric oxide, mercuric sulfate, mercuric acetate, silver fluoroborate, silver perchlorate and silver isocyanate.

When the compound of formula III is used as starting material in the reaction, this is preferably carried out in the presence of a Lewis acid such as sulfuric acid, benzenesulfonic acid, toluenesulfonic acid, polyphosphoric acid, aluminum chloride, titanium chloride or boron trifluoride.

When the compound of formula IV or V, where Z denotes halogen, is used as starting material in the reaction, this is preferably carried out in the presence of a dehydrohalogenating agent such as silver fluoroborate, silver isocyanate, silver perchlorate or silver acetate.

When water is used as a solvent in the reaction, the reaction is preferably carried out at a pH value of approx. 7, and when an organic solvent such as formamide is used, the reaction is preferably carried out in the presence of an inorganic base such as an alkali metal hydroxide (for example sodium or potassium hydroxide), an alkaline earth metal hydroxide (for example magnesium or calcium hydroxide) or carbonate or hydrogen carbonate or an organic base such as trialkylamine (for example trimethylamine and triethylamine), pyridine, 5-picoline, 1,8-diazabicyclo[5,4,0]undecene-7, 1,5-diazabicyclo[4, 3,0]non-5-ene, 1,4-diazabicyclo[2,2,2]octane, or a quaternary ammonium hydroxide compound.

There is no particular limitation with regard to the reaction temperature and reactions can be carried out at room temperature.

The invention also covers the case where a protected carboxyl group is converted into another protected carboxyl group or into a free carboxyl group during the reaction or during the processing after the reaction.

"In the method according to the present invention, the compound of formula Ia, where A is a group of the general formula

also produced by reacting the compound of formula III with a Lewis acid.

This reaction is usually carried out in the presence of a solvent such as methylene chloride, chloroform, benzene, tetrahydrofuran, dimethylformamide or another solvent, which has no adverse effect on the reaction.

Suitable Lewis acids for use in this reaction are, for example, boron halide (for example boron chloride, boron bromide and boron fluoride), titanium halide (for example titanium chloride and titanium bromide), zirconium halide (for example zirconium chloride and zirconium bromide), stannous halide (for example stannous chloride and stannous bromide), anti-monohalide (for example, antimony trichloride and antimony pentachloride), bismuth chloride, aluminum halide (for example, aluminum chloride and aluminum bromide), zinc chloride, ferric chloride, toluenesulfonic acid, polyphosphoric acid ester, sulfuric acid, trichloroacetic acid, trifluoroacetic acid, zinc sulfate, ferric sulfate, zinc nitrite, and ferric nitrite.

There is no particular limitation with regard to the reaction temperature.

The compound of formula Ib and the compound of formula

VII and the compound of formula XVII can be prepared by oxidation

of the compound of formula Ia, the compound of formula VI and the compound of formula XVI, respectively.

This oxidation is carried out under such conditions that the -S group can be converted into an £ group.

Suitable oxidation methods that can be used in this reaction are methods where an oxidizing agent is used, for example isocyanuroyl chloride, phenyliododichloride, ozone, inorganic peracid (for example periodic acid and persulphuric acid), organic peracid (perbenzoic acid, m-chloroperbenzoic acid, permauric acid, peracetic acid, chloroperacetic acid and trifluoroperacetic acid ), a metal salt of the inorganic or organic peracid and hydrogen peroxide.

The reaction is preferably carried out in the presence of a compound containing a metal from group Vb or VIb in the periodic table, for example tungstic acid, molybdic acid or vanadium acid or an alkali metal salt of these (for example the sodium or potassium salt), the alkaline earth metal salt of these (for example calcium -or the magnesium salt) or the ammonium salt of these or vanadium pentoxide.

This oxidation is usually carried out in the presence of a solvent such as chloroform, methylene chloride, pyridine, water, tetrahydrofuran, dimethylformamide, dioxane, acetic acid or another solvent which has no adverse effect on the reaction.

There is no particular limitation with regard to the reaction temperature, and the reaction is usually carried out at room temperature or under cooling.

The present invention also includes the replacement of the protected carboxy group with another protected carboxy group or the conversion of the protected carboxy group to the free carboxy group during the reaction or during the treatment after the reaction.

The compound of formula IX can be prepared by subjecting the compound of formula VIII to an elimination reaction of the amino protecting group.

This elimination reaction is carried out in the usual way, for example by using an acid, hydrazine or reduction. These

methods can be chosen taking into account the protective groups to be eliminated. When the protecting group is an acyl group, it can also be eliminated by treatment with an iminohalogenating agent and then with an iminopreparative agent, if necessary followed by hydrolysis. The elimination reaction with acid is one of the most commonly used methods in connection with protecting groups such as benzyloxycarbonyl, substituted benzyloxycarbonyl, alkoxycarbonyl, substituted alkoxycarbonyl, aralkyloxycarbonyl, adamantyloxycarbonyl, trityl, substituted phenylthio, substituted aralkylidene, substituted alkylidene and substituted cycloalkylidene. A suitable acid in this case is an acid which easily distils off under reduced pressure. Suitable acids are formic acid, trifluoroacetic acid, benzenesulfonic acid and p-toluenesulfonic acid.

The suitable acid for the reaction can be selected taking into account the protecting group to be eliminated and other conditions. When the elimination reaction with the acid can be carried out in the presence of a solvent, this can be a hydrophilic organic solvent, water or a mixed solvent. The elimination reaction with hydrazine is usually used in conjunction with phthaloyl. The reduction is generally used in connection with trichloroethoxycarbonyl, benzyloxycarbonyl, substituted benzyloxycarbonyl and 2-pyridylmethoxycarbonyl.

The reduction which is applicable as an elimination reaction according to the present invention comprises, for example, reduction with a metal (for example tin, zinc and iron) or a combination of a metal compound (for example chromium chloride and chromium acetate) and an organic or inorganic acid (for example acetic acid, propionic acid and hydrochloric acid) and reduction in the presence of a metal catalyst for catalytic reduction. Metal catalysts for catalytic reduction are, for example, Raney nickel, platinum oxide and palladium/charcoal. The trifluoroacetyl protecting group can usually be eliminated by treatment with water in the presence or absence of a 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 can be eliminated by reacting with the iminohalogenating agent and then with the iminoesterifying agent, if necessary followed by hydrolysis. Suitable iminohalogenating agents are, for example, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride and phosgene. There is no restriction with regard to the reaction temperature for the iminohalogenation and the reaction takes place sufficiently rapidly at room temperature or during cooling. Suitable iminophoretic agents, which react with the end-ci 1 lc3.no 1 product from the iminohalogenation reaction, are alcohols such as a v (for example methanol, ethanol, propanol, isopropanol, butanol and tert.-butanol) or the corresponding alkanol with alkoxy (for Example

methoxy, ethoxy, . propoxy, isopropoxy and butoxy) as substituents at the alkyl group and a metal alkoxide such as an alkali metal alkoxide (for example sodium alkoxide and potassium alkoxide) or an alkaline earth metal alkoxide (for example calcium alkoxide and barium alkoxide) derived from this alcohol. The temperature of the iminophoresis is not limited and the reaction proceeds at room temperature or under cooling.

If necessary, the reaction product obtained is hydrolysed. The hydrolysis can be carried out by pouring the reaction mixture into water or a mixture of water and a hydrophilic solvent such as methanol and ethanol. In this hydrolysis, the water may contain a base such as an alkali metal hydrogen carbonate or trialkylamine or an acid such as dilute hydrochloric acid or acetic acid. When the protecting group is acyl, this can be removed by hydrolysis as indicated above or by means of another common hydrolysis method.

There is no limitation in the reaction temperature and the temperature range can be suitably chosen taking into account the amino protecting group and the elimination method, and the reaction is preferably carried out under mild conditions such as during cooling or slight heating. In the method according to the invention, the protected carboxyl group can be replaced with another protected carboxyl group or converted into a free carboxyl group during the reaction or during the treatment after the reaction.

The obtained compound of formula IX can, if desired, be converted into a desired acid addition salt in the usual way.

The compound of formula X can be prepared by reacting the compound of formula IX or a salt thereof with an acylating agent.

Suitable salts of the compound of formula IX are, for example, organic acid salts (for example acetate, maleate, tartrate, benzene sulphonate and toluene sulphonate) and inorganic acid salts (for example hydrochloride, sulphate and phosphate).

As acylating agents in the method according to the present invention, an aliphatic, aromatic and heterocyclic carboxylic acid and the corresponding sulphonic acid, carboxylic acid ester, carbamic acid and thioic acid and the reactive derivatives of these acids can be used.

An acid anhydride, an activated amide, an activated ester, an isocyanate and an isothiocyanate can be mentioned as reactive derivatives.

Examples of these can be an acid azide, a mixed acid anhydride with an acid such as dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, dialkylphosphoric acid, sulfuric acid, thiosulphuric acid, halogen acid (for example acid chloride), sulfuric acid, monoalkyl carbonate, aliphatic carboxylic acid ( for example acetic acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid) and aromatic carboxylic acid (for example benzoic acid) or symmetrical acid anhydrides, an acid amide with pyrazole, imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole and an ester (for example cyanomethyl ester, methoxymethyl ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, methanesulfonylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, p-cresylthioester, carboxymethylthioester, pyranyl ester, pyridyl ester, piperidyl ester , 8-quinolyl thioester or an ester with N,N-dimethylhydroxylamine, l-hydroxy-2(lH)pyridone, N-hydroxysuccinimide or N-hydroxyphthalimide).

The above-mentioned reactive derivatives are selected with regard to the acid used. When a free acid is used in the acylation reaction, a condensing agent such as N,N<*->dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholino-ethylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide can preferably be added imide, N,N'-diethylcarbodiimide, N,N'-diidopropylcarbodiimide, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, N,N'-carbonyldi(2-methylimidazole), pentamethyleneketene-N-cyclohexylimide, diphenylketene- N-Cyclohexylimine, Alkoxyacetylene, 1-Alkoxy-l-chloroethylene, Trialkylphosphite, Ethylpolyphosphate, 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 and 2,2,4,4,6,6-hexa-chloro-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 (for example carbon tetrachloride and carbon tetrabromide) or e t halogen (for example chlorine and bromine).

An example of an acyl group, which can be introduced into the amino group in the above-mentioned acylating agent, can be a group that is dehydroxylated from an aliphatic, aromatic and heterocyclic carboxylic acid, and the corresponding sulfonic acid, carboxylic acid ester, carbamic acid and thioic acid, and in particular the acyl group can be the the same acyl group as indicated in connection with the definition of the acyl group i

. the acylamino group in connection with R"<*>".

This acylation reaction is usually carried out in a solvent which has no adverse effect on the reaction, for example water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethane dichloride, tetrahydrofuran, ethyl acetate, dimethylformamide and pyridine,

and a hydrophilic solvent as indicated above may be used as a mixed solvent with water.

The acylation reaction can be carried out in the presence of a base such as an inorganic base (for example alkali metal hydrogen carbonate) and an organic base (for example trialkylamine, N,N-dialkylamine, N,N-dialkylbenzylamine, pyridine, 1,5-diazabicyclo[4,3 ,0]non-5-ene, 1,4-diazabicyclo[2,2,2]octane and 1,8-diazabicyclo[5,4,0]undecrn-7.

A liquid base or

a liquid condensing agent as a solvent.

There is no restriction with regard to the temperature and the reaction can be carried out during cooling or at room temperature.

The invention also covers the replacement of the protected carboxyl group with another protected carboxyl group or with a free carboxyl group during the reaction or during the post-treatment.

The compound of formula IV, where Z is halogen, can be prepared by reacting the compound of formula II or III with a hydrogen halide or metal halide. Suitable hydrogen halides for use in this reaction are, for example, hydrogen chloride, hydrogen bromide and hydrogen iodide, and suitable metal halides are, for example, mercury chloride, cupric chloride and zinc chloride.

This reaction is usually carried out in a solvent which has no adverse effect on the reaction, for example alcohol, chloroform, acetic acid, methylene chloride, acetone and avetonitrile.

There is no particular limitation with respect to the reaction temperature, and the reaction temperature may be selected with respect to the compounds II or III, the hydrogen halide, or the metal halide.

The invention also covers the replacement of the protected carboxyl group with another protected carboxyl group or with a free carboxyl group during the reaction or during the post-treatment.

The compound of formula V, wherein Z is halogen, may be prepared by subjecting the compound of formula IV, wherein Z is halogen,

a transformation reaction. This conversion reaction can be carried out by adding or heating the reaction mixture obtained by reacting compound II or III with a hydrogen halide or a metal halide, or by adding or heating the compound IV, where Z is halogen, which is isolated from the reaction mixture with or without a solvent , or by subjecting the compound IV, where Z is halogen, to column chromatography on silica gel.

Suitable solvents for this reaction are any solvent which has no adverse effect on the reaction, for example water, acetone, methylene chloride, acetonitrile, chloroform, tetrahydrofuran, tert.butanol, isopropanol, benzene, dioxane, dimethylformamide, dimethylsulfoxide and pyridine.

This reaction is preferably carried out in the presence of a Lewis acid or Lewis base.

According to the invention, the protected carboxy group can be converted into another carboxy group or into a free carboxy group during the reaction or after the reaction.

The compound of formula II can be prepared by reacting the compound of formula XV with a thiol compound or a salt

of this one.

