CH615186A5 - Process for the preparation of cephem compounds - Google Patents

Description

The invention relates to a process for the preparation of cephem compounds of the formula I.

1

R

CH

COOH

wherein

R1 is a free or protected amino group; and Y is the residue of a thiourea bonded via sulfur, which may be substituted, means thioamides, thiols or thiophenols, it also being possible for the compounds to carry substituents in the 2- or 7-position.

Cephalosporin compounds which carry a methyl group substituted by the rest of a nucleophile in the 3-position are generally known and in many cases show valuable antibiotic properties. Particularly valuable properties are those compounds which have the formula A

, a

R

COOH

wherein

Ra is an acylamido group derived from a carboxylic acid; and X is the residue of a nucleophile, e.g. B. a group in which the nucleophilic properties are concentrated on the carbon, nitrogen, oxygen or sulfur atom, correspond.

A disadvantage of the compounds of the formula A is that the nucleophilic radical X and the ring atoms in the 3-, 4-, 5- and 8-position tend to activate the compounds with a view to degrading fragmentation reactions. Here, for example, a nucleophilic attack on the carbonyl group in the 8-position, e.g. B. by amino groups which are present in side chains of the group arranged in the 7-position, as is the case for example with 2-amino-2-phenylacetamido and 5-amino-5-carboxypentamido groups, the elimination of group X and consequently a loss accelerate the antibiotic effectiveness.

Certain compounds of formula A also show the tendency to effect cyclization by reaction between the carboxy group in the 4-position and the nucleophilic center in group X, for example with the formation of a 5-membered y-lactone ring, or the tendency to spiro-cyclic To form compounds containing 5-membered rings. Such reactions in turn lead to an inhibition of the antibiotic effect.

The disadvantages mentioned can therefore distract from the value of the cephalosporin antibiotics which are of interest in other respects, so that, in order to avoid these disadvantages, an interest in the use of higher homologs of these compounds has developed. It has been shown, for example, that in compounds in which the nucleophilic radical is a β-substituent of an alkyl group with at least 2 carbon atoms in the 3-position, e.g. B. Compounds which have a substituted ethyl group in the 3-position show a much lower tendency to undergo a fragmentation reaction. The additional methylene group present between the nucleophilic radical X and the cephem ring system prevents the interaction between the nucleophilic radical X and the ring atoms in the 3-, 4-, 5- and 8-position. The higher homologues mentioned also reduce the tendency to deactivate spirocyclization or lactone formation reactions, since the formation of such rings with at least 6 ring members is less favored than the formation of the corresponding 5-membered rings, as is the case with compounds with a substituted methyl group in 3- Position is the case. For the reasons set out above, there is a need to provide a process which allows the production of cephalosporin compounds with a β-substituted ethyl group in the 3-position. It has now been found that such compounds can be prepared if cephalosporin compounds which have a vinyl group in the 3-position are reacted with a compound which introduces the residue of a thiourea, a substituted thiourea, a thioamide, thiols or thiophenol. The nucleophilic residue bonded via sulfur is added to the β-carbon atom of the vinyl group and an addition of a hydrogen atom to the a-carbon atom of this group.

The process according to the invention for the preparation of compounds of the formula I takes advantage of this knowledge and is characterized in that a compound of the formula II

COOH (II),

optionally with intermediate protection of the 4-carboxyl group, with a thiourea, substituted thiourea, thioamide, thiol or thiophenol.

The compounds of the formula I obtainable according to the invention also include those which still carry substituents in the 2- or 7-position, which include, for example, 2-methyl, 2-methylene, 2,2-dimethyl and 7-methoxy compounds.

In addition to the ceph-3-em compounds of the formula I, the reaction product often contains a proportion of the corresponding ceph-2-em compound. In some cases, the resulting ceph-2-em compound can be converted to the ceph-3-em compound, for example by treatment with a base, which is particularly possible when the equilibrium between the À2 and A3 isomers is such A3 isomer favored.

It has been found that the formation of the cephem compounds bearing a β-substituted ethyl group in the 3-position is supported in many cases by adding a base to the reaction mixture. Although it is not intended to be based on theoretical considerations, it appears that an existing base does not perform the desired reaction sequence, for example by withdrawing a proton.

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supports, at the same time an isomerization of intermediates, such as compounds of formula IV

1

R

ooor to the desired A3 cephem compound of formula I. In some cases, the cepham products of the formula IV can be sufficiently stable for isolation; they can then be separated off from the reaction mixture and then converted into the corresponding A3 cephem compound using a base. The base can also serve in certain cases to activate the sulfur nucleophile, for example by converting thiols into their more nucleophilic conjugated bases.

As bases, which can be used in carrying out the method according to the invention, both organic and inorganic bases are suitable, examples of organic bases being tertiary nitrogen bases, for. B. tri-lower alkylamines, such as trimethylamine or triethylamine, and aromatic heterocyclic nitrogen bases, such as pyridine, and as inorganic bases alkali metal carbonates, hydrogen carbonates and phosphates, e.g. B. with a buffering to pH 8, are to be mentioned. The amount of base added is generally 0.1 to 3, preferably 0.1 to 1 equivalent, based on the compound of the formula II. To promote the reaction, it is also possible to use anionic exchangers, including anionic resins.

The following compounds are suitable, for example, for the reaction with the 3-vinyl-cephem compound of the formula II:

a) Compounds of formula V

Rx ^

> rN \ (v)

R4 S R6

wherein R3, R4, R5 and R6, which are identical or different, each represent hydrogen or an aliphatic, alicyclic, aromatic, araliphatic or heterocyclic group or at least two of the radicals R3, R4, R5 and R6 form one or more polyvalent groups and / or at least one of the radicals R4 and R6 is a group v

corresponds and the remaining groups have the meanings given;

b) compounds of the formula VI

wherein R7 and Rs, which are the same or different, each represent an aliphatic, alicyclic, aromatic, araliphatic or heterocyclic group and R7 also represents a hydroxyl or esterified hydroxyl group and R9 represents an aliphatic or araliphatic group or together with R7 and / or R8 forms a bivalent group; or c) compounds of the formula VII

R3'-SH (vil)

wherein R3 'represents an aliphatic, alicyclic, aromatic, araliphatic or heterocyclic group.