Suitable thiol compounds for this reaction are a substituted or unsubstituted aliphatic thiol, aromatic thiol or heterocyclic thiol.

r Suitable aliphatic thiols are, for example, lower alkanethiol (for example methanethiol, ethanethiol, propanethiol, isopropanethiol, butanethiol and isobutanethiol) and lower alkenethiol (for example 1-isopropenethiol and 3-butenethiol);

suitable substituted aliphatic thiols are for example lower alkoxy(lower)alkanethiol (for example methoxymethanethiol and ethoxyethanethiol), ar(lower)alkanethiol (for example phenylmethanethiol, phenylethanethiol and xylylmethanethiol), halophenyl(lower)alkanethiol (for example 4-chloro-phenylmethanethiol and 4-bromophenylmethanethiol), nitrophenyl(lower)alkanethiol (e.g. 4-nitrophenylethanethiol), mono(or di)lower alkoxyphenyl(lower)alkanethiol (e.g. 4-methoxyphenylmethanethiol and 2,4-dimethoxyphenylmethanethiol), halogen- and lower alkoxy-substituted phenyl- (lower)alkanethiol (eg 2-chloro-4-methoxyphenylmethanethiol);

suitable aromatic thiols are, for example, arenthiol (eg benzenethiol, xylentiol, toluenethiol, naphthalenethiol);

suitable substituted aromatic thiols are, for example, mono(or di)halobenzenethiol (for example chlorobenzenethiol, bromobenzenethiol and dichlorobenzenethiol), nitrobenzenethiol, mono(or di)lower alkoxybenzenethiol (for example methoxybenzenethiol and dimethoxybenzenethiol) and halogen- and nitrosubstituted benzenethiol (for example chloronitrobenzenthiol);

suitable heterocyclic rings in the heterocyclic thiol may contain at least one heteroatom such as an oxygen, nitrogen and sulfur atom. Suitable heterocyclic rings include, for example, unsaturated 3-8-membered heteromonocyclic rings containing a sulfur atom (for example, thiophene), unsaturated 3-8-membered heteromonocyclic rings containing an oxygen atom (for example, furan), unsaturated 3-8-membered heterocyclic rings containing 1-4 nitrogen atoms (for example, pyrrole, pyridine, imidazole, triazole, and tetrazole), saturated 3- to 8-membered heteromonocyclic rings containing 1-2 nitrogen atoms (for example, pyrrolidine, piperazine, piperizine, and homopiperazine, unsaturated fused heterocyclic rings containing 1-3 nitrogen atoms (for example quinoline, isoquinoline and benzimidazole), unsaturated 3-8 membered heteromonocyclic rings containing an oxygen atom and 1-3 nitrogen atoms (for example oxazole,

oxadiazole and oxatriazole), unsaturated 3 - 8-membered heteromonocyclic rings containing a sulfur atom and 1 - 3 nitrogen atoms (for example, thiazole, thiadiazole and thiatriazole), unsaturated fused heterocyclic rings containing an oxygen and nitrogen atom (for example, benzoxazole), unsaturated fused heterocyclic rings containing a sulfur and nitrogen atom (for example, benzothiazole);

and suitable substituted heterocyclic rings in the substituted heterocyclic thio compounds are, for example, the above-mentioned heterocyclic groups substituted with 1 - 6 suitable substituents as

such as lower alkyl (for example methyl and ethyl), lower alkoxy (for example methoxy and ethoxy), a halogen atom (for example fluorine, chlorine and bromine), nitro, aryl .(for example phenyl, tolyl and xylyl) , substituted aryl ( for example chlorophenyl and nitrophenyl) and ar(lower)alkyl (for example benzyl and phenylethyl).

Suitable salts of the thiol compounds are the metal salt such as the sodium and potassium salt. When the compound of formula XV, where X denotes halogen, is used in the reaction, this is preferably carried out in the presence of a halogen-removing agent, for example a base. When a liquid thiol compound is used in the reaction, the liquid thiol compound can be used as a solvent.

The reaction is usually carried out in a solvent which

does not have any adverse effect on the reaction.

Suitable solvents are, for example, acetone, water,

dioxane, tetrahydrofuran, methylene chloride, chloroform and phosphate buffer.

With the method according to the present invention, the compound of formula II can also be obtained, where R is a group of the general formula

which is derived from a compound of formula XV which is different from the thiol compound.

There is no restriction with regard to the reaction temperature and the reaction can be carried out at room temperature.

The protected carboxy group can be converted into another protected carboxy group or into a free carboxy group during the reaction or after the reaction.

The compound of formula XII can be prepared by subjecting the compound of formula XI to elimination reaction with respect to the protecting group on the carboxy group, and the compound of formula XIV can be prepared by subjecting the compound of formula XIII to elimination reaction on the carboxy protecting group. In this elimination reaction, all the usual methods for elimination reactions on protected carboxy groups can be used, for example reduction and hydrolysis. When the protected group is an active ester, an active amide, acid halide or acid azide, they can be eliminated by hydrolysis, usually under mild hydrolysis conditions, for example by contact with water. The reduction can, for example, be carried out in connection with the ,2-iodoethyl ester, the 2,2,2-trichloroethyl ester and the benzyl ester. The elimination reaction with an acid can be used in connection with protecting groups such as p-methoxybenzyl ester, tert-butyl ester, tert-pentyl ester, trityl ester, diphenyl methyl ester, bis(methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester and 1-cyclopropyl ethyl ester. The elimination reaction with an anhydrous basic catalyst can be used for protecting groups such as ethynyl ester and 4-hydroxy-3,5-di(tert.butyl)benzyl ester. The reduction, which is applicable in the elimination reaction according to the present invention, can for example be reduction

by using a metal (for example zinc and zinc amalgam) or

a chromium salt compound (for example chromium chloride and chromium acetate) and an organic or inorganic acid (for example acetic acid, propionic acid,

and hydrochloric acid) and reduction in the presence of a metal catalyst. Metal catalysts for catalytic reduction are, for example, platinum catalyst (for example, platinum wire, platinum sponge, platinum black and colloidal platinum), palladium catalyst (for example, palladium sponge, palladium black, palladium oxide, palladium/barium sulfate, palladium/barium carbonate, palladium/coal, palladium/silica gel and colloidal palladium dium), nickel catalyst (eg reduced nickel, nickel oxide, Raney nickel and Urushibara nickel). Suitable acids for use in the elimination reaction are, for example, formic acid, trihaloacetic acid (for example trichloroacetic acid and trifluoroacetic acid), hydrochloric acid, hydrofluoric acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid and mixed acid of hydrochloric acid and acetic acid.

Suitable anhydrous basic catalysts for the elimination reaction are, for example, sodium thiophenphenate and (CH^^LiCu.

When the protected group is eliminated by treatment with water or with a liquid acid, the reaction can be carried out without a solvent. When a solvent is used in the reaction, any solvent which has no adverse effect on the reaction can be used, for example dimethylformamide, methylene chloride, chloroform, tetrahydrofuran and acetone.

There is no limitation with regard to the reaction temperature and it can be appropriately chosen with regard to the starting compound and the elimination method used.

The invention also covers the case that a protected carboxy, hydroxy, mercapto or amino group in the starting compound is converted into the corresponding carboxy, hydroxy, mercapto or amino group during the reaction or after the reaction. Thus, the obtained compounds of formula XII or XIV can, if necessary, be converted into a desired metal salt (for example sodium and potassium salt) or an organic base salt.

The invention is illustrated by means of the following examples:

Reaction A

Example Al.

0.65 g of 2,2,2-trichloroethyl-2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)dithio-a-isopropenyl-1-azetidine acetate is dissolved in 15 ml of chloroform. 0.16 g cupric chloride is added to this solution, and the mixture is then stirred for 8 hours at room temperature. The precipitate is filtered off and the filtrate is washed with a saturated aqueous sodium

bicarbonate solution and then with water and dried over magnesium sulphate. The solvent is distilled off and 0.56 g of oily 2,2,2-trichloroethyl-2-chloromethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate is obtained.

IR absorption spectrum (film): 3350, 1785, 1760 and 1685 cm"1.

Example A2.

0.63 g of 2,2,2-trichloroethyl-2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-a-isopropenyl-1-azetidine acetate is dissolved in 15 ml of chloroform. 0.16 g of cupric chloride is added to this solution,

and the mixture is stirred for 8 hours at room temperature. The precipitate is filtered off and the filtrate is washed with a saturated aqueous sodium hydrogen carbonate solution and then with water and dried over magnesium sulfate. After the solvent has been distilled off, the crystals are washed with

ether and 0.45 g of 2,2,2-trichloroethyl-2-chloromethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate is obtained;

melting point 108 - 109°C.

IR absorption spectrum (Nujol): 3300, 1785, 1763 and

16 56 cm

Example A3..

0.63 g of 2,2,2-trichloroethyl-2-oxo-3-(2-phenylacetamido>4-(benzothiazol-2-yl)dithio-a-isopropenyl-1-azetidine acetate is dissolved in 12 ml of acetonitrile. To this solution 0.44 g of mercuric chloride is added, and the mixture is stirred for 24 hours at room temperature.

After the reaction, the precipitate is filtered off, the filtrate is evaporated under reduced pressure and the residue obtained is dissolved in ethyl acetate. The ethyl acetate phase is washed with water and dried and the solvent is removed by distillation. The residue was purified by chromatography on silica gel, and 190 mg of colorless needles of 2,2,2-triclpretyl-2-chloromethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate with melting point 104 - 105° are obtained C from the third and fourth fractions of fractions each consisting of 50 ml.

IR absorption spectrum (Nujol): 3300, 1785, 1763 and

1656 cm<1>.

Example A4.

A solution of 0.12 g of methyl-2-oxo-3-(2-phenoxyacetamido)-4-anilinthio-a-isopropenyl-1-azetidine acetate in 5 ml of dried methylene chloride is added to 0.8 ml of 5% methanolic hydrochloric acid, and the mixture is stirred for 10 hours at room temperature. After the reaction, methylene chloride is removed by distillation under reduced pressure. The residue is extracted with ethyl acetate, and the extract is washed with water and dried. The solvent is removed by distillation and 0.085 g of oily methyl-2-chloromethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate is obtained.

IR absorption spectrum (chloroform): 3400, 1790, 1760 and

1680 cm"<1>.

Example A5.

By treating 0.43 g of 2-oxo-3-(2-phenoxyacetamido)-4-propylamino-thio-a-isopropenyl-1-azetidine acetate in a similar manner as described in example A4, 0.36 g of oily methyl-2 -chloromethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate.

The following compounds are prepared by proceeding as described in the examples: 1) 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate; melting point 90 - 93 C (decomposition), 2) 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-[N-(2,2,2-trichloroethoxy)-carbonylphenylglycyl]aminopenam-3-carboxylate ( powder). 3) 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)-penam-3-carboxylate (gum), 4) 1-cyclopropylethyl-2-bromomethyl-2-methyl-6 -(2-phenylacetamido)-penam-3-carboxylate (oil), 5) 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-[2-(sydnon-3-yl)acetamido]-penam -3-carboxylate (amorphous), 6) 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-[2-(4-hydroxyphenyl)-2-(1-cyclopropylethoxy)carbonylaminoacetamido]penam-3- carboxylate (powder), 7) 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-[2-(2-thienyl)acetamido]-penam-3-carboxylate (oil), 8) 3.5 -di-tert.butyl-4-hydroxybenzyl-2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (white crystalline powder), 9) 2,2,2-trichloroethyl-2-bromomethyl -2-methyl-6-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]aminopenam-3-carboxylate; melting point 130 - 135°C and 10) 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-(2-cyanoacetamido)-penam-3-carboxylate (amorphous).

Example Bl.

0.63 g of 2,2,2-trichloroethyl-2-oxo-3-(2-phenylacetamido)-4-(benzthiazol-2-yl)dithio-cc-isopropenylazetidin-1-acetate is dissolved in 12 ml of acetonitrile. 0.44 g of mercuric chloride is added to this solution, and the mixture is stirred for 24 hours at room temperature. After the reaction, the precipitate is filtered off and the filtrate is evaporated under reduced pressure. The residue is dissolved in ethyl acetate and the ethyl acetate phase is washed with water and dried. The solvent is removed by distillation and the residue is purified by column chromatography on silica gel, and 70 mg of powdered 2,2,2-trichloroethyl-3-chloro-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate is obtained from the fifth and sixth fraction of the fractions of each 50 ml.

IR absorption spectrum (Nujol): 3400, 1775 and 1675 cm^.

Example B2.

1.26 g of 2,2,2-trichloroethyl-2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenylazetidin-1-acetate are dissolved in 15 ml of methylene chloride. 0.40 g of dried zinc chloride is added to this solution, and the mixture is stirred for 2 days at room temperature. After the reaction, the reaction mixture is filtered and the filtrate is washed with aqueous sodium bicarbonate solution and then with water.

The residue is subjected to column chromatography on 20 g of silica gel and eluted with chloroform. The third fraction of the 30 ml fractions is isolated and the solvent is removed by distillation, and 2,2,2-trichloroethyl-3-chloro-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate is obtained.

Example B3.

0.12 g of methyl-2-oxo-3-(2-phenoxyacetamido)-4-anilintide-α-isopropenylazetidine-1-acetate is dissolved in 5 ml of dry methylene chloride. 0.8 ml of 5% methanolic hydrochloric acid is added to this solution, and the mixture is stirred for 10 hours at room temperature. After the reaction, the reaction mixture is evaporated under reduced pressure and the residue is extracted with ethyl acetate. The extract is washed with water and dried. The solvent is removed by distillation and the residue is subjected to column chromatography on silica gel using chloroform as a developing agent, and 0.07 g of oily methyl-3-chloro-3-methyl-7-(2-phenoxyacetamido) cepham-4-carboxylate is obtained .

IR absorption spectrum (chloroform): 3410, 1775, 1742 and 1690 cm"<1>.

Example B4.