Examples of the substituents R3, R4, Rs and R6 in the compounds of the formula V are as follows: Preferred aliphatic groups, not lower alkyl groups, such as methyl, ethyl, n-propyl, isopropyl or hexyl; preferred alicyclic groups are Cs-C7-cyclo-alkyl groups, such as cyclopentyl or cyclohexyl, Cs-C7-cyclo-alkenyl or cycloalkadienyl groups, such as cyclohexenyl or cyclopentadienyl; preferred aromatic groups are mono- or bicyclic aryl groups, such as phenyl or naphthyl; preferred araliphatic groups are aryl-lower alkyl groups, where the aryl group is for example phenyl or naphthyl and the alkyl part contains 1 to 4 carbon atoms, e.g. B. benzyl or phenethyl; preferred heterocyclic groups are, for example, groups with a 5- or o-membered ring which contains at least one heteroatom, such as oxygen, nitrogen or sulfur. Furthermore, 2 or more of the radicals R3, R4, R5 and R6 can form a polyvalent group or groups, the remaining groups having the meanings given above. For example, R3 and R4 or R3 and R5 together can form a lower alkylene group, such as ethylene, propylene, butylene or pentamethylene or a similar group, which is interrupted by a double bond or a heteroatom, such as oxygen, nitrogen or sulfur. Similarly, R3, R4 and R5 together can form a trivalent group. In addition, R4 and / or R6 can represent a group —NR3RS, where R3 and R5 have one of the meanings mentioned above. Accordingly, thiosemicarbazide derivatives, such as thione and thiol compounds, e.g. B. 2-mercaptopyrimidine and 2-mercapto-4-methylpyrimidine, which are in tautomeric forms, are included.

If compounds of the formula VI are used, the groups R7 and R8 can have the following meanings:

Preferred aliphatic groups are, for example, lower alkyl groups, such as methyl, ethyl, n-propyl, isopropyl or hexyl; preferred alicyclic groups are, for example, C3-C7-cycloalkyl groups, such as cyclopentyl or cyclohexyl, C5-C7-cycloalkenyl groups and cycloalkadienyl groups, such as cyclohexenyl and cyclopentadienyl; preferred aromatic groups are, for example, mono- and bicyclic aryl groups, such as phenyl and naphthyl; preferred araliphatic groups are, for example, aryl-lower alkyl groups in which the aryl group is, for example, a phenyl or naphthyl group and the alkyl part has 1 to 4 carbon atoms, e.g. B. benzyl or phenethyl; preferred heterocyclic groups are, for example, groups with a 5- or 6-membered ring which contains at least one heteroatom, such as oxygen, nitrogen or sulfur. These groups include thienyl, furyl, pyridyl, piperidinyl, including piperidino, and piperazinyl and 4-methylpiperazinyl, including piperazin-l-yl and 4-methylpiperazin-l-yl. R7 represents a hydroxy group or an etherified hydroxy group, e.g. B. a lower alkoxy group, R8 can also be hydrogen. For R9, straight-chain or branched-chain lower alkyl or aryl-lower alkyl groups are preferred. There is also the possibility that R9 forms a bivalent group together with R7 and / or R8,

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e.g. B. a lower alkylene, alkenylene, alkadienylene, alkylidene or alkynylidene group or a corresponding group which is interrupted by a heteroatom, such as oxygen, nitrogen or sulfur. This group of compounds also includes cyclic thioamides, such as pyrid-2-thione, of which thiol tautomers are also present. The compound of the formula VIII can be mentioned as particularly useful compounds from the group of cyclic thioamides

(VIII),

I.

R10

wherein R10 represents a hydrogen atom or a hydroxyl, lower alkyl or lower alkoxy group.

If thiols or thiophenols of the formula VII are used for the reaction, the following meanings are particularly suitable for the group R3 ':

If R3 'is an aliphatic group, preference is given, for example, to lower alkyl groups such as methyl, ethyl or n-propyl, it being possible for these groups to be substituted one or more times by amino, hydroxyl, carboxy, esterified carboxy or aryloxy, for example groups such as hydro -xymethyl, 2-hydroxymethyl, acetoxymethyl, carboxymethyl, methoxycarbonylmethyl or diphenylmethoxycarbonylmethyl. If R3 'is an aromatic group, phenyl, naphthyl or one or more halogen, substituted alkyl, lower alkoxy, nitro, haloalkyl, cyano, carboxy, esterified carboxy, hydroxy, acyl, acyloxy, amido or substituted amido are substituted phenyl or phenyl Naphthyl, preferred; Examples of such groups are p-tolyl and p-nitrophenyl; R3 'represents an araliphatic group, aryl-lower alkyl groups such as benzyl or phenethyl or substituted phenyl-lower alkyl groups are particularly suitable for this purpose; if R3 'denotes an alicyclic group, C5-C7-cycloalkyl groups such as cyclopentyl or cyclohexyl are particularly preferred for this purpose; if R3 'denotes a heterocyclic group, groups with a 5- or 6-membered ring which has at least one heteroatom, such as oxygen, nitrogen or sulfur, are particularly suitable. In addition, the ring can optionally be part of a condensed ring system, examples being pyridyl, e.g. B. pyrid-2-yl, pyrimidyl, such as pyrimid-2-yl or 4-methylpyrimid-2-yl, thiadiazolyl, especially 5-methyl-l, 3,4-thiadiazol-2-yl, diazolyl, triazo-lyl, Tetrazolyl, for example l-methyl-tetrazol-5-yl, thiazo-lyl, oxazolyl, oxadiazolyl, benzimidazolyl, benzoxazolyl, triazolopyridyl and purinyl, may be mentioned. Some of these heterocyclic thiols can also be present in the form of their thione tautomers which fall within the range of the compounds of the formulas V and VI.

The reaction of the compounds of formula II with their reactants is generally carried out in an inert organic solvent, e.g. B. an ester such as ethyl acetate, a chlorinated hydrocarbon, e.g. B. methylene dichloride, chloroform or trichloroethane, or a cyclic ether such as tetrahydrofuran. Solvent mixtures, e.g. B. water and an organic solvent can also be used if the solubility conditions require, e.g. B. when an inorganic base is used. Such mixtures of solvents can be homogeneous or heterogeneous.

Reaction temperatures in the range from -100 to + 150 ° C. can be used, temperatures in the range from 0 to 100 ° C. being preferred and, in particular, room temperature being favorable. The course of the reaction can be monitored, for example by thin layer chromatography or UV spectroscopy. In connection with the latter, the disappearance of a signal at Amax 295 ± 5 nm, which is characteristic of 3-vinyl-cephalosporins, is a valuable indication of the progress of the addition to the vinyl group, except for an insignificant absorption in this region.

The nucleophilic addition to the vinyl group can be accelerated in certain cases by adding an electrophile as the activating agent. Suitable electrophiles include metals and metallic cations, e.g. B. Ag + or Hg ++, in the form of salts such as perchlorates, nitrates, trifluoroacetates and tetrafluoroborates, in which the anions have a low nucleophilic activity, but cause a suitable solubility in the reaction medium. Lewis acids, for example acetic acid, can also be used as electrophiles.

The 3-vinyl-cephalosporin starting materials used in the present process can be prepared by any suitable method, for example by reacting a cephalo-sporin compound which, as 3 substituents, has the group -CH = P (Ru) 3 (in which Rn is an organic one Group is) can be prepared with formaldehyde as described in British Patent 1,342,241.

If the 4-carboxyl group is present in the compounds of the formula II in protected form, esterifying groups in particular are suitable as protective groups. Suitable esterifying agents are, for example, aliphatic or araliphatic alcohols, phenol, silanol or stannanol. In addition, the 4-carboxyl function can be protected by anhydride formation, acids which form a group which can be easily split off in a later stage of the reaction preferably being used for the formation of anhydride. In general, it is particularly advantageous to remove the carboxyl protecting group during the last stage of the manufacturing process. If an alcohol, phenol, silanol or stannanol is used to form the protective group, these compounds preferably contain no more than 20 carbon atoms.

A number of suitable protecting groups which are derived from alcohols, phenols or silanols are described together with the process which is suitable for the intermediate protection of the 4-carboxyl group in British Pat. No. 1,342,241. Another group derived from an alcohol and suitable for protecting the 4-carboxyl group is the tetrahydrofur-2-yl group. Anhydride groups suitable for protecting the 4-carboxyl group and methods suitable for introducing and eliminating them are described in BE-PS 784 982.

If a 7β-acylamino compound is obtained when the process according to the invention is carried out, in which the acyl group is not the desired one for the end product, the 7β-acylamino compound obtained can be deacylated to the corresponding 7β-amino compound and the latter can be acylated again with a suitable acylating agent.

Suitable processes for the deacylation of 7β-acylamino compounds are described in GB-PS 1 041 985.1 119 806, 1 227 014, 1 239 814, 1 244 191 and 1 241 655. The N-deacylation can also be effected by acid catalysis. For example, a 7β-formamido compound can be deformylated with the aid of a mineral acid, as described, for example, in British Pat. No. 1,290,397. In addition, the deacylation can be effected with the aid of a Lewis acid, as described, for example, in British Pat. No. 1,321,265.

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The 7β-amino compound obtained by deacylation can be separated off in the form of an insoluble salt, for example the hydrochloride or the hydrogen p-tohiol sulfonate, or by adjusting the pH, for. B. to the isoelectric point, after which the precipitate, if necessary, can be extracted with a suitable solvent. The 7β-amino compound thus obtained can then be acylated again. This renewed acylation can be carried out using an appropriately selected acylating agent. A large number of such acylating agents are described in the relevant literature.

If the 7ß-acylamido group also contains a free amino group, this must be protected during the various reaction stages. Protective groups are suitably carried out for this purpose, which can be removed by hydrolysis without impairing the remaining molecule, in particular the lactam and the 7β-amido bond. Suitable amino protecting groups are described, for example, together with methods for their introduction and subsequent elimination in GB-PS 1 342 241. It is particularly advantageous to eliminate the amino protecting group and the 4-carboxyl protecting group using the same reagent or the same reagents. It is particularly advantageous to remove both protective groups in the last stage of the manufacturing process.

As indicated above, the protected amino group R1 in formulas I and II is preferably an acylamido group, suitably such a group containing 1 to 20 carbon atoms. In general, R1 can be selected from a wide range of acylamido groups and suitably be an acylamido group of a penicillin obtained by a fermentation process. e.g. B. Phenylacetamido or Phenoxyace-tamido, since compounds of formula II can be derived from such penicillins by ring enlargement techniques. The group R1 can also be the formamido group. This group is essentially stable under the reaction conditions and can then be easily cleaved off to allow the introduction of another acyl group.

The acylamido group need not be the group desired in the final product, but this can be remedied by subsequent conversions as described above. It is not necessary for an acylamido group R1 in a compound of the formula II to be completely inert to the reaction conditions, since it can be split off by such subsequent conversions.

Examples of specific acyl groups that may be present in the acylamido groups R1 in the starting materials and / or end products are described by the attached list, which is not exhaustive.

(i) RuCnH2nCO-, wherein Ru is aryl (carbocyclic or heterocyclic) cycloalkyl, substituted aryl, substituted cycloalkyl, cycloalkadienyl or a non-aromatic or mesoionic group and n represents an integer from 1 to 4. Examples of this group include phenylacetyl, substituted phenylacetyl, e.g. B. fluorophenylacetyl, nitrophe-nylacetyl, aminophenylacetyl, acetoxyphenylacetyl, methoxy-phenylacetyl, methylphenylacetyl or hydroxyphenylacetyl, N, N-bis (2-chloroethyl) aminophenyl-propionyl, thien-2- and -3-yoxacylyl, 4 substituted 4-isoxazolylacetyl, pyridylacetyl, tetrazolylacetyl, cyclohexadienyl or a sydnone acetyl group. The substituted 4-isoxazolyl group can be a 3-aryl-5-methyl-isoxazol-4-yl group, the aryl group being for example phenyl or halophenyl, e.g. B. chlorophenyl or bromophenyl. An acyl group of this type is 3-o-chlorophenyl-5-methyl-isoxazol-4-yl-acetyl.

(ii) CnHn + lCO-, where n represents an integer from 1-7. The alkyl group can be straight or branched chain and, if desired, can be interrupted by an oxygen or sulfur atom or can be substituted, for example, by a cyano group, carboxy group, an alkoxycarbonyl group, a hydroxy group or a carboxycarbonyl group (-CO.COOH). Examples of such groups include cyanoacetyl, hexanoyl, heptanoyl, octanoyl and butylthioacetyl.

(iii) CnH2n-1 CO—, where n is an integer from 2-7. The alkenyl group can be straight or branched chain and, if desired, can be interrupted by an oxygen or sulfur atom. An example of such a group is allylthioacetyl.