0.43 g of methyl-2-oxo-3-(2-phenoxyacetamido)-4-propylaminothio-α-isopropenylazetidine-1-acetate is dissolved in dried methylene chloride. To this solution, 2 ml of 51% methanolic hydrochloric acid is added and the mixture is stirred for 10 hours at room temperature. After the reaction, the reaction mixture is evaporated under reduced pressure and the residue is extracted with ethyl acetate. The extract is washed with water and dried. The solvent is removed by distillation and the residue is subjected to column chromatography

on silica gel using chloroform as developer,

and 310 mg of oily methyl-3-chloro-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate are obtained. The following compounds are obtained by applying the procedures in Examples Bl - 4:

Example Cl.

1.06 g methyl-2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)-dithio-α-isopropenyl-1-azetidine acetate and 0.34 g silver acetate

is suspended in tert.butanol and the mixture is heated under reflux for 48 hours. After the reaction, the precipitate is filtered off and the filtrate is evaporated under reduced pressure. The residue is extracted with ethyl acetate. The ethyl acetate phase is washed with water and dried and the solvent is removed by distillation. The residue is purified by column chromatography on silica gel using chloroform as a developing agent, and 490 mg of methyl-2-acetoxymethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate is obtained in the form of a weak oil . IR absorption spectrum (CHClj): 3410, 1792, 1745, 1740

and 1690 cm<-1>.

Example C2.

0.63 g of 2,2,2-trichloroethyl-2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-a-isopropenyl-1-azetidine acetate is dissolved in 10 ml of chloroform. 1.77 g of lead tetraacetate is added to this solution and the mixture is heated under reflux for 24 hours. Water is added to the reaction mixture and the precipitate is filtered off. The filtrate is divided into a chloroform phase and an aqueous phase and the aqueous phase is extracted with chloroform. The chloroform fractions are combined and dried over magnesium sulfate and the solvent is distilled off. The residue is purified by column chromatography on silica gel using chloroform as developing agent, and 0.11 g of 2,2,2-trichloroethyl-2-acetoxy-methyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate is obtained ;

melting point 122 - 123°C.

Example C3.

1.26 g of 2,2,2-trichloroethyl-2-oxo-6-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-a-isopropenyl-1-azetidine acetate are dissolved in a mixture of 10 ml of chloroform and 10 ml of acetic acid. 1.80 g of lead tetraacetate is added to this solution and the mixture is stirred for 7 hours at room temperature. A further 1.80 g of lead tetraacetate is added to the solution and this is stirred for 8 hours at 50°C. Chloroform is added to the reaction mixture, and the solution is washed with a saturated aqueous sodium bicarbonate solution, then with water and dried over magnesium sulfate. After removal of the solvent by distillation, the residue is purified by column chromatography on silica gel using chloroform as a developing agent, and one obtains

0.26 g of 2,2,2-trichloroethyl-2-acetoxymethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate.

IR absorption spectrum (Nujol): 3280, 1792, 1748 and

1660 cm"<1>.

Example C4..

1.52 g of 2,2,2-trichloroethyl-2-oxo-3-[N-(1-cyclopropylethoxy)-carbonylphenylglycyl]amino-4-(benzothiazol-2-yl)dithio-a-isopropenyl-1-azetidine acetate is dissolved in 15 ml of dry methylene chloride under ice-cooling. 10 ml of a solution of thiocyanogen in methylene chloride (1 millimol) is added dropwise to this solution and the mixture is stirred for 24 hours at this temperature. The precipitate is filtered off and the filtrate is washed with a saturated aqueous sodium bicarbonate solution and then with water. After drying over magnesium sulphate, the solvent is removed by distillation under reduced pressure, and 1.3 g is obtained

oily 2,2,2-trichloroethyl-2-thiocyanatomethyl-2-methyl-6-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]aminopenam-3-carboxylate.

IR absorption spectrum (film): 1780, 1765 and 1680 cm^.

Example C5.

0.63 g of 2,2,2-trichloroethyl-2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)dithio-a-isopropenyl-1-azetidine acetate is dissolved in 10 ml of dried methylene chloride under ice-cooling . 5 ml of a solution of thiocyanogen in methylene chloride (0.6 millimoles) is added dropwise to this solution. The mixture is stirred for 24 hours at this temperature and then the precipitate is filtered off. The filtrate is evaporated under reduced pressure and the residue is dissolved in 10 ml of ethyl acetate. The ethyl acetate phase is washed with a saturated aqueous sodium bicarbonate solution and then with water and dried over magnesium sulfate. After the removal of the solvent by distillation, the residue is crystallized by adding a small amount of ether. The crystals are filtered off and the filtrate is evaporated to give 0.49 g of oily 2,2,2-trichloroethyl-2-thiocyanatomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate.

IR absorption spectrum (film): 1785, 1760 and 1690 cm 1.

Example C6.

5.04 g of 2,2,2-trichloroethyl-2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-a-isopropenyl-1-azetidine acetate are dissolved in 20 ml of dried methylene chloride. A solution of thiocyanogen (4.5 millimoles) in methylene chloride is added dropwise to this solution over the course of 5 minutes under ice cooling. After stirring for 7 hours at the same temperature, the precipitate is filtered off. The filtrate is washed with a saturated aqueous sodium bicarbonate solution, then with water and dried over magnesium sulfate. After the removal of the solvent by distillation under reduced pressure, the residue is crystallized by adding a small amount of ether, and 3.58 g of 2,2,2-trichloroethyl-2-thio-cyanatomethylr2-methyl-6-(2-phenylacetamido)penam are obtained -3-carboxylate; melting point 137 - 140°C.

Example C7.

0.63 g of 2,2,2-trichloroethyl-2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-a-isopropenyl-1-azetidine acetate and 150 mg of potassium thiocyanate are dissolved in 10 ml dried acetone. 0.19 g of p-toluenesulfonic acid monohydrate is added to this solution and the mixture is stirred for 24 hours at room temperature. The precipitate is filtered off and the filtrate is evaporated under reduced pressure and the residue is dissolved in ethyl acetate.

The ethyl acetate phase is washed with a saturated aqueous sodium bicarbonate solution, then with water and dried over magnesium sulfate. After the removal of the solvent by distillation, the residue is crystallized by adding a small amount of ether, and 330 mg of 2,2,2-trichloroethyl-2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate is obtained.

Example C8.

0.70 g 2,2,2-trichloroethyl-2-oxo-3-[3-(2-chlorophenyl)-5-methyl-isoxazole-4-carboxamido]-4-(benzothiazol-2-yl)dithio-a -isopropenyl-1-azetidine acetate is dissolved in 10 ml of dried methylene chloride under ice-cooling. A solution of thiocyanogen (0.5 millimoles) in 5 ml of methylene chloride is added dropwise to this solution and the mixture is stirred for 24 hours at this temperature. The precipitate is filtered off and the filtrate is washed with a saturated aqueous sodium bicarbonate solution, then with water and dried. The solvent is removed by distillation, the residue is pulverized by adding approx. 10 ml kerosene bottle

and 500 mg of 2,2,2-trichloroethyl-2-thiocyanatomethyl-2-methyl-6-[3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido]penam-3-carboxylate is obtained.

IR absorption spectrum (Nujol): 1785, 1770, 1670 cm 1.

Example C9.

5 ml of acetic acid is added to a solution of 1.26 g of 2,2,2-trichloroethyl-2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)-dithio-α-isopropenyl-1- azetidine acetate in 15 ml of ethyl acetate. To this solution is added. 0.68 g of silver acetate with stirring at room temperature and the mixture is stirred for 4 hours at this temperature.

After the reaction, the precipitate from the reaction mixture is filtered, the filtrate is washed with water and 5% aqueous sodium bicarbonate solution and then filtered. The filtrate is washed with water and dried and the solvent is distilled off. The oily residue (0.87 g) is purified by thin-layer chromatography and recrystallized with ether, and colorless needles of 2,2,2-trichloroethyl-2-acetoxymethyl-2-methyl-6-(2-phenylacetamido)-penam-3 are obtained -carboxylate; melting point 116 - 118°C.

Example CIO.

454 mg of methyl-2-oxo-3-(2-phenoxyacetamido)-4-anilinothio-α-isopropenyl-1-azetidine acetate are dissolved in 20 ml of methylene chloride. 5 ml of methanol and then 0.124 g of boron trifluoride etherate are added to this solution while cooling at 0°C. The mixture is stirred for 3 hours at this temperature and stirred for a further 2 hours at 5 - 10°C.

After the reaction, the reaction mixture is washed with 5% aqueous sodium bicarbonate solution and then with water and dried, and the solvent is removed by distillation. The oily residue (25 g) is subjected to column chromatography on silica gel and eluted with chloroform. The eluate is divided into fractions of 50 ml each and the seventh and eighth fractions are combined. The solvent is distilled off, and oily methyl-2-methoxymethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate is obtained.

IR absorption spectrum (CHClj): 3370, 1787, 1742 and 1685 cm"<1>

The following compounds are prepared by applying the methods in examples C 1 - 10:

Reaction D.

Example Dl.

1.17 g of potassium thiocyanate is dissolved in a mixture of 20 ml of water and 100 ml of acetone. 5.45 g of 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-(2-phenyl-acetamido)penam-3-carboxylate are added to this solution at room temperature and the mixture is stirred for 5 hours at room temperature. After removal of acetone under reduced pressure at room temperature, the precipitate is isolated by filtration, washed with water and further washed with ethanol, and 4.10 g of 2,2,2-trichloroethyl-2-thiocyanatomethyl-2-methyl-6-(2 -phenylacetamido(penam-3-carboxylate. This material is recrystallized from isopropyl ether containing

51 acetone and the pure compound with a melting point is thereby obtained

133 - 135°C.

Analysis:

Calculated for C19H18<N>3<0>4S2C13: C 43.64 H 3.47 N 8.0.4 S 12.27

Cl 20.34

Found : C 43.84 H 3.26 N 7.99 S 12.31

Cl 20,31.

Example D2.

A mixture of 1.08. g 2 , 2 , 2-trichloroethyl-2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate, 0.26 g sodium azide, 20 ml acetone and 4 ml water are stirred for 4 hours at room temperature.

After removal of acetone under reduced pressure, the residue is extracted with ethyl acetate. The ethyl acetate phase is washed with water, saturated aqueous sodium bicarbonate solution and again with water, then dried over magnesium sulfate. The solvent is removed by distillation and a small amount of ether is added to the residue. Precipitated crystals are filtered off and the solvent is distilled from the filtrate. The crystalline residue is purified by column chromatography on silica gel using chloroform as developing agent, and 150 mg of 2,2,2-trichloroethyl-2-azidomethyl-2-methyl-6-(2-phenylacetamide penam-3-carboxylate) is obtained. This material is crystallized by adding a small amount of a mixture of ether and pettoether, and the crystals are recrystallized from ether, and the pure compound is obtained with a melting point of 105 - 106°C.

Analysis:

Calculated-for C18H18N504SC13: C 42.66 H 3.58 N 13.82 S 6.33

Cl 20.99

Found : C 42.66 H 3.40 N 13.69 S 6.79

r Cl 20.74.

Example D3.

0.16 g of 5-methyl-1,3,4-thiadiazole-2-thiol is dissolved in a mixture of 5 ml of phosphate buffer with a pH value of 6.5 and 10 ml of acetone. 0.54 g of 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate is added to this solution and the mixture is stirred for 3 hours at room temperature. The reaction mixture is evaporated under reduced pressure, acetone is distilled off and the residue is extracted with ethyl acetate. The ethyl acetate phase is washed with aqueous sodium bicarbonate solution, then with water and then dried over magnesium sulfate. The solvent is distilled off and the residue is purified by column chromatography on silica gel using chloroform as developing agent, and 0.09 g of oily 2,2,2-trichloroethyl-2-(5-methyl-1,3,4-thiadiazole-2) is obtained -yl)thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate from the second and third fractions of the fractions of each approx. 30 ml.

IR absorption spectrum (CHClj): 3320, 1790, 1765 and 1680cm<-1.>

Example D4.

0.20 g of 5-methyl-1,3,4-thiadiazole-2-thiol and 0.85 g of sodium bicarbonate are dissolved in 7 ml of formamide. 0.54 g of 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate is added to this solution and the mixture is stirred for 5 hours at room temperature. Water is added to the reaction mixture and the mixture is extracted with ethyl acetate. The ethyl acetate phase is washed with a saturated aqueous sodium bicarbonate solution, then with water and then dried over magnesium sulfate. After the removal of the solvent by distillation, the residue is purified by column chromatography on silica gel using chloroform as developing agent, and 0.20 g of oily 2,2,2-trichloroethyl-2-(5-methyl-1,3,4) is obtained -thiadiazol-2-yl)thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate from the third fraction of the fractions of each approx. 30 ml.

Example D5.

0.20 g of benzothiazole-2-thiol is dissolved in a mixture of 15 ml of phosphate buffer with a pH value of 6.7 and 15 ml of dioxane. To this solution is added 0.54 g of 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-(2-phenyl-

acetamido)penam-3-carboxylate and the mixture is stirred for 7 hours at room temperature. After completion of the reaction, the dioxane is distilled off and the residue is extracted with ethyl acetate. The ethyl acetate phase is washed with 2% aqueous potassium carbonate solution, then with water and dried over magnesium sulfate. After the removal of the solvent by distillation, the residue is purified by column chromatography on silica gel using chloroform as developing agent, and 0.15 g of 2,2,2-trichloroethyl-2-(benzothiazol-2-yl)thiomethyl-2-methyl-6 -(2-phenylacetamido)penam-3-carboxylate of the second fraction of fractions of each 30 ml.

IR absorption spectrum (CHC13): 3400, 1790, 1765 and 1680c<m_1.>

Example D6.