(iv) RuO (p-CO-,

Rv-

wherein Ru has the meaning given under (i) and may additionally mean benzyl and Rv and Rw, which may be the same or different, each represent hydrogen, phenyl, benzyl, phenethyl or lower alkyl. Examples of such groups include phenoxyacetyl, 2-phenoxy-2-phenylacetyl, phenoxypropionyl, 2-phenoxybutyryl, benzoyl-oxycarbonyl, 2-phenoxypropionyl, 2-phenoxybutyryl and methylthiophneoxyacetyl.

(v) RuS- <J: -CO-

RW

wherein Ru has the meaning given under (i) and can additionally mean benzyl and Rv and Rw have the meanings given under (iv). Examples of the groups given include S-phenylthioacetyl, S-chlorophenylthioacetyl, S-fluorophenylthioacetyl, pyridylthioacetyl and S-benzylthioacetyl.

(vi) R «Z (CH2) mCO-, in which Ru has the meaning given under (i) and can additionally mean benzyl, Z represents an oxygen or sulfur atom and m represents an integer from 2-5. An example of such a group is S-benzylthiopropionyl.

(vii) RuCO-, where Ru has the meaning given under (i). Examples of such groups include benzoyl, substituted benzoyl (e.g. aminobenzoyl), 4-isoxazolyl and substituted 4-isoxazolylcarbonyl, cyclopentane carbonyl, sydnoncarbonyl, naphthoyl and substituted naphthoyl

(e.g. 2-ethoxynaphthoyl), quinoxalinylcarbonyl and substituted quinoxaline carbonyl (e.g. 3-carboxy-2-quinoxalinecarbonyl). Other possible substituents for benzoyl include alkyl, alkoxy, phenyl, carboxy, alkylamido, cycloalkylamido, allylamido, phenyl- (lower) alkylamido, morpholino-carbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, tetrahyropyridino, furfurylamido or N-alkyl-N- anilino or derivatives thereof, and such substituents can be in the 2- or 2- and 6-position. Examples of such substituted benzoyl groups are 2,6-dimethoxybenzoyl, 2-methylamidobenzoyl and 2-carboxylbenzoyl. If the group Ru represents a substituted 4-isoxazolyl group, the substituents can have the meaning given under (i). Examples of such 4-isoxazolyl groups are 3-phenyl-5-methyl-isoxazol-4-yl-carbonyl, 3-o-chlorophenyl-5-methyl-isoxazol-4-yl-carbonyl and 3- (2,6-dichlorophenyl) - 5-methyl-isoxazol-4-yl-carbonyl.

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(viii)

Ru- (pH-CO-, X

where Ru has the meaning given under (i) and X is amino, substituted amino (e.g. acylamido or a group which is formed by reacting the a-aminoacylamido group of the 7-side chain with an aldehyde or ketone, e.g. acetone , Methyl ethyl ketone or ethyl acetoacetate is obtained), hydroxy, carboxy, esterified carboxy, triazolyl, tetrazolyl, cyano, halogen, acyloxy (e.g. formyloxy or lower alkanoyloxy) or etherified hydroxy. Examples of such acyl groups are 2-amino-2-phenylacetyl, 2-hydroxy-2-phenylacetyl and 2-carboxy-2-phenylacetyl and substituted derivatives thereof, such as 2-t-butoxycarbonylamino-2-phenyl-acetyl, 2- (2 , 2,2-trichloroethoxycarbonylamino) -2-phenylacetyl and 2-dichloroacetoxy-2-phenylacetyl.

(ix)

f

Ry-c-co-

Rz wherein Rx, Rv and R2, which may be the same or different, each represent lower alkyl, phenyl or substituted phenyl or Rx represents hydrogen. An example of such an acyl group is triphenylcarbonyl.

00

Ï

Ru — NH-C-

wherein Ru has the meaning given under (i) and can additionally denote hydrogen, lower alkyl or halogen-substituted lower alkyl and Y represents oxygen or sulfur. An example of such a group is Cl (CH2) 2NHCO.

(xi)

(CH2) n

"CH2

/ Ï "

-CHi X

CO-,

where X has the meaning given above under (viii) and n is an integer from 1 to 4. An example of such an acyl group is 1-aminocyclohexanecarbonyl.

(xii) aminoacyl, e.g. B. RWCH (NH2) • (CH2) nCO-, where n is an integer from 1 to 10, or NH2 • CnH2

R ^ -CHCONH

b nAr (CH2) mCO, wherein m represents 0 or an integer from 1-10 and n represents 0, 1 or 2, Rw represents a hydrogen atom or an alkyl, aralkyl or carboxy group or a group as defined above under Ru and Ar is an arylene group, e.g. B. p-phenylene or 1,4-naphthylene. Examples of such groups are described in British Patent 1,054,806. One group of this type is the p-aminophenylacetyl group. Other acyl groups of this type include those e.g. B.ö-aminoadipoyl, which are derived from naturally occurring amino acids and their derivatives, eg. B. N-Benzoyl-ö-aminoadipoyl.

(xiii) Substituted glyoxyl groups of the formula Ry • CO • CO-, wherein Ry is an aliphatic, araliphatic or aromatic group, e.g. B. is a thienyl group, a phenyl group or is a mono-, di- or tri-substituted phenyl group, the substituents being, for example, one or more halogen atoms (F, Cl, Br or J), methoxy groups, methyl groups or amino groups or a condensed benzene ring . This group also includes the a-carbonyl derivatives 20 of the above substituted glyoxyl groups, e.g. B. the a-hydroxy-imino, a-alkoxyimino, a-aryloxyimino and a-acyloxyimino derivatives, especially those which have a syn configuration, such as in the syn-2-hydroxyimino-2- (thien- 2-yl) -acetyl and 2-phenoxyimino-2-phenylacetyl-25 groups.

(viv) formyl.

(xv) hydrocarbyloxycarbonyl and substituted hydrocarbyloxy groups (in which the 7-amino group forms part of an urethane), in particular lower alkoxycarbonyl groups

30 (such as methoxycarbonyl, ethoxycarbonyl and most preferably t-butoxycarbonyl groups), halogen-lower alkoxy-carbonyl groups, e.g. B. 2,2,2-trichloroethoxycarbonyl, aralkoxycarbonyl groups such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl and 4-nitrobenzyl-35 oxycarbonyl groups. Cycloalkoxycarbonyl groups are also advantageous, especially the adamantyloxycarbonyl groups.

(xvi) haloformyl, e.g. B. chloroformyl.

The compounds of For-40 mei I obtainable according to the invention are new compounds. Of these compounds, those in which R1 is an acylamido group and their non-toxic derivatives are distinguished by an antibiotic action which makes the compounds usable in human and veterinary medicine. As already indicated in the preceding, the compounds of the formula I are relatively insensitive to deactivating fragmentation and cyclization reactions.

Of the compounds of formula I are those of formula XIII

c.h9ch2-s-

n

(xiii)

particularly effective. In this formula, R12 represents an aromatic group, e.g. B. phenyl, or by halogen, e.g. B.

Chlorine or bromine, hydroxy, lower alkyl, nitro, amino, lower alkanoyl, lower alkoxy or lower alkyl thio-substituted phenyl or a heterocyclic group, in particular a 5- or 6-membered heterocyclic group which has at least one heteroatom, such as oxygen, nitrogen or sulfur , e.g. B. Thien-2-yl, or Thien-3-yl. B means amino or substituted amino, e.g. B. acylamido, hydroxyl or substituted hydroxyl, e.g. B. Acyloxy. Furthermore, the non-toxic derivatives of this compound are preferred; These include, for example, basic salts, if these are suitable, acid addition salts, if these are suitable, and compounds which are obtained by reacting a compound of the formula XIII, in which B is an amino group, with an aldehyde or ketone, e.g. As acetone or methyl ketone can be obtained. Such compounds have significant activity against a variety of gram-positive and gram-negative organisms and have good oral absorption properties.

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Examples of new compounds which can be prepared according to the invention are given below.

(6R, 7R) -3- [2- (pyrid-2-ylthio) ethyl] -7- (thien-2-yI-

acetamido) -ceph-3-em-4-carboxylic acid;

(6R, 7R) -3- (2-methoxycarbonylmethylthioethyl) -7-

(thien-2-yl-acetamido) -ceph-3-em-4-carboxylic acid;

(6R, 7R) -7- (Thien-2-ylacetamido) -3- (2-p-tolylthioethyl) -

ceph-3-em-4-carboxylic acid;

(6R, 7R) -3- [2- (4-methylpyrimidin-2-ylthio) ethyl] -7- (thien-2-ylacetamido) ceph-3-em-4-carboxylic acid; (6R, 7R) -3- (2-methylthioethyl) -7- (thien-2-ylacetamido) ceph-3-em-4-carboxylic acid;

(6R, 7R) -3- (2-n-propylthioethyl) -7- (thien-2-ylacetamido) -ceph-3-em-4-carboxylic acid; (6R, 7R, 2'R) -7- (2'-t-butoxycarbonylamino-2'-phenylacetamido) -3- [2- (pyrid-2-ylthio) ethyl] -ceph-3-em-4- carboxylic acid;

(6R, 7R, 2'R) -7- (2'-amino-2'-phenylacetamido) -3- [2- (pyrid-2-ylthio) ethyl] -ceph-3-em-4-carboxylic acid and their di-trifluoroacetic acid salt; (6R, 7R, 2'R) -7- (2'-t-butoxycarbonylamino-2'-phenyl-acetamido) -3- (2-methoxycarbonylmethylthioethyl) -ceph-3-em-4-carboxylic acid;

(6R, 7R, 2R) -7-2'-amino- (2'-phenylacetamido) -3-

(2-methoxycarbonylmethylthioethyl) -ceph-3-em-4-carbon-

acid and its trifluoroacetic acid salt; (6R, 7R, 2'R) -7- (2'-t-butoxycarbonylamino-2'-phenyl-acetamido) -3- [2- (pyrimid-2-ylthio) ethyl] -ceph-3 -em- 4-carboxylic acid;

(6R, 7R, 2'R) -7- (2'-t-Butoxycarbonylamino-2'-phenyl-acetamido) -3- (2-nitrophenylthioethyl) -ceph-3-em-4-carboxylic acid;

(6R, 7R, 2'R) -7- (2 / -amino-2 / -phenylacetamido) -3- (2-p-nitrophenylthioethyl) -ceph-3-em-4-carboxylic acid and its trifluoroacetic acid salt;

(6R, 7R, 2'R) -7- (2'-t-butoxycarbonylamino-2 / -phenyl-

acetamido) -3- (2-diphenylmethoxycarbonylmethyl-

thioethyl) ceph-3-em-4-carboxylic acid;

Trifluoroacetic acid salt of (6R, 7R, 2 / R) -7- (2 / -amino-

2'-phenylacetamido) -3- (2-carboxymethylthioethyl) -3-ceph-3-

em-4-carboxylic acid;

(6R, 7R, 2'R) -7- (2'-t-butoxycarbonylamino-2'-phenyl-acetamido) -3- [2- (4-methylpyrimidin-2-ylthio) ethyl] -ceph-3 - em-4-carboxylic acid;

(6R, 7R, 2'R) -7- (2'-amino-2'-phenylacetamido) -3- [2- (4-methylpyrimidin-2-ylthio) ethyl] -ceph-3 -em-4- carboxylic acid and its ditrifluoroacetic acid salt; (6R, 7R, 2'R) -7- (2 / -t-butoxycarbonylamino-2'-phenyl-acetamido) -3- (2-methylthioethyl) -ceph-3-em-4-carboxylic acid; (6R, 7R, 2'R) -7- (2 / -amino-2'-phenylacetamido) -3- (2-methylthioethyl) -ceph-3-em-4-carboxylic acid and its trifluoroacetic acid salt;

(6R, 7R) -7-formamido-3- [2- (pyrid-2-ylthio) ethyl] ceph-3-em-4-carboxylic acid;

(6R, 7R) -7-formamido-3- (2-methoxycarbonylmethylthioethyl) -ceph-3-em-4-carboxylic acid; (6R, 7R) -7-phenoxyacetamido-3- [2- (pyrid-2-ylthio) ethyl] ceph-3-em-4-carboxylic acid;

(6R, 7R, 2'R) -7- [2- (2,2,2-trichloroethoxycarbonylamino) -

2-phenylacetamido] -3- [2- (pyrid-2-ylthio) ethyl] ceph-

3-em-4-carboxylic acid;

(6R, 7R) -7-amino-3- [2-pyrid-2-ylthio) ethyl] -ceph-3-em-4-carboxylic acid and its hydrochloride and dihydrochloride; (6R, 7R) -7- [2-Hydroxyimino-2- (thien-2-yI) acetamido] -3- [2- (pyrid-2-ylthio) ethyl] -ceph-3-em-4- carboxylic acid (syn isomer);

(6R, 7R) -7- (2-phenoxyimino-2-phenylacetamido) -3- [2- (pyrid-2-ylthio) ethyl] -ceph-3-em-4-carboxylic acid (syn-isomer) and their Hydrochloride; (6R, 7R, 2'R) -7- (2-dichloroacetoxy-2-phenylacetamido) -3- [2- (pyrid-2-ylthio) ethyl] ceph-3-em-4-carboxylic acid; and (6R, 7R, 2'R) -7- (2'-hydroxy-2-phenylacetamido) -3 - [2-pyrid-2-ylthio) ethyl] ceph-3-em-4-carboxylic acid.