A solution of 0.23 g of 1-methyl-1H-tetrazol-5-thidl in a mixture of 15 ml of phosphate buffer with a pH value of 6.9 and 20 ml of acetone is added to 0.54 g of 2,2,2-trichloroethyl-2 -bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate and the mixture is stirred for 5 hours at room temperature. Acetone is distilled from the reaction mixture. The aqueous phase is extracted with ethyl acetate and the extract is washed with aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution. After drying the extract over magnesium sulphate, the solvent is distilled off. The residue is purified by column chromatography on silica gel, and 0.27 g of oily 2,2,2-trichloro-ethyl-2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-methyl-6-(2 -phenylacetamido)-penam-3-carboxylate.

IR absorption spectrum (CHC13): 3300, 1790, 1765 and 1680cm<_1.>

Example D7.

20 ml of acetone and 0.12 g of thioacetic acid are added to 20 ml of phosphate buffer with a pH value of 6.7. 0.54 g of 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate is added to this mixture while stirring. After stirring for 5 hours at room temperature, the reaction mixture is post-treated as described in example D6, and 0.173 g of oily 2,2,2-trichloroethyl-2-acetylthio-methyl-2-methyl-6-(2-phenylacetamido)penam-3- carboxylate.

IR absorption spectrum (CHClj): 3390, 1790, 1965, 1690

1685 cm<-1>.

Example D8.

0.37 g of sodium piperidine-1-dithiocarboxylate is dissolved in a mixture of 20 ml of phosphate buffer with a pH value of 6.7 and 25 ml of acetone,

0.54 g of 2,2,2-trichloroethyl-2-bromo-methyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate is then added to the solution. After stirring at room temperature for 3 hours, the reaction mixture is post-treated in a similar manner as described in example D6, and 0.11 g of oily 2,2,2-trichloroethyl-2-piperidinothiocarbonyl-thiomethyl-2-methyl-6-(2- phenylacetamido)penam-3-carboxylate.

IR absorption spectrum (CHClj): 3300, 1788, 1764 and 1675 cm"1

Example D9.

25 ml of acetone is added to a solution of 0.23 g of 1-methylimidazole-2-thiol in 20 ml of phosphate buffer with a pH value of 6.9. To this solution is added 0.54 g of 2,2,2-trittorethyl-2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate, and the mixture is stirred for 3 hours at room temperature.

The reaction mixture is post-treated in a similar manner as described in example D6, and 0.29 g of oily 2,2,2-trichloro-ethyl-2-(1-methylimidazol-2-yl)thiomethyl-2-methyl-6-(2 -phenylacetamido)-penam-3-carboxylate.

IR absorption spectrum (CHC13): 3200, 1790, 1770 and 1678cm<-1.>

Example D10.

25 ml of acetone is added to a solution of 0.22 g of pyridine-4-thiol in 20 ml of phosphate buffer with a pH value of 6.8. 0.54 g of 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate is added to this solution and the mixture is stirred for 3 hours at room temperature.

The reaction mixture is post-treated in a similar manner as described in example D6, and 0.15 g of oily 2,2,2-trichloro-ethyl-2-(4-pyridyl)thiomethyl-2^methyl-6-(2-phenylacetamido)penam are obtained -3-carboxylate.

IR absorption spectrum (film): 3250 , 1780 , 1765 and ^Scm<-1>.

Example Dli.

0.4 g of 5-methyl-1,3,4-thiadiazole-2-thiol is dissolved in one mixture of 20 ml of phosphate buffer with a pH value of 7.3 and 20 ml of acetone. A solution of 0.80 g of methyl-2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate in 10 ml of acetone is added to this solution, and the mixture is stirred for 4 hours at room temperature. After completion of the reaction, acetone is distilled from the reaction mixture and the residue is extracted with ethyl acetate. The extract is washed with aqueous sodium hydrogen carbonate solution, then with water and then dried over magnesium sulfate. The solvent is distilled off and the residue is submitted

column chromatography on 60 g silica gel and eluted with chloroform. The eluate is divided into fractions of approx. 30 ml and from fractions 4-7, 0.28 g of methyl-2-(5-methyl-1,3,4-thiadiazol-2-yl)-thio-methyl-2-methyl-6-(2-phenoxyacetamido) is obtained )penam-3-carboxylate.

IR absorption spectrum (film): 3300, 1785, 1745 and 1690cm<-1.>

Example D12.

2 ml of acetic acid is added to a solution of 0.54 g of 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate in 10 ml of methylene chloride. 0.34 g of silver acetate is added to this solution while stirring at room temperature, and the mixture is stirred for 2 hours. After completion of the reaction, the reaction mixture is filtered under reduced pressure and the filtrate is washed with 5% hydrochloric acid and filtered again. The oily residue is crystallized by treatment with ether, the crystals are isolated by filtration and dried,

and 0.21 g of colorless needles of 2,2,2-trichloroethyl-2-acetoxy-methyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate are obtained; melting point 116 - 118°C.

Example D13.

A solution of 6.75 g of 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]aminopenam-3-carboxylate in 50 ml of acetone is added to a solution of 2 .6 g of 1-methyl-1H-tetrazol-5-thiol in a mixture of 200 ml of phosphate buffer and 200 ml of acetone under cooling at 5°C, and the mixture is stirred for 5 hours at the same temperature. After completion of the reaction, acetone is distilled from the reaction mixture under reduced pressure and the residue is extracted with ethyl acetate. The extract is washed with 5% aqueous sodium bicarbonate solution, then with water and then dried. The solvent is distilled off. The oily residue is subjected to column chromatography on 180 g of silica gel and eluted with chloroform. The eluate is divided into fractions of 50 ml each, and after collection of fractions 11 - 16, the solvent is distilled off, and 3.15 g of oily 2,2,2-trichloroethyl-2-(1-methyl-1H-tetrazol-5-yl) are obtained )thiomethyl-2-methyl-6-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]aminopenam-3-carboxylate.

IR absorption spectrum (film): 3270, 1780, 1760 and 1680cm<_1.>

Example D14.

By proceeding as described in example D13 and by using 6.72 g of 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]aminopenam-3 -carboxylate, 1.98 g of 5-methyl-1,3,4-thiadiazole-2-thiol,' 200 ml of phosphate buffer with a pH value of 6.8 and 250 ml of acetone gives oily 2,2,2-trichloroethyl-2 -(5-Methyl-1,3,4-thiadiazol-2-yl)thiomethyl-2-methyl-6-[N-(1-cyclopropylethoxy)-carbynylphenylglycyl]aminopenam-3-carboxylate (1.16 g).

IR absorption spectrum (CHCl 1 ): 3420, 1790, 1770 and 1687 cm -1 .

Example D15.

A solution of 3.6 g of 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]aminopenam-3-carboxylate in 40 ml of formamide is added to a solution of 0.66 g of sodium bicarbonate and 1.1 g of 5-methyl-1,3,4-thiadiazole-2-thiol in 60 ml of formamide under ice-cooling and the mixture is stirred for 1 hour at the same temperature. After completion of the reaction, the reaction mixture is poured into water and extracted with ethyl acetate. The extract is washed with 51 µg aqueous sodium bicarbonate solution, then with water, dried and the solvent is distilled off. The oily residue is subjected to column chromatography on 110 g of silica gel and eluted with chloroform. The eluate is divided into fractions of 50 ml each and after collection of fractions 15 - 17, the solvent is distilled off, and 0.42 g of oily 2,2,2-trichloroethyl-2-(5-methyl-1,3,4-thiadiazole- 2-yl)thiomethyl-2-methyl-6[N-(1-cyclopropylethoxy)-carbonylphenylglycyl]-aminopenam-3-carboxylate.

Example D16.

Dissolve 1.10 g of 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate in 15 ml of methylene chloride. 0.28 g of aniline is added to this solution while cooling at -10°G

and then 0.43 g of silver fluoroborate, and then the mixture is stirred for 2 hours. After completion of the reaction, the reaction mixture is washed with a dilute aqueous phosphoric acid solution, then with water, dried over magnesium sulfate, and the solvent is distilled off. The residue is subjected to column chromatography on 20 g of silica gel and eluted with chloroform. The eluate is divided into fractions of approx. 20 ml. Fractions 2-7 are isolated, and the solvent is distilled off, yielding 0.84 g of 2,2,2-trichloroethyl-2-anilinomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate with a melting point of 148 - 149°C.

IR absorption spectrum (CHCip: 3400 , 1780 , 1765 and 1680cm<_1.>

Example D17.

By proceeding in a similar way as described in the example

D16 and by using 0.88 g methyl-2-bromomethyl-2-methyl-6-(2-phenoxy acetamido)penam-3-carboxylate, 0.28 g aniline, 0.43 g silver fluoroborate and 15 ml methylene chloride, you get 0.41 g of oily methyl-2-anilinomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate from fractions 3-7.

IR absorption spectrum (CHC13): 3410, 1785, 1748 and 1690cm<-1.>

Example D18.

1.10 g of 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate is dissolved in 12 ml of methylene chloride, and 3 ml of methanol is added. 0.45 g of silver is added to the solution. fluoroborate while stirring and upon cooling to -10°C and then the mixture is stirred for 2 hours at this temperature. After completion of the reaction, the reaction mixture is filtered, the filtrate is washed with aqueous sodium bicarbonate solution, then with water and dried over magnesium sulfate and evaporated. The residue is subjected to column chromatography on 25 g of silica gel and eluted with chloroform. The eluate is divided into fractions of approx. 20 ml, and fractions 1 and 2 are isolated.

After removal of the solvent by distillation, the residue is dried, and oily 2,2,2-trichloroethyl-2-methoxymethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate is obtained.

IR absorption spectrum (VHClj):3360, 1785, 1757 and 1666cm<_1>.

Example D19.

By proceeding in a similar manner as described in Example D18 and by using methyl 2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)-penam-3-carboxylate instead of 2,2,2-trichloroethyl- 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate gives oily methyl-2-methoxymethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate.

IR absorption spectrum (CHC1,) : 3370 , 1787 , 1742 and

-1

168 5 cm

Example D20.

By proceeding in a similar manner as described in example Dll and by using 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-[3-(2-chlorophenyl)-5-methylisoxazole-4- carboxamido]penam-3-carboxylate and 1-methyl-1H-tetrazole-5-thiol in a mixture of phosphate buffer with a pH value of 6.85 and acetone gives amorphous 2,2,2-trichloroethyl-2-(1-methyl -1H-tetrazol-5-yl)thiomethyl-2-methyl-6-[3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido]penam-3-carboxylate.

IR absorption spectrum (Nujol): 3300 , 178.0 ,1770 and 1665cm<_1.>

Example D 21.

By proceeding in a similar manner as described in Example Dll and by using 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-[2-(1H-tetrazol-1-yl)acetamido]penam- 3-carboxylate and 1-methyl-1H-tetrazole-5-thiol in a mixture of phosphate buffer with pH value 6.85

and acetone gives amorphous 2,2,2-trichloroethyl-2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-methyl-6-[2-(1H-tetrazol-1-yl)acetamido] penam-3-carboxylate.

IR absorption spectrum (Nujol): 3220, 1780, 1760 and 1700 cm_1.

The following compounds are prepared by proceeding as described in examples D1 - 21.

Reaction E.

Example El.

1.10 g of 2,2,2-trichloroethyl-3-bromo-3-methyl-7-(2-phenylacetamido)-cepham-4-carboxylate is dissolved in 15 ml of methylene chloride, and 0.28 g of aniline is added. 0.45 g of silver fluoroborate is added to the solution with stirring and ice-cooling and the mixture is stirred for 4 hours at this temperature. After completion of the reaction, the reaction mixture is filtered. The filtrate is washed with a dilute aqueous solution of phosphoric acid, then with water, dried over magnesium sulphate and evaporated. The residue is subjected to column chromatography on 25 g of silica gel and eluted with chloroform. The eluates are dissolved in fractions of approx. 20 ml, fractions 2-8 are isolated and the solvent is removed by distillation, and 0.54 g of 2,2,2-trichloroethyl-2-anilinomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate is obtained with melting point 148 - 149°C.

IR absorption spectrum (CHClj): 3400, 1780, 1765 and 1680cm<-1.>

The following compounds are prepared by using the method described in example El.

Example Fl.

A solution of 1.39 g of m-chloroperbenzoic acid in 15 ml of chloroform is added to a solution of 3.74 g of 2,2,2-trichloroethyl-2-bromo-methyl-2-methyl-6-(2-phenylacetamido)penam- 3-carboxylate in 35 ml of chloroform under ice-cooling. The mixture is stirred under ice-cooling for 1

hour and then the precipitate is filtered off. The filtrate is washed with saturated aqueous sodium bicarbonate solution and water in the order indicated and dried over magnesium sulfate. After evaporation

of the solvent under reduced pressure, the residue is crystallized by the addition of a small amount of ether. The crystals are filtered off and 3.15 g of colorless crystals of 2,2,2-trichloroethyl-2-bromo-methyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate-1-B-oxide are obtained with melting point .114 - 115°C (decomposition) .

Analysis:

Calculated for C^H^O^SCljBr: C 38.55 H 3.24 N 4.99

Found : C 38.40 H 3.12 N 4.68.

Example F2.

540 mg of 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate are suspended in a mixed solution of 10 ml of pyridine and m ml of water at a temperature between - 35 and -40°C. 110 mg isocyanuroyl chloride is added dropwise to the suspension. The mixture is stirred for 1 hour and 20 minutes and then poured into a mixture of 50 ml of 20% aqueous phosphoric acid solution and 20 ml of ethyl acetate under ice cooling. The ethyl acetate fraction is separated. After extraction of the aqueous phase with ethyl acetate, the ethyl acetate extract is poured together with the above-mentioned ethyl acetate phase. The extract is washed with 5% phosphoric acid solution, water, saturated aqueous sodium bicarbonate solution and water in the order indicated and then dried over magnesium sulfate. After removal of the solvent, the residue is subjected to column chromatography on silica gel with chloroform. The third fraction is evaporated, and 130 mg of 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate-1-B-oxide is obtained. The fifth fraction is evaporated and 170 mg of 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate-1-a-oxide is obtained.