The following examples illustrate the invention. All temperatures are in ° C, and unless otherwise specified, the following experimental procedures were used.

The melting points were determined in capillaries and are not corrected. The ultraviolet spectra were measured in ethanol and the optical rotations in chloroform. The ultraviolet extinction coefficients and yields have been corrected for product solvation. The solids were dried in vacuo at 20 to 25 ° C. Pre-coated Merck GF2S4 plates were used for thin layer chromatography, and the components were exposed under 254 nm ultraviolet light and then by exposure to iodine vapor. Column chromatography was carried out on Merck silica gel (0.05 to 0.2 mm) and preparative thin layer chromatography on 20 × 20 cm plates coated with Merck silica gel GF254 + 366.

The Rf values (system B) were based on Whatman No. 1 paper, buffered to pH 6, determined and developed at 20 to 25 ° C down with an upper phase of n-butanol: ethanol: water = 4: 1: 5 in equilibrium with the soil phase. The Rf values (System C) were based on Whatman No. 1 paper, buffered to pH 5, determined and developed downward at 37 ° C. with an upper phase of ethyl acetate: n-butanol: 0.1 M sodium acetate = 8: 1: 8 in equilibrium with a lower phase. 7- (Thien-2-ylacetamido) cephalosporanic acid (TACA) was used as a reference.

The infrared and NMR spectra were measured in bromoform and deuterochloroform, respectively. The NMR spectra were measured at 60 MHz or 100 MHz. In all cases, the spectra matched the assigned structures.

All experiments were carried out at 20 to 25 ° C unless otherwise specified. The ratio of the components in the mixed solvent systems is given by volume.

If esters are stated as process products in some of the examples, these are the compounds obtainable before the 4-carboxy protective group has been eliminated. The protective group can be eliminated in the same way as described in the other examples.

Example l a) Diphenylmethyl- (6R, 7R) -3- (2- [pyrid-2-ylthio] ethyl) -7 - (thien-2-ylacetamido) -ceph-3-em-4-carboxylate

Triethylamine (400 mg, 4.0 mmol) was added to Diphenylme-thy] - (6R, 7R) -7- (thien-2-ylacetamido) -3-vinyl-ceph-3-em-4-carboxylate (2.07 g, 4.0 mmol) and 2-mercapto-pyridine (890 mg, 8.0 mmol) in dichloromethane (15 ml) were added. The solution was stirred at 20 ° C for 16 hours and then evaporated to an oil which was chromatographed on silica gel (100 g). The title compound was eluted with benzene containing 10% ethyl acetate which was isolated as a foam (1.474 g, 59%); Melting point 64 to 70 ° (dec.); [a] ^ 3 - 7.4 ° (c 1.01); /.Max. 242 nm (e 22400) and 282 nm (e 11100).

b) (6R, 7R) -3- (2- [pyrid-2-ylthio] ethyl) -7- (thien-

2-ylacetamido) -ceph-3-em-4-carboxylic acid

Diphenylmethyl- (6R, 7R) -3- (2- [pyrid-2-ylthio] ethyl-

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7- (thien-2-ylacetamido) -ceph-3-em-4-carboxylate (1.205 g, 1.92 mmol) in anisole (1 ml) was shaken with trifluoroacetic acid (5 ml) for 5 minutes. The volatile materials were then removed in vacuo at 40 °. The residue was slurried with ethyl acetate (10 ml) and the slurry evaporated again. The residue, in chloroform (30 ml), was extracted with saturated aqueous sodium carbonate solution (3 X 25 ml). The organic phase was then dried, concentrated to about 3 ml and run into vigorously stirred petroleum ether (50 ml). The precipitate was filtered, washed with petroleum ether and dried to give the desired acid (145 mg, 16%).

The combined bicarbonate extracts were acidified to pH 2 over chloroform (25 ml) by the dropwise addition of concentrated hydrochloric acid with stirring. The organic layer was separated and the aqueous layer extracted with further chloroform (3 X 25 ml). The combined chloroform extracts were dried and evaporated to give further product in the form of a foam. The two product samples were combined in the form of a foam to achieve the desired acidity; (546 mg, 62%). Melting point 84 to 91 ° (dec.); [ajg7 + 16 ° (c 1.0); Xmax. 244 nm (e 17,600); Xinfl. 275 nm (s 8300);

Rf 0.56 (System B), 0.38 (System C) when TACA had an Rf of 0.41 and 0.38, respectively.

Example 2

a) Diphenylmethyl- (6R, 7R) -3- (2 / - [methoxycarbonyl-methylthio] ethyl) -7- (thien-2-ylacetamido) -ceph-3-em-4-carboxylate The procedure of Example 1 ( a) was repeated with the exception that methyl thioglycolate was used instead of 2-mercapto-pyridine. The title compound was obtained as a foam (65%); Melting point 50 to 66 ° (dec.); [a] 23 + 1.9 ° (c, 1.06); Xinfl. 235 nm (e 14 700), 267 nm (e 5900) and 318 nm (e 1400).

b) (6R, 7R) -3- (2- [methoxycarbonylmethylthio] ethyl) - 7- (thien-2-ylacetamido) -ceph-3-em-4-carboxylic acid diphenylmethyl- (6R, 7R) -3- ( 2- [methoxycarbonylmethylthio] ethyl 7- (thien-2-ylacetamido) -ceph-3-em-4-carboxylate (765 mg, 1.23 mmol) in anisole (0.5 ml) was treated with trifluoroacetic acid ( 2.0 ml) was shaken for 4 minutes, the solvents were removed at 40 ° in vacuo and the residue was partitioned between ethyl acetate (20 ml) and water (5 ml) and saturated aqueous sodium bicarbonate solution was added with stirring until the pH of the aqueous layer reached 8.0 The organic layer was extracted with further aqueous bicarbonate (2 × 25 ml) and the combined extracts, with ethyl acetate (20 ml), acidified to pH 2 with concentrated hydrochloric acid extracted more ethyl acetate (2 X 20 ml) and the combined extracts dried, concentrated and in stirred petroleum ether (100 ml) to obtain the desired acid in the form of a white powder (4th 05 mg. 72%) shrunk; Melting point 64 to 78 ° (dec.); [a] ^ + 38 ° (c 0.98); amax. (pH 6 phosphate buffer) 235 nm (e 12900) and 330 nm (e 3700);

Xinfl. 260 nm (s 7000); Rf 0.29 (System B) and 0.49 (System C) when TACA had an Rf of 0.19 and 0.17, respectively.