IR absorption spectrum (CHCl^) of the α-oxide: 3420, 1795, 1770 and 1665 cm"<1>.

Example F3.

210 mg of m-chloroperbenzoic acid are added dropwise under ice-cooling to a. solution of 522 mg of 2,2,2-trichloroethyl-2-thiocyano-methyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate in 10 ml of chloroform. The mixture is stirred under ice cooling for 1 hour and the solid material is filtered off. The filtrate is washed with a saturated aqueous sodium bicarbonate solution and water in the order indicated and dried over magnesium sulfate. The solvent is removed and 540 mg of a colorless powder is obtained which consists of 2,2,2-trichloroethyl-2-thiocyanomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate-1-3-oxide.

Example F4.

522 mg of 2,2,2-trichloroethyl-2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate are suspended in a mixed solution of 10 ml of pyridine and 1 ml of water at a temperature between - 35

and -40°C. 110 mg isocyanuroyl chloride is added dropwise to the suspension at a temperature between -35 and -40°C. The mixture is stirred at this temperature for 1 hour, and is then poured onto a mixture of 50 ml of ice-cooled 201g phosphoric acid and 20 ml of ethyl acetate and then the ethyl acetate phase is separated. The aqueous phase is extracted with ethyl acetate and the extract is combined with the above-mentioned ethyl acetate phase. The extracts are washed with 5% phosphoric acid, water, saturated

aqueous sodium bicarbonate solution and water in the specified order and dried over magnesium sulfate. The solvent is distilled off and the residue is purified by column chromatography on silica gel with chloroform, and 140 mg of 2,2,2-trichloroethyl-2-thiocyanatomethyl-2-methyl-6-(2T-phenylacetamido)penam-3-carboxylate-1-3-oxide is obtained .

Example F5.

522 mg of 2,2,2-trichloroethyl-2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate are suspended in a mixed solution of 12 ml of pyridine and 12 ml of water at a temperature between - 25 and -35°C. 550 mg of phenyliodine dichloride is added to this solution. The mixture is stirred for 3 hours at a temperature between -25 and -35°C and then a further 550 mg of phenyliodine dichloride is added. After stirring for 1 hour, 550 mg of phenyliodine dichloride is again added to the mixture; The reaction mixture is stirred for a further 1 hour and poured into a mixture of 50 ml of 20% phosphoric acid and 20 ml of ethyl acetate and the ethyl acetate phase is separated. The aqueous phase is extracted with ethyl acetate, which is combined with the above-mentioned ethyl acetate phase. The combined ethyl acetate phases are washed with 5% phosphoric acid, water, saturated aqueous sodium bicarbonate solution and water in the specified order and dried over magnesium sulfate. After removing the solvent under reduced pressure, the residue is subjected to column chromatography on silica gel with a mixed solution of 2 parts benzene and 1 part . ethyl acetate. Fractions 3-7 are evaporated, and 250 mg of 2,2,2-trichloroethyl-2-thiocyantomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate-1-3-oxide is obtained.

Example F6.

A solution of 2.03 g of m-chloroperbenzoic acid in 30 ml of chloroform is added dropwise to a solution of 5.0 g of 2,2,2-trichloroethyl-2-chloromethyl-2-methyl-6-(2-phenylacetamido)penam-3 -carboxylate in 40 ml chloroform at a temperature between -10 and -5°C with stirring, then the mixture is stirred for 1 hour at a temperature between -10

and -5°C. After filtering off solid material, the filtrate is washed with a saturated aqueous sodium bicarbonate solution and water in the order indicated and dried over magnesium sulfate. After removal of the solvent, the residue is crystallized by adding ethanol. The crystals are filtered off and recrystallized from ethanol, and 4.10 g of 2,2,2-trichloroethyl-2-chloromethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate-1-oxide with melting point 130 - 131°C.

Analysis:

Calculated for C18<H>18<0>5<N>2SC14: c 41.87 H 3.51 N 5.43 S 6.21

Found : C 41.80 H 3.45 N 5.50 S 6.44.

Example F7.

P 0.02 g of sodium tungstate is added to a solution of 3.1 g of 2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylic acid in 8 ml of acetic acid at 7 - 10°C with stirring, and then 1.2 ml of 30% aqueous hydrogen peroxide solution is added to the mixture. The mixture is stirred at 7 - 10°C for 1 hour. After the reaction, 50 ml of ice water is added to the reaction mixture and then extracted with ethyl acetate. The extract is washed with water and extracted again with 5% aqueous sodium bicarbonate solution. The aqueous phase is washed twice with ethyl acetate, acidified with 5% hydrochloric acid solution to pH 2 and then extracted with ethyl acetate. The extract is washed with water, dried and evaporated to give 2 g of powdered 2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylic acid-1-oxide.

IR absorption spectrum (CHC13): 3350, 1795, 1740 and

1688cm"1.

Example F8.

A solution of 0.445 g of m-chloroperbenzoic acid in 5 ml of chloroform is added to a solution of 1.21 g of 2,2,2-trichloroethyl-3-bromo-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate under stirring at a temperature between -5 and -10°C, and then the mixture is stirred for 1 hour at this temperature. After the reaction, the reaction mixture is washed with 5 µg aqueous sodium bicarbonate solution and water in the order indicated and dried. After the removal of the solvent by distillation, the residue is crystallized by the addition of ether. The crystals obtained are recrystallized from ethanol and 1.10 g of 2,2,2-trichloroethyl-3-bromo-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate-1-oxide with melting point 159 - 161 is obtained °C.

Reaction G.

Example Gl. 1.12 g of 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate-1-oxide is dissolved in 10 ml of dried methylene chloride. To this solution, 0.36 g of dimethylaniline is added while cooling to -15°C and then 0.6 g of phosphorus pentachloride, and the mixture is stirred for 3 hours. 0.7 g of anhydrous methanol is added to the solution while cooling to -40°C and the solution is stirred for 2 hours and for a further 1 hour at -15°C. After the reaction, precipitated crystals are isolated by filtration, washed with a small amount of methylene chloride and dried, and 0.70 g of 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-aminopenam-3-carboxylate-1- oxide-hydrochloride with melting point 147 - 154°C (decomposition).

IR absorption spectrum (Nujol): 1820, 1800 and 1760 cm 1.

Example G2.

10.8 g of 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate are dissolved in 300 ml of dried methylene chloride. 3.6 g of dried dimethylaniline and then 6.4 g of phosphorus pentachloride are added to this solution while cooling to -35°C, and the mixture

stirred for 2| hour at the same temperature. 6.4 g of anhydrous methanol are added dropwise to the solution at the same temperature, and the mixture is stirred for 1 hour at -15°C. 6.5 ml of water is added to the solution and this is stirred vigorously for 30 minutes. After the reaction, the precipitate is isolated by filtration, washed with methylene chloride and with ether and dried, and 7.8 g of powdered 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-aminopenam-3-carboxylate hydrochloride is obtained.

IR absorption spectrum (Nujol): 3350 - 3400, 1790 and 1770 cm -1 .

Example 63.

0.53 g of 2,2,2-trichloroethyl-2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate is dissolved in 10 ml of dried methylene chloride. 0.43 g of dimethylaniline and then 0.23 g of phosphorus pentachloride are added to this solution while cooling to a temperature between -20 and -30°C, and the mixture is stirred for 1 hour. 0.34 g of anhydrous methanol is then added dropwise to the solution, and the solution is stirred for 5 hours. At 0°C, 7 ml of water is added to the solution and the mixture is stirred for 10 minutes. The aqueous phase is separated. The aqueous phase is adjusted to pH 9 by adding 1N aqueous sodium hydroxide solution and extracted with 10 ml of ethyl acetate.

The extract is dried over magnesium sulfate, and the solvent is distilled off. The residue is dissolved in a small amount of ethyl acetate and 0.1 g of toluenesulfonic acid monohydrate and 5 ml of ethyl acetate are added to this solution. The mixture is cooled and the precipitated crystals are isolated by filtration, and 0.06 g of 2,2,2-trichloroethyl-2-thio-cyanatomethyl-2-methyl-1-6-aminopenam-3-carboxylate is obtained luensulfonate with melting point 182 - 185°C (decomposition).

IR absorption spectrum (Nujol): 2150, 1795 and 1750 cm^.

Reaction H.

Example Hl.

To a solution of 1.95 g of ethyl chlorocarbonate in 120 ml of dried methylene chloride is added dropwise while cooling to -5°C

a solution of 4.74 g of N-(1-cyclopropylethoxy)carbonylphenylglycine and 1.83 g of triethylamine in 50 ml of dried methylene chloride. The solution containing a mixed anhydride of N-(1-cyclopropylethoxy)carbonylphenylglycine and ethyl chlorocarbonate prepared by stirring the above mixture for 1 hour at -5°C is cooled to a temperature between -30 and -35°C. A solution of 6.95 g of 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-aminobpenam-3-carboxylate hydrochloride and 3.0 g of triethylamine in 100 ml of dried methylene chloride is added dropwise to this solution, and the mixture is stirred for 3 hours. After completion of the reaction, the reaction mixture is washed with 51% hydrochloric acid solution, water, 5% aqueous sodium bicarbonate solution and

water in the order indicated and dried. The solvent is distilled off and 9.7 g of amorphous 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-[N-(1-cyclopropylethoxy)phenylglycyl]aminopenam-3-carboxylate are obtained.

IR absorption spectrum (CHClj): 3410, 1785, 1765 and

1690 cm-1.

Example H2.

A solution of 1.4 g of pivaloyl chloride in 100 ml of dried methylene chloride is added dropwise while cooling to -5°C a solution of 1.81 g of 1H-tetrazole-1-acetic acid and 1.4 g of triethylamine in 30 ml of dried methylene chloride, and the mixture is stirred for 2 hours at this temperature. The solution containing mixed anhydride of 1H-tetrazole-1-acetic acid and pivalic acid is cooled to -35°C, and the solution is added dropwise to a solution of 4.0 g of 2,2,2-tri-chloroethyl-2-bromomethyl-2-methyl -6-aminopenam-3-carboxylate hydrochloride and 200 g of triethylamine in 80 ml of dried methylene chloride, and the mixture is stirred for 4 hours at this temperature. After completion of the reaction, the reaction mixture is worked up in a similar manner as described in Example H1, and 3.85 g of oily 2,2,2-trichloroethyl-2-bromo-methyl-2-methyl-6-[2-(1H-tetrazole- 1-yl)-acetamido]penam-3-carboxylate.

IR absorption spectrum (film): 3250, 1783, 1765 and

1685 cm ^.

Example H3.

A solution of 6.95 g of 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-aminopenam-3-carboxylate hydrochloride and 3.0 g of triethylamine in 100 ml of dried methylene chloride is cooled to -25°C. A solution of 4.5 g of 3-(2-chlorophenyl)-5-methylisoxazole-4-carbonyl chloride in 30 ml of dried methylene chloride is added dropwise to this solution, and the mixture is stirred for 3 hours at the same temperature. After completion of the reaction, the reaction mixture is worked up in a similar manner as described in example H1, and 6.75 g of oily 2,2,2-trichloro-ethyl-2-bromomethyl-2-methyl-6-[3-(2-chlorophenyl) are obtained -5-methylisoxazole-4-carboxamido]penam-3-carboxylate.

IR absorption spectrum (film): 3370, 1790, 1765 and 1670 cm"<1.>

The following compounds are prepared in the same way as indicated in examples H1 - 3.

Reaction J.

Example Jl.

1 ml of acetic acid and 0.75 g of zinc dust are added to a solution of 0.65 g of 2,2,2-trichloroethyl-2-acetylthiomethyl-2-methyl-6-(2-£enylacetamido)penam-3-carboxylate in 3 ml of dimethylformamide under ice- cooling and the mixture is stirred for 2 hours at the same temperature.

After the reaction, the reaction mixture is filtered and the filtrate is poured into 20 ml of 5% hydrochloric acid solution and extracted with ethyl acetate. The extract is washed with water and dried, the solvent is distilled off, and 0.365 g of an oil is obtained. After dissolving the oil in 0.7 ml of acetone, a solution of 0.142 g of N,N'-dibenzylethylenediamine diacetate in 5 ml of water is added to the solution and the precipitated powder is filtered off. The powder is purified by re-extraction from a mixture of methanol and water and 0.211 g of N,N'-dibenzyl-ethylenediamine-2-acetylthiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate with a melting point of 105 - 107°C.

Analysis: Calculated for C18H19H205S2.1/2 C16H22N2.H20: C 57.19 H 5.87 N 7.69

Found : C 57.18 H 5.58 N 7.44.

IR absorption spectrum (Nujol): 3300, 1772, 1690 and

1670 cm"<1>.

Example J2.

1 ml of acetic acid and 0.80 g of zinc dust are added to a solution of 0.95 g of 2,2,2-trichloroethyl-2-piperidinothiocarbonylthiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate in 5 ml of dimethylformamide

under ice-cooling and the mixture is stirred for 1 hour and 40 minutes. After the reaction, the zinc dust is filtered off and the filtrate is poured into ethyl acetate. The solution is washed with 31 µg hydrochloric acid solution and then four times with water and dried over magnesium sulfate. After drying, the solvent is distilled off and the residue is dissolved in a small amount of methanol. An aqueous solution of N,N'-dibenzylethylenediamine diacetate is added to this solution, and the precipitate is isolated by filtration and washed with water, and 0.30 g of N,N'-

dibenzylethylenediamine-2-piperidinothiocarbonylthiomethyl-2-methyl-6-(2-£enylacetamido)penam-3-carboxylate with melting point 100°C (decomposition).

Analysis:

Calculated for C22H26°4N3S3*C16H22: C 57>03 H 6>22 N 8'87

Found : C 57.00 H 5.87 N 8.60.