Example 3

Diphenylmethyl- (6R, 7R) -7- (thien-2-ylacetamido) -3- (2- [p-tolylthio] ethyl) -ceph-3-em-4-carboxylate The procedure of Example l (a) was followed repeated with the exception that p-thiocresol was used instead of 2-mercaptopyridine. The desired compound was obtained in the form of crystals (27%) from dichloromethane: ether;

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Melting point 145 to 147 ° (dec.); [a] g7 -9.9 ° (c 1.00); Infl. 240 nm (s 17400) and 272 nm (e 9500).

Example 4

Diphenylmethyl- (6R, 7R) -3- (2- [methylpyrimidin-2-ylthio] ethyl-7- (thien-2-ylacetamido) -ceph-3-em-4-carboxy-

lat

Triethylamine (150 mg, 1.5 mmol) was added to a suspension of 2-mercapto-4-methylpyrimidine hydrochloride (165 mg, 1.0 mmol) in dichloromethane (10 ml), the diphenylmethyl- (6R, 7R) -7 - (thien-2-ylacetamido) -2-vinyl-ceph-3-em-4-carboxylate (260 mg, 0.5 mmol). The suspension was stirred and quickly cleared, then a white precipitate formed. The mixture was stirred at 25 ° C for 48 hours. The suspension was then concentrated to a slurry which was chromatographed on silica gel. Elution with dichloromethane, which contained 3% acetone, gave the title ester as a foam (81 mg, 25%), melting point 86-99 ° (dec.); [a] ^ 1 -37 ° (c 0.94); Xmax. 246 nm (s 21500); Xinfl. 270 nm (e 11800).

Example 5

a) Diphenylmethyl- (6R, 7R) -3- (2-methylthioethyl) -7- (thien-2-ylacetamido) -ceph-3-em-4-carboxylate Diphenylmethyl- (6R, 7R) -7- (thien- 2-ylacetamido) -3-vinyl-ceph-3-em-4-carboxylate (3.10 g, 6.0 mmol) with triethylamine (600 mg, 6.0 mmol) in dry dichloroethane (20 ml) was added to - Cooled 50 ° C in a 50 ml Carius tube. Methane thiol (about 1.5 ml, 1.3 g, 30 mmol) was condensed in the tube, which was then sealed. The contents were stirred at 25 ° C for 48 hours, then the tube was cooled and opened and the excess methanethiol was suctioned off through a wash bottle containing acidified aqueous potassium permanganate. The remaining volatile materials were evaporated under reduced pressure and the residue was chromatographed on silica gel (120 g). The column was eluted with benzene containing 5 to 15% ethyl acetate and gave the title ester as a foam (500 mg, 15%); Melting point 142 to 148 ° C (dec.); [aß2 -2.5 "(c 0.97); Xinfl. 235 nm (e 13700), 267 nm (e 6200); Xmax. 326 nm (e 2900).

b) (6R, 7R) -3- (2-methylthioethyl) -7- (thien-2-ylacetamido) -ceph-3-em-4-carboxylic acid By deesterification of the product according to (a) according to the method of Example 2 ( b) the title compound was obtained by precipitation from ethyl acetate / petroleum ether as a whitish powder (78%); Melting point 60 to 68 ° C (dec.); [ajg3 + 52 ° (c 1.01); Xmax. (pH phosphate buffer) 235 nm (e 12900), 334 nm (e 1100); Xinfl. 260 nm (e 8000); Rf 0.61 (System B), 0.74 (System C) when TACA had Rf values of 0.53 and 0.31, respectively.

Example 6

a) Diphenylmethyl- (6R, 7R) -3- (2-n-propylthioethyl) -7- (thien-2-ylacetamido) -ceph-3-em-4-carboxylate Diphenylmethyl- (6R, 7R) -7- ( thien-2-ylacetamido) -3-vinyl-ceph-3-em-4-carboxylate (2.08 g, 4.0 mmol) in dichloromethane (10 ml) was treated successively with n-propanethiol (0.57 ml, 480 mg, 6.0 mmol) and triethylamine (400 mg, 4.0 mmol) were treated. The solution was stirred at 25 ° C for 24 hours, then more vinyl ester (1.04 g, 2.0 mmol) and propanethiol (240 mg, 3.0 mmol) were added and stirring continued for 24 hours. The volatile materials were evaporated and the residue was chromatographed on silica gel (100 g). Elution with 10% ethyl acetate in benzene gave the title ester as a foam (910 mg, 25%); Melting point 76 to 83 ° C (dec.); [a] ^ - 5.5 ° (c, 0.98); Xinfl. 235 nm (e 3600) and 268 nm (e 6400); Xmax. 317 nm (e 3600).

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Example 7 10

a) Diphenylmethyl- (6R, 7R, 2'R) -7- (2'-t-butoxycarbonylamino-2'-phenylacetamido) -3- (2- [pyrid-2-ylthio] ethyl) -

ceph-3-em-4-carboxylate triethylamine (1.05 g, 1.44 ml, 10.4 mmol) in dichloromethane (10 ml) was added dropwise over 5 minutes with stirring for xs to a solution of 2-mercaptopyridine (4, 62 g, 41.6 mmol) and diphenylmethyl- (6R, 7R, 2 / R) -7- (2'-t-butoxycarbo-nylamino-2'-phenylacetamido) -3-vinyl-ceph-3-em-4 -carboxy-lat (13.01 g, 20.8 mmol) in dichloromethane (140 ml). The solution was stirred at 20 ° C. for 2 hours and then evaporated for a further 16 hours at 5 ° C., then to an oil which was chromatographed on silica gel (350 g). Elution with benzene containing 5 to 20% ethyl acetate gave the desired ester in the form of white crystals of ether / dichloromethane (5.00 g, 33%); Melting point 175 to 25 177 ° C; [ex] 21-44 ° (c, 1.02); Xmax. 248 nm (e 16100), 284 nm (e 10300).