IR absorption spectrum (Nujol): 3280, 1777 and 1660 cm 1.

Example J3. ~"

1.00 g 2 ,2,2-trichloroethyl-2-anilinomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate is dissolved in 5 ml of dimethylformamine.

To this solution, 0.5 ml of acetic acid and then zinc dust are added while cooling to -15°C, and the mixture is stirred for 6 hours. After the reaction, the zinc dust is filtered off and the filtrate is poured into ethyl acetate. The solution is washed four times with water and dried with magnesium sulfate. After drying, the solvent is distilled off, the residue is dissolved in a small amount of methanol and crystallized by adding water. The powder is isolated by filtration, washed with water and dried to give 0.50 g of 2-anilinomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylic acid with a melting point of 120°C.

Analysis:

Calculated for C22H2304N3.1/2 H20: C 60.81 H 5.56 N 9.67

Found : C 60.49 H 5.40 N 9.44.

IR absorption spectrum (Nujol): 3400, 1780 and 1745 cm 1.

Example J4.

0.67 g 2,2,2-trichloroethyl-2-(1-methyl-1H-tetrazol-5-yl)thio-methyl-2-methyl-6-[ 3-,(2-chlorophenyl)-5- methylisoxazole-4-carboxamido]penam-3-carboxylate is dissolved in 5 ml of dimethylformamide. To this solution, 0.8 ml of acetic acid and 0.7 g of zinc dust are added while cooling to -15°C and the mixture is stirred for 2 hours at this temperature. After the reaction, the zinc dust is filtered off, the filtrate is poured into 20 ml of 51 µg hydrochloric acid solution and extracted with ethyl acetate. The extract is washed with water and dried and the solvent is distilled off. The residue is dissolved in 0.8 ml of methanol, and to this solution is added a solution of 0.18 g of N,N'-dibenzylethylenediamine diacetate in 5 ml of water,

and the precipitate is isolated by filtration, washed with water and dried,

and 0.24 g of N,N'-dibenzylethylenediamine-2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-methyl-6-[3-(2-chlorophenyl)-5-methylisoxazole- 4-Carbox-amido]penam-3-carboxylate with melting point 117 - 119PC (decomposition).

IR absorption spectrum (Nujol): 3400, 1778 and 1665 cm 1.

Example J5.

0.6 g 2,2,2-trichloroethyl-2-(1-methyl-1H-tetrazol-5-yl)thio-methyl-2-methyl-6-[2-(1H-tetrazol-1-yl)acetamido ]penam-3-carboxylate is dissolved in 5 ml of dimethylformamide. To this solution, 0.9 ml of acetic acid and 0.8 g of zinc dust are added while cooling to -15°C, and the mixture is stirred for 11 hours at this temperature. After the reaction, the zinc dust is filtered off and the filtrate is poured into 20 ml of 51 µg hydrochloric acid solution and extracted with ethyl acetate. The extract is washed with water and dried, and the solvent is distilled off. The residue is crystallized from ether, and 0.25 g of 2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-methyl-6-[2-(1H-tetrazol-1-yl) is obtained acetamido]penam-3-carboxylic acid with melting point 152 - 154°C.

IR absorption spectrum (Nujol): 3230, 1780, 1738 and

1692 cm"<1>.

Example J 6.

0.94 g of 2,2,2-trichloroethyl-2-(1-methyl-1H-tetrazol-5-yl)thio-methyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate is dissolved in 5 ml of dimethylformamide. To this solution, 0.7 ml of acetic acid and then 0.80 g of zinc dust are added while stirring and the mixture is stirred for 2 hours. After the reaction, the zinc dust is filtered off and the filtrate is dissolved in ethyl acetate. The solution is washed with 31 µg hydrochloric acid solution, three times with water and dried over magnesium sulfate. After drying, the solvent is distilled off and the residue is dissolved in a small amount of methanol and then crystallized by adding an aqueous solution of 0.36 g of N,N'-dibenzylethylene diamine diacetate. The crystals are isolated by filtration, washed with a mixture of ethanol and water and dried to give 0.50 g of 2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-methyl-6-(2-phenylacetamido) penam-3-carboxylate with melting point 150 - 152°C (decomposition).

Analysis:

Calculated for C18H1804N6S2.1/2 C16H22N2.1/2 H20: C54.48 H 5.28

N 17,17

Found : C 54.45 H 5.29

N 17.00.

IR absorption spectrum (Nujol): 3370, 1763 and 1674 cm 1.

Example J7.

1.5 g of 2,2,2-trichloroethyl-2-chloromethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate is dissolved in 8 ml of dried dimethylformamide,

and to this solution 1.5 ml of formic acid and then 1.5 g of zinc dust are added while stirring and ice-cooling. After stirring for 2 hours at this temperature, the zinc dust is filtered off and washed with 5 ml dimeylformamide. The filtrate and the washing liquids are added to a mixed, cold solution of 30 ml of ethyl acetate and 15 ml of 51% hydrochloric acid. After extraction with ethyl acetate, the extract is washed with water and dried over magnesium sulfate. After removal of the solvent by distillation under reduced pressure, 1.16 g of a gummy material is obtained which is crystallized from a mixed solvent of ethyl acetate and isopropyl ether, and 660 mg of 2-chloromethyl-2-methyl-6-(2-phenylacetamido) is obtained penam-3-carboxylic acid with melting point 110 - 112°C (decomposition).

Analysis:

Calculated for C-^H^N^SCl: C 52.10 H 4.65 N 7.60 S 8.69 Cl 9.61 Found : C 51.90 H 4.73 N 7.46 S 8.67 Cl 9.84.

IR absorption spectrum (Nujol): 3325, 1788, 1730 and

1635 cm

Example J8.

0.90 g of 2,2,2-trichloroethyl-2-(benzothiazol-2-yl)thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate is dissolved in 5 ml of dimethylformamide. To this solution, 0.7 ml of acetic acid is added under ice cooling and then 0.80 g of zinc dust while stirring and then the mixture is stirred for 2 hours. After filtering off the zinc dust, the filtrate is dissolved in ethyl acetate, the solution is washed with 31 µg hydrochloric acid solution, then three times with water and then dried over magnesium sulfate. After removal of the solvent by distillation, the residue is dissolved in a small amount of acetone. A solution of 250 mg of sodium 2-ethylhexanoate in 5 ml of acetone is added to this solution, and the solution is evaporated again. The residue is crystallized by adding ethanol, the crystals are isolated by filtration, washed with a small amount of ethanol and dried, and 0.50 g of sodium 2-(benzothiazol-2-yl)-thiomethyl-2-methyl-6-(2 -phenylacetamido)penam-3-carboxylate with melting point 200°C (decomposition).

IR absorption spectrum (Nujol): 3400, 1760, 1670 and

1600 cm"<1>.

Example J9.

0.80 g 2,2,2-trichloroethyl-2-(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate dissolve in 5 ml of dimethylformamide. 0.5 ml of acetic acid is added to this solution

and then 0.80 g of zinc dust under ice-cooling and the mixture is stirred for 2 hours. The zinc dust is filtered off and the filtrate is dissolved in ethyl acetate. The solution is washed with 5% hydrochloric acid solution and then four times with water and dried with magnesium sulphate. After removal of the solvent by distillation, the residue is dissolved in a small amount of ethyl acetate and a solution of 250 mg of sodium 2-ethylhexanoate in 5 ml of acetone is added to the solution, and the solution is then evaporated. The residue is pulverized from ethyl acetate, and the powder is recrystallized from ethanol. The crystals are isolated by filtration, washed with ethanol and dried, and 0.28 g of sodium 2-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-2-methyl-6-(2- phenylacetamido)penam-3-carboxylate with melting point 185 - 186°C (decomposition).

IR absorption spectrum (Nujol): 3200, 1757, 1670 and

1625 cm 1.

By proceeding in a similar manner, 2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylic acid with a melting point of 164.5 - 165.5°C is obtained.

Reaction K.

Example At

.454 mg of methyl-2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)-dithio-α-isopropenyl-1-azetidine acetate are dissolved in 20 ml of methylene chloride. To this solution is added 5 ml of methanol and then at 0°C 0.124 g of boron trifluoride etherate. The mixture is stirred for 3 hours at this temperature and for a further 2 hours at 5 - 10°C. After re-

the mixture is washed with 5% aqueous sodium bicarbonate solution and with water. After drying the mixture, this is evaporated and the oily residue (250 mg) is purified by column chromatography on silica gel, and oily methyl-3-methyl-3-methoxy-7-(2-phenoxyacetamido)cepham-4-carboxylate is obtained.

IR absorption spectrum (CHClj): 3400, 1772, 1739 and

1688cm"1.

Example K2.

1.06 g of methyl-2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)-dithio-α-isopropenyl-1-azetidine acetate are dissolved in 20 ml of methylene chloride. 0.28 g of aniline and then 0.80 g of silver fluoroborate are added to this solution, and the mixture is stirred for 2 days at room temperature. After the reaction, the reaction mixture is filtered, and the filtrate is washed with dilute aqueous phosphoric acid solution and then with water. After drying the mixture, it is evaporated and the residue is purified by column chromatography on 25 g of silica gel, and 0.38 g of methyl-3-methyl-3-anilino-7-(2-phenoxyacetamido)cepham-4-carboxylate is obtained with a melting point of 129 - 130 °C.

Example K3.

1.26 g of 2,2,2-trichloroethyl-2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-a-isopropenyl-1-azetidine acetate are dissolved in 15 ml of ethyl acetate. To this solution, 5 ml of acetic acid is added, and then 0.68 g of silver acetate while stirring at room temperature. The mixture is stirred for 4 hours at this temperature. After the reaction, the reaction mixture is filtered, the filtrate is washed with water and then with 5% aqueous sodium bicarbonate solution. The solution is filtered again, the filtrate is washed with water and dried. The solvent is distilled off and the residue is purified by thin-layer chromatography using a mixture of acetone and benzene (1:9), and amorphous 2,2,2-trichloroethyl-3-acetoxy-3-methyl-7-(2- phenylacetamido)-cepham-4-carboxylate.

IR absorption spectrum (CHC13): 3425, 1780, 1750 and

1680 cm"<1>.

Example K4.

2.12 g of methyl-2-oxo-3-(2-phenoxyacetamido)-4-(benzbthiazol-2-yl)-dithio-α-isopropenyl-1-azetidine acetate are dissolved in 80 ml of methanol. 0.68 g of silver nitrate is added to this solution, and the mixture is heated under reflux for 28 hours. After the reaction, the precipitate is filtered off and the filtrate is evaporated. The obtained remainder

extracted with ethyl acetate, the extract is washed with water and dried.-The solvent is distilled off, and the residue obtained is purified

by column chromatography on silica gel using chloroform as developer, and 620 mg of pale yellow oil of methyl 3-methoxy-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate is obtained.

IR absorption spectrum (CHC1,): 3400, 1772, 1739 and

1688 cm..

The same result is obtained by using methylene chloride as solvent and silver fluoroborate instead of silver nitrate.

Example K5.

0.53 g of methyl-2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)-dithio-α-isopropenyl-1-azetidine acetate is dissolved in 20 ml of methanol. 0.17 g of silver acetate is added to this solution, and the mixture is heated under reflux for 39 hours. After the reaction, the reaction mixture is worked up in a similar manner as described in example Kl, and 200 mg of oily methyl-3-methyl-3-methoxy-7-(2-phenoxyacetamido)cef am-4-carboxylate is obtained.

Example K6.

A mixture of 0.53 g of methyl-2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidine acetate, 0.3 g of mercuric acetate and 20 ml of methanol is heated under reflux for 48 hours. After the reaction, the reaction mixture is worked up in a similar way as indicated in example Kl, and. 180 mg of oily methyl-3-methyl-3-methoxy-7-(2-phenoxyacetamido)cepham-4-carboxylate are obtained.

Example K7.

0.53 g of methyl-2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)-dithio-a-isopropenyl-1-azetidine acetate is dissolved in 20 ml of methanol. 0.27 g of mercuric chloride is added to this solution, and the mixture is then heated under reflux for 24 hours. After the reaction, the reaction mixture is worked up in a similar way

as described in example Kl, and 220 mg of oily methyl-3-methyl-3-methoxy-7-(2-phenoxyacetamido)cepham-4-carboxylate are obtained.

Example K8.

0.53 g of methyl-2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)-dithio-a-isopropenyl-1-azetidine acetate is dissolved in 20 ml of methanol. 0.15 g cupric oxide is added to this solution, and the mixture is heated under reflux for 72 hours. After the reaction, the reaction mixture is worked up in a similar way as described in

example Kl, and 50 mg of oily methyl-3-methyl-.3-methoxy-7-(2-phenoxyacetamido)cepham-4-carboxylate are obtained.

Example K9.

0.63 g 2,2,2-trichloroethyl-2-oxo-3-(2-phenylacetamido)-4-

r

(Benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidine acetate and 0.19 g of p-toluenesulfonic acid monohydrate are dissolved in a mixture of 15 ml of methanol and 5 ml of methylene chloride. The mixture is stirred for 4 hours at 50°C. After the reaction, methanol and methylene chloride are distilled off and the residue is dissolved in 10 ml of ethyl acetate. The ethyl acetate phase is washed with a saturated aqueous sodium bicarbonate solution, then with water and then it is dried over magnesium sulfate. After the removal of the solvent by distillation, the residue is purified by means of column chromatography on silica gel using chloroform as developing agent, and 120 mg of 2,2,2-trichloroethyl-3-methyl-3-methoxy-7-(2-phenylacetamido) are obtained )cefam-4-carboxylate with melting point 132 - 133 °C.

The following compounds are prepared by applying the method in examples Kl - 9: 1) 2,2,2-trichloroethyl-3-methyl-3-azido-7-(2-phenylacetamido)cepham-4-carboxylate, m.p. 136 - 140°C, 2) 2,2,2-trichloroethyl-3-methyl-3-hydroxy-7-(2-phenylacetamido)cepham-4-carboxylate, m.p. 169 - 171°C, 3) 2,2,2-trichloroethyl-3-methyl-3-isopropoxy-7-(2-phenylacetamido)-cepham-4-carboxylate (oil), 4) 1-cyclopropylethyl-3-methyl -3-anilino-7-(2-phenylacetamido)cepham-4-carboxylate (fareyless oil), 5) 2,2,2-trichloroethyl-3-methyl-3-anilino-7-(2-phenylacetamido)cepham-4 -carboxylate (oil),

6) 3-anilino-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylic acid,

m.p. 119 - 123°C (decomposition).

Reaction L.

Example LI.

A mixture of 1.08 g of 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate, 0.26 g of sodium azide,

20 ml of acetone and 4 ml of water are stirred for 4 hours at room temperature. Acetone is distilled off under reduced pressure and the residue is extracted

with ethyl acetate. The ethyl acetate phase is washed with water, saturated aqueous sodium bicarbonate solution, then with water, and then dried over magnesium sulfate. The solvent is distilled off under reduced pressure and a small amount of ether is added to the residue, and 170 mg of colorless crystals are obtained which consist of 2,2,2-trichloroethyl-3-azido-3-methyl-7-(2-phenylacetamido)cepham- 4-carboxylate. The material is recrystallized from carbon tetrachloride, and crystals with a melting point of 136 - 140°C are obtained.

IR absorption spectrum (Nujol): 3310, 2110, 1770, 1746 and 16 58 cm

Example L2.

Dissolve 0.54 g of 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate in 5 ml of absolute dimethylsulfoxide. To this solution, add 0.20 g of silver fluoroborate, and then the mixture is stirred under the exclusion of light for 3 hours at room temperature. A solution of 0.1 g of triethylamine in 0.5 ml of dimethylsulfoxide is added to the solution, and the solution is stirred for a further 5 hours, and is then allowed to stand overnight at room temperature. The precipitate is filtered off, and the filtrate is poured into ice water and extracted with ethyl acetate. The extract is washed with water and dried. After the removal of the solvent by distillation under reduced pressure, the residue is crystallized from a small amount of ether, and 280 mg of colorless crystals of 2,2,2-trichloroethyl-3-hydroxy-3-methyl-7-(2-phenylacetamido)cepham- 4-carboxylate (58% of theory). Material is recrystallized from a mixed solvent of benzene and N-hexane and colorless needles with a melting point of 169 - 171°C are obtained.

Analysis:

Calculated for C18<Hi>gN205SCl3: C44.87 H 3.97 N 5.81 S 6.66 Cl 22.08 Found : C 45.08 H 3.93 N 5.75 S 6.45 Cl 21.96

Example L3.

0.55 g of 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate is dissolved in a mixture of 5 ml of tetrahydrofuran and 5 ml of methanol. 0.24 g of silver fluoroborate is added to this solution while cooling and the mixture is stirred for 1 hour. The reaction mixture is evaporated and the residue is dissolved in chloroform. dissolve-

the mixture is washed with a saturated aqueous sodium bicarbonate solution and water and dried over magnesium sulfate. After the removal of the solvent by distillation, the residue is subjected to chromatography on silica gel using chloroform as developing agent. The crystals obtained are recrystallized from carbon tetrachloride, and 0.27 g of 2,2,2-trichloroethyl-3-methyl-3-methoxy-7-(2-phenylacetamido)cepham-4-carboxylate with melting point 132 - 133°C is obtained .

A similar result is obtained by using methylene chloride instead of tetrahydrofuran.

IR absorption spectrum (Nujol): 3300, 1780, 1760 and

1683 cm 1.

Example L4.

0.55 g of 2,2,2-trichloroethyl-3-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate is dissolved in a mixture of 5 ml of tetrahydrofuran and 5 ml of isopropanol. 0.24 g of silver fluoroborate is added to this solution under ice cooling and the mixture is stirred for 1 hour. The reaction mixture is evaporated and the residue obtained is dissolved in chloroform. The solvent is washed with a saturated and aqueous sodium bicarbonate solution and. water and dried over magnesium sulfate. After the removal of the solvent by distillation, the residue is purified by chromatography on silica gel using chloroform as a developing agent,

and 0.10 g of oily 2,2,2-trichloroethyl-3-methyl-3-isopropoxy-7-(2-phenylacetamido)cepham-4-carboxylate are obtained.

IR absorption spectrum (film): 3300, 1760, 1750 and

1670 cm"<1>.

Example L5.

0.88 g of methyl 2-bromomethyl-2-methyl.-6-(2-phenoxyacetamido)-penam-3-carboxylate is dissolved in 13 ml of methylene chloride containing methanol. 0.45 g of silver fluoroborate is added to this solution, and the mixture is stirred for 2 hours. After the reaction, the reaction mixture is filtered, and the filtrate is washed with dilute aqueous sodium hydrogen carbonate solution and then with water. The solution is dried over magnesium sulfate and evaporated. The residue is subjected to column chromatography on 25 g of silica gel and eluted with chloroform. The eluate is divided into fractions of approx. 20 ml and fractions 7-10 are combined. The solvent is distilled off, and 0.60 g of methyl-3-methoxy-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate is obtained.

1688 cm"<1>.IR<->absorption spectrum (CHClj): 3400, 1772, 1739 and

The following compounds are obtained by proceeding as in examples LI - 5. 1) Methyl 3-anilino-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate, m.p. 129 - 130°C, 2) 1-tyclopropylethyl-3-anilino-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate (colorless oil), 3) 2,2,2-trichloroethyl-3-anilino -3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate (oil), 4) 3-anilino-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylic acid.

Reaction M.

Example Ml.

0.28 g of aniline is added to a solution of 1.10 g of 2,2,2-trichloroethyl-3-bromo-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate in 15 ml of methylene chloride. 0.45 g of silver fluoroborate is added to the solution under ice-cooling and stirring, and the mixture is stirred at this temperature for 4 hours. After the reaction, the mixture is filtered, and the filtrate is washed with dilute aqueous phosphoric acid and then with water. The solution is dried over magnesium sulfate and evaporated. The residue is subjected to column chromatography on 25 g of silica gel using chloroform. Fractions 12 - 13 of fractions, each of which is divided into 20 ml, are evaporated, and oily 2,2,2-trichloroethyl-3-anilino-•3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate is obtained . IR absorption spectrum (CHClj): 3420, 1772, 1750 and

1680 cm"1.

The following compounds are prepared by proceeding as described in example Ml.

Reaction N.

Example NINE.

0.4 g of 1-cyclopropylethyl-2-oxo-3-(2-phenoxyacetamido)-4-anilinothio-α-isopropenyl-1-azetidine acetate is dissolved in 10 ml of dried methylene chloride. A solution of 50 mg of boron trifluoride etherate in 3 ml of dried methylene chloride at 0°C is added dropwise to this solution,

and the mixture is stirred for 5 hours at this temperature. After the reaction, the reaction mixture is washed with 5% aqueous sodium hydrogen carbonate solution and several times with water and then dried. After removal of the solvent by distillation, the oil obtained is purified by column chromatography on silica gel using

chloroform as developer, and 198 mg of 1-cyclopropylethyl-3-anilino-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate is obtained in the form of a colorless oil.

IR absorption spectrum (film): 3300, 1777, 1740 and 1690 cm"<1>.

Example N2.

170 mg of methyl-2-oxo-3-(2-phenoxyacetamido)-4-anilinothio-α-isopropenyl-1-azetidine acetate are dissolved in 4 ml of dried methylene chloride. This solution is added dropwise to a solution of 25 mg of boron trifluoride etherate in 2 ml of dried methylene chloride under ice cooling, and the mixture is stirred for 1 hour at this temperature. After reaction, the reaction mixture is washed with 5% aqueous sodium bicarbonate solution and water and dried. After removal of the solvent by distillation, the oil is subjected to column chromatography on silica gel. using chloroform as a creamer, and 80 mg of methyl-3-anilino-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate is obtained with. melting point 129 - 130°C from fractions 5 - 8 of fractions of 50 ml each.

IR absorption spectrum (CHClj): 3420, 1775, 1736 and 1691 cm"<1.> In a similar manner, 3-anilino-3-methyl-7-(2-phenoxyacetamido)cef am-4-carboxylic acid is produced; melting point 119 - 123°C (decomposition).

Reaction 0.

Reaction 01.

142 mg of 1-cyclopropylethyl-3-anilino-3-methyl-7-(2-phenoxyacetamido)cef am-4-carboxylate are dissolved in 1.5 ml of ice-cooled trifluoroacetic acid, and the mixture is stirred for 1 hour under ice-cooling. After the reaction, the reaction mixture is evaporated under reduced pressure. The residue is dissolved by adding ethyl acetate and extracted with a 5% aqueous sodium bicarbonate solution. The extract is adjusted to a pH value of 2 by adding 51 µg hydrochloric acid and extracted again with ethyl acetate. The extract is washed with water and dried and the solvent is distilled off. The amorphous residue is dissolved in methanol, and water is added little by little to this solution. The precipitate is isolated

by filtration and dried, and 62 mg of 3-anilino-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylic acid is obtained in the form of a powder with a melting point of 119 - 123°C (decomposition).

Analysis:

Calculated for C22H23<0>5<N>3S. 3/2 H 2 O: C 56.40 H 4.95 N 8.97 Found : C 56.57 H 5.05 N 8.97.

IR spectrum (Nujol): 3300, 1770, 1735 and 1665 cm"<1>.

In a similar way, 3-bromo-3-methyl-7-(2-phenoxyacetamido) cepham-4-carboxylic acid (amorphous) is prepared.

Reaction P.

Example Pl.

0.16 g of 5-methyl-1,3,4-thiadiazole-2-thiol is dissolved in a mixture of 5 ml of phosphate buffer with a pH value of 6.5 and 10 ml of acetone. 0.54 g of 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate is added to this solution, and the mixture is stirred for 3 hours at room temperature. The reaction mixture is extracted with ethyl acetate, and the ethyl acetate phase is washed with aqueous sodium bicarbonate solution and water, and then dried over magnesium sulfate. The solvent is distilled from the extract, and the residue is purified by column chromatography on silica gel using chloroform as developing agent and from fractions 5 - 9 of fractions of 30 ml each, 0.24 g of 2,2,2-trichloroethyl-2-oxo-3- (2-phenylacetamido)-4-(5-methyl-1,3,4-thiadiazol-2-yl)dithiophene-α-propenyl-1-azetidine acetate with m.p. 108 - 109°C.

IR absorption spectrum (Nujol): 3280, 1788, 1760 and 1654 cm"<1.>

Example P2.

0.20 g of 2-mercaptobenzothiazole is dissolved in a mixture of 15 ml of phosphate buffer with a pH value of 6.7 and 15 ml of dioxane. 0.54 g of 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate is added to the solution, and the mixture is stirred for 7 hours at room temperature. Dioxane is distilled off from the mixture and the residue is extracted with ethyl acetate. The ethyl acetate phase is washed with 2% aqueous potassium carbonate solution

and water and then dried over magnesium sulfate. After removal of the solvent by distillation, the residue is purified by column chromatography on silica gel using chloroform as developing agent, and from fractions 4 - 6 of fractions of 30 ml each, 0.10 g of 2,2,2-trichloroethyl-2-oxo- 3-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-a-propenyl-1-azetidine acetate with melting point 140 - 141°C.

Example P3..

0.4 g of 5-methyl-1,3,4-thiadiazole-2-thiol is dissolved in a mixture of 20 ml of phosphate buffer with a pH value of 7.3 and 20 ml of acetone. A solution of 0.80 g of methyl-2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate in 10 ml of acetone is added to the solution, and the mixture is stirred for 4 hours at room temperature. After completion of the reaction, acetone is distilled from the reaction mixture and the residue is extracted with ethyl acetate. The extract is washed with aqueous sodium bicarbonate solution and water and dried over magnesium sulfate and the solvent is distilled off. The residue is subjected to column chromatography on 60 g silica gel and eluted with chloroform. The eluate is divided into fractions of approx. 30 ml and from fractions 11-13 0.22 g of oily methyl-2-oxo-3-(2-phenoxyacetamido)-4-(5-methyl-1,3,4-thiadiazol-2-yl)-dithio is obtained -α-propenyl-1-azetidine acetate.

IR absorption spectrum (chloroform): 3430, 1779, 1742 and

1692 cm"<1>.

From fractions 8 - 10 of the above fractions, 0.30 g of oily 4,4-dithio-bis-[methyl-2-oxo-3-(2-phenoxyacetamido)-α-propenyl-1-azetidine acetate] is obtained.

IR absorption spectrum (film): 3280, 1770, 1740 and 1680 cm"<1>.

The following compounds are prepared by proceeding in the same way as in examples P1 - 3:

Claims (35)

In the following, different methods and products are reproduced which are written as claims 1-35. However, these should not represent requirements, but form part of the description. 1.. Method of making connection with it general formula where R 1 denotes optionally substituted amino, R 2 denotes optionally protected carboxy, and A denotes a group with the general formula where R 3 denotes lower alkyl, and Y denotes the remainder of a nucleo- file, characterized by that connection with the general formula where R 1, R 2 and R 3 have the above meaning, and R 4 denotes the remainder of a thiol compound HR 4, or compounds ".with - the general formula where R 1, R 2 and R 3 have the above meaning, and R 5 denotes amino or the residue of an amine, or compounds with the general formula where R 1, R 2 and R 3 have the above meaning, and Z denotes a group that can be converted into the residue of a nucleophile, or compounds with the general formula where R 1, R 2 and R 3 have the above meaning, and Z denotes a group, which can be converted into the residue of a nucleophile, is reacted with a nucleophile. 2. Method of making connection with it general formula where R 1 denotes optionally substituted amino, R 2 denotes optionally protected carboxy,, R denotes lower alkyl, and Y denotes the remainder of a nucleophile, characterized by the fact that connections with the general formula where R , R and R have the meaning given above, and R denotes the residue of a thiol compound HR 4, or compounds with the general formula r r 1 2 3 5 where R , R and R have the meaning stated above, and R denotes amino or the residue of an amine, or compounds with the general formula where R 1, R 2 and R 3 have the above meaning, and Z denotes a group that can be converted into the residue of a nucleophile, or compounds with the general formula where R 1, R 2 and R 3 have the above meaning, and Z denotes a group which can be converted into the residue of a nucleophile, is reacted with a nucleophile. 3. Process for the preparation of a compound of the general formula where R 1 denotes optionally substituted amino, R 2 denotes optionally protected carboxy, R 7 denotes lower alkyl, and Y denotes the residue of a nucleophile, characterized in that compounds with the general formula where R 1, R 2 and R 3 have the above meaning, and R 4 denotes the remainder of a thiol compound HR 4 is reacted with a nucleophile. 4. Method for making connection with it general formula where R 1 denotes optionally substituted amino, R 2 denotes optionally protected carboxy, R 3 denotes lower alkyl, and Y denotes the residue of a nucleophile, characterized by that connection with the general formula where R 1 , R 2 and R 3 have the above meaning, and R 5 denotes amino or the residue of an amine, is reacted with a nucleophile. 5. Process for the preparation of a compound of the general formula where R 1 denotes optionally substituted amino', R 2 denotes optionally protected carboxy, R <3> denotes lower alkyl, and Y denotes the residue of a nucleophile, characterized by the connection with the general formula: where R 1 , R 2 and R 3 have the meaning given above, and Z denotes a group which can be converted into the residue of a nucleophile, reacted with a nucleophile. 6. Method for the preparation of a compound of the general formula where R 1 denotes optionally substituted amino, R 2 denotes optionally protected carboxy, R 3 denotes lower alkyl, and Y denotes the remainder of a nucleophile, characterized in that connection with the general formula where R 1 , R 2 and R 3 have the meaning given above, and Z denotes a group which can be converted into the residue of a nucleophile, reacted with a nucleophile. 7. Process for the preparation of a compound of the general formula where R 1 denotes optionally substituted amino, R 2 denotes optionally protected carboxy, R 3 denotes lower alkyl, and Y denotes the residue of a nucleophile, characterized in that connection with the general formula where R , R and R have the above meaning, and R denotes the residue of a thiol compound HR 4, or compounds with the general formula where R 1 , R 2 and R 3 have the above meaning and R 5 denotes amino or the residue of an amine, or connection with the general formula where R , R and R have the meaning given above, and Z denotes a group which can be converted into the residue of a nucleophile, or compounds of the general formula where R 1, R 2 and R 3 have the above meaning, and Z denotes a group which can be converted into the residue of a nucleophile, is reacted with a nucleophile. 8. Process for the preparation of a compound of the general formula where R 1 denotes optionally substituted amino, R 2 denotes optionally protected carboxy, R denotes lower alkyl, and Y denotes the remainder of a nucleophile, characterized in that connection with the general formula where R <1> , R <2> and R^ have the above meaning, and R^ denotes the residue of a thiol compound HR^, is reacted with a nucleophile. 9. Method for making connection with it general formula where R 1 denotes optionally substituted amino, R 2 denotes optionally protected carboxy, R denotes lower alkyl, and Y denotes the residue of a nucleophile, characterized in that connection with the general formula where R 1, R 2 and R. <3> have the above meaning, and R <5> denotes amino or the residue of an amine, is reacted with a nucleophile. 10. Process for the preparation of a compound of the general formula where R 1 denotes optionally substituted amino.,. R 2 denotes optionally protected carboxy, R 3 denotes lower alkyl, and Y denotes the residue of a nucleophile, characterized by that connection with the general formula where R 1 , R 2 and R 3 have the meaning given above, and Z denotes a group which can be converted into the residue of a nucleophile, reacted with a nucleophile. 11. Process for the preparation of a compound of the general formula where R 1 denotes optionally substituted amino, R 2 denotes optionally protected carboxy, R^ denotes lower alkyl, and Y denotes the remainder of a nucleophile, characterized by that connection with the general formula where R 1 , R 2 and R 3 have the meaning given above, and Z denotes a group which can be converted into the residue of a nucleophile, reacted with a nucleophile. 12. Process for the preparation of a compound of the general formula where R 1 denotes optionally substituted amino, R 2 denotes optionally protected carboxy, R 3 denotes lower alkyl, and R 5 denotes amino or the remainder of an amine, characterized in that connection with the general formula where R 1 , R 2 , R 3 and R 5 have the above meaning, is reacted with a Lewis acid. 13. Process for the preparation of a compound of the general formula where R 1 denotes optionally substituted amino, R 2 denotes optionally protected carboxy, and A denotes a group with the general formula where R 3 denotes lower alkyl, and Y denotes the remainder of a nucleophile, characterized in that compounds with the general formula where R 1 , R 2 and A have the meaning indicated above, are oxidized. 14. Process for the preparation of a compound of the general formula where R 1 denotes optionally substituted amino, R 2 denotes optionally protected carboxy, R^ denotes lower alkyl, and Y denotes the residue of a nucleophile, characterized in that connection with the general formula where R 1 , R 2 , R 3 and Y have the meaning indicated above, are oxidized. 15. Procedure for the preparation of/for compound with the general formula where R 1 denotes optionally substituted, amino, R 2 denotes optionally protected carboxy, R <3> denotes lower alkyl, and V denotes halogen, characterized in that compound meo/the general formula where R 1 , R 2 , R 3 and Z' have the meaning stated above, are oxidized. 16. Process for the preparation of a compound of the general formula where R 2 denotes optionally protected carboxy, R 3 denotes lower alkyl, X denotes -S- or t, and Y' denotes halogen or -S-residue of a nucleophile, or salts thereof, characterized in that connection with the general formula where R 2 , R 3 , X and Y' have the above meaning, and R' 1 denotes protected amino, the amino protecting group is subjected to an elimination reaction. 17. Process for the preparation of a compound of the general formula where R" 1 denotes acylamino, R<2> denotes optionally protected carboxy, R 3 denotes lower alkyl, X denotes -S- or 0Jg_5 and Y' denotes halogen or the residue of a nucleophile, characterized in that a compound with the general formula where R 2 , R 3 , X and Y' have the meaning stated above or a salt thereof, is reacted with an acylating agent. 18. Process for the preparation of a compound of the general formula where R denotes optionally protected amino, R <3> denotes lower alkyl, X denotes -S- or _*„_ , and Y' denotes halogen or the residue of a nucleophile, or salts thereof, characterized by the fact that connections with the general formula where R 1, R 3 , X and Y' have the above meaning, and R? 2 denotes protected carboxy, is subjected to elimination reaction on the carboxy protecting group. 19. Process for the preparation of compounds of the general formula where R 1 denotes optionally protected amino, R 3 denotes lower alkyl, X denotes -S- or_^_, and Y' denotes halogen or the residue of a nucleophile, or salts thereof, characterized in that compounds with the general formula where R 1, R 3 , X and Y <*> have the above meaning, and R' 2 denotes protected carboxy, is subjected to an elimination reaction on car- the boxy protection group. 20. Process for the preparation of a compound of the general formula where R 1 denotes optionally protected amino, R 2 denotes optionally protected carboxy, R 3 denotes lower alkyl, and Z' denotes halogen, characterized in that a compound with the general formula where R , R and R have the meaning given above, and R denotes the residue of a thiol compound HR 4, or compound with the general formula where R 1 , R 2 and R 3 have the meaning given above, and R 5 denotes amino or the residue of one. amine, is reacted with a hydrogen halide or a metal halide. 21. Process for the preparation of a compound of the general formula where R denotes optionally protected amino, R denotes optionally protected carboxy, R<3> denotes lower alkyl, and Z' denotes halogen, characterized in that a compound of the general formula;. where R, R and R^ have the above meaning, and R^ denotes the residue of a thiol compound HR^, or compound with the general formula where R 1, R 2 and R 3 have the above meaning, and R 5 denotes amino or the residue of an amine, is reacted with a hydrogen halide or a metal halide to form compounds with the general formula where R 1, R 2 , R 3 and Z' have the above meaning, after which the obtained compounds are subjected to conversion reaction. 22.Procedure for the preparation of a compound with the general formula where R 1 denotes optionally protected amino, R 2 denotes optionally protected carboxy, R <3> denotes lower alkyl, and R 4 denotes the residue of a thiol compound HR^, characterized in that connection with the general formula where R 1 , R 2 and R 3 have the meaning given above, and Z" denotes the residue of an acid, is reacted with a thiol compound or a salt thereof. 23. Connections, characterized in that they have the general formula where R denotes optionally protected amino, R denotes optionally protected carboxy, X denotes -S- or 7?, and A' denotes a group -S- with the general formula where R 3 denotes lower alkyl, and Y" denotes the residue of a strong nucleophile. 24. Compound as stated in claim 23, characterized in that they have the general formula where R 1 , R 2 , R 3 , X and Y" have the meaning stated above. 25. Compound as stated in claim 24, characterized in that R 1 denotes amino or acylamino. R 2 denotes carboxy or a protected carboxy group, for example an ester, an acid amide, an acid anhydride or a carboxy salt, R 3 denotes lower alkyl, X denotes -S- or / j\ , and Y" denotes the residue of a strong nucleophile, -S- for example azido, thiocyanato, arylamino, acylthio, heterocyclic thio and heterocyclic thiocarbonylthio. 26. Compounds as stated in claim 24, characterized in that R <1> denotes amino, phenyl(lower)alkanoylamino, phenoxy(lower)alkanoylamino, N-lower alkoxycarbonylphenylglycylamino, 3-halophenyl-5-(lower)alkylisoxazol-4-ylcarboxamido or tetra-2 zoyl(lower)alkanoylamino, R denotes carboxy, lower alkoxycarbonyl, trihalo(lower) alkoxycarbonyl or a carboxy salt with metal or an N,N'-phenyl(lower)alkyl(lower)alkylenediamine, R^ denotes lower alkyl, X denotes - S- or , and Y" denotes azido, thiocyanato, arylamino, lower alkanoylthio, pyridylthio, lower alkyl-substituted thiadiazolylthio, lower alkyl-substituted imidazolylthio, lower alkyl-substituted tetrazolylthio, benzothiazolylthio or piperidinothiocarbonylthio. 27. Compounds as stated in claim 24, characterized in that R<1> denotes amino, phenylacetamido, phenoxyacetamido, N-(1-cyclopropylethoxy)carbonylphenylglycylamino, 3-(2-chlorophenyl)-5-methylisoxazol-4-ylcarboxamido or 1H- tetrazol-1-ylacetamido, R <2> denotes carboxy, methoxycarbonyl, 2,2,2-trichloroethoxycarbonyl or a carboxy salt with sodium or N,N'-dibenzylethylenediamine, R*^ denotes methyl, X denotes -S- or , and Y " denotes azido, thiocyanato, anilino, acetylthio, 4-pyridylthio, 5-methyl-1,3,4-thiadiazol-2-ylthio, 1-methylimidazol-2-ylthio, 1-methyl-1H-tetrazol-5- ylthio, benzo[iazol-2-ylthio or piperidinothiocarbonylthio. 28. Compounds as stated in claim 23, characterized in that they have the general/frormel where R 1, R 2 , R 3, X. and Y' have the same meanings as stated in claim 23, 29. Compounds as stated in claim 28, characterized in that R 1 denotes amino or acylamino, R 2 denotes carboxy or protected carboxy, for example ester, acid amide, acid anhydride or carboxylic salt, R 3 denotes lower alkyl, X denotes -S-, and Y" denotes azido or arylamino. 30. Compounds as set forth in claim 28, characterized in that R<1> denotes phenyl(lower)alkanoylamino or phenoxy(lower)alkanoylamino, R 2 denotes carboxy, lower alkoxycarbonyl or trihalo(lower)alkyloxycarbonyl, R^ denotes lower alkyl, and Y" denotes azido or arylamino. 31. Compounds as specified in claim 28, characterized 1 2 in that R denotes phenylacetamido or phenoxyacetamido, R denotes carboxy, mefoxycarbonyl or 2,2,2-trichloroethoxycarbonyl, R 3 denotes methyl, and Y" denotes azido or anilino. 32. Compounds with the general formula where R"' denotes amino, tetrazolyl(lower)alkanoylamino or 3-halophenyl-5-(lower)alkylisoxazol-4-ylcarboxamido, R 2 denotes optionally protected carboxy, R 3 denotes lower alkyl, X denotes -S- or_^ _, and Z' denotes halogen. 33. Connections as stated in claim 32, characterized by e d . that R'" <1> denotes amino, tetrazolyl(lower)-alkanoylamino or 3-halogen-5-(lower)alkylisoxazol-4-ylcarboxamido, R denotes lower alkyl, X denotes -S- or _°t-_, and Z' denotes halogen. 34. Compounds as stated in claim 32, characterized in that R'"1 denotes amino, 1H-tetrazol-1-yl-acetamido or 3-(2-chlorophenyl)-5-methylisoxazol-4-ylcarboxamido, R 2 denotes 3 2, 2, 2^-trichloroethoxycarbonyl, R denotes methyl, X denotes -S- or° S 2' denotes bromine. 35. Compounds with the general formula where R denotes optionally substituted amino, R denotes optionally protected carboxy, R denotes lower alkyl, and Z' denotes halogen.