b) Di-trifluoroacetic acid salt of (6R, 7R, 2'R) -7- (2 / -amino-2'-phenylacetamido) -3- (2- [pyrid-2-ylthio] ethyl) - 3 ° ceph -3-em-4-carboxylic acid diphenylmethyl- (6R, 7R, 2 / R) -7- (2 / -t-butoxycarbonylamino-2'-phenylacetamido) -3- (2- [pyrid-2-ylthio] ethyl ) -ceph-3-em-4-carboxylate (562 mg, 0.76 mmol) in anisole (0.6 ml) were shaken with 3 ml of trifluoroacetic acid for 5 minutes at 20 to 25 ° C. for 5 minutes. The volatile materials were then evaporated in vacuo at 400 C, the residue dissolved in ethyl acetate and the solution evaporated again. The residue in 10 ml of ethyl acetate was extracted with aqueous trifluoroacetic acid (5% v / v, 3X15 ml). The extracts were combined, washed with 10 ml of ether 40, briefly rotary evaporated and freeze-dried and gave the desired salt as a white foam (545 mg, 93% corrected for 1/2 CF3CO2H • 1/2 H2O solvate); Melting point 53 to 56 ° C; [a] ^ 1 + 34 ° (c 0.56.2n hydrochloric acid); Xmax. (pH 6 phosphate buffer) 249 nm (e 12800) 45 and 264 nm (e 10000); Rf 0.32 (system B), 0.20 (system C),

when TACA had Rf values of 0.52 and 0.27, respectively.

so c) (6R, 7R, 2'R) -7- (2'-amino-2'-phenylacetamido) -3- (2- [pyrid-2-ylthio] ethyl ceph-3-em-4- carboxylic acid diphenylmethyl- (6R, 7R, 2'R) -7- (2'-t-butoxycarbonylamino-2'-phenylacetamido) -3- (2- [pyrid-2-ylthio] ethyl) -ceph-3-em -4-carboxylate (6.02 g, 8.2 mmol) with 6 ml anisole was shaken with 24 ml trifluoroacetic acid for 5 minutes and the volatile materials were evaporated in vacuo at 40 ° C for 30 55 minutes leaving a sticky solid The resulting white powder was filtered, washed with ether and briefly dried in vacuo, then stirred with 50 ml of water and trifluoroacetic acid was added dropwise until the solution was almost complete filtered and briefly evaporated on a rotary evaporator, the pH was then adjusted to 4.7 by the dropwise addition of aqueous ammonia (d = 0.880) with stirring, the precipitate was washed with water (3 X10 ml) and in a vacuum Dried phosphorus pentoxide and gave the desired amino acid as white crystals (3.66 g, 88%); Melting point 150 to 153 ° C; [a] ^ 1 + 42 ° (c, 0.59.2n salt

acid); Xmax. 250 nm (e 14300) and 286 nm (e 6500); the chromatographic behavior is similar to that of the trifluoroacetic acid salt described above under (b).

Example 8

a) Diphenylmethyl- (6R, 7R, 2'R) -7- (2-t-butoxycarbonylamino-2'-phenylacetamido) -3- (2- [methoxycarbonylmethylthio] ethyl ceph-3-em- 4-carboxylate The procedure of Example 13 (a) was repeated except that the methyl-thioglycolic acid ester was used instead of 2-mercaptopyridine to give the title compound as a foam (53%), melting point 56-70 ° C (dec. ); [a8 -16 ° (c 1.2); Xmax. 258 nm (s 5800) and 325 nm (e 1600).

b) Trifluoroacetic acid salt of (6R, 7R, 2'R) -7- (2 / -amino-2 / -phenylacetamido) -3- (2- [methoxycarbonyl-

methylthio] -ethyl) -ceph-3-em-4-carboxylic acid By ester cleavage and removal of the N-protecting group of the product, the desired compound was obtained as a white foam from the freeze-dried aqueous trifluoroacetic acid extracts (37%); Melting point 53-60 ° C (dec.); [a] ^ + 52 ° C (c 1,2, DMSO); Xmax. (pH6 phosphate buffer) 260 nm (e 7500) and 330 nm (e 1900); Rf 0.12 (System B), 0.06 (System C) when TACA had an Rf of 0.43 and 0.23, respectively.

Treatment with ether of the non-extracted material gave the crude desired salt as a whitish powder (38%); Melting point 54-62 ° C (dec.); [a] g> + 24 ° (c 0.98, DMSO); Xmax. (pH6 phosphate buffer) 258 nm (e 5900), 330 nm (s 3600) and 360 nm (e 2800); the chromatographic behavior was similar to that of the sample described above.

Example 9

Diphenylmethyl- (6R, 7R, 2'R) -7- (2'-t-butoxycarbonylamino-2 / -phenylacetamido) -3- (2- [pyrimid-2-ylthio] ethyl)

ceph-3-em-4-carboxylate The procedure of Example 7 (a) was repeated except that 2-mercaptopyrimidine was used instead of 2-mercaptopyridine. The desired compound was obtained as a foam (41%); F = 135-143 ° C (dec.); [a] 21-55 ° (c 1.01); Xmax. 251 nm (e 19200); Xinfl. 273 nm (e 10400).

Example 10

a) DiphenylmethyI- (6R, 7R, 2'R) -7- (2'-t-butoxycarbonylamino-2'-phenylacetamido) -3- (2-p-nitrophenylthioethyl) -

ceph-3-em-4-carboxylate The procedure of Example 7 (a) was repeated except that p-nitrothiophenol was used in place of 2-mercaptopyridine. The desired compound was obtained as a foam (25%); F = 88-96 "C (dec.); [A | 9 -29 ° (c 0.88); Xmax. 336 nm (e 13600); Xinfl. 250 nm (e 9400) and 280 nm (e 7400) .

Trifluoroacetic acid salt of (6R, 7R, 2'R) -7- (2 / -Amino-2'-phenylacetamido) -3- (2-p-nitrophenyl-thioethyl) -ceph-3-em-4-carboxylic acid The product according to example (a) above, an ester cleavage was carried out and the protective group on the N atom was removed; the desired product was obtained as a whitish powder (73%); F = 76-90C (dec.); [a] g> + 46 ° C (c 1.07, DMSO); Xmax. 338 nm (e 11700); Xinfl. 250 nm (e 9600) and 266 nm (e 8500); Rf 0.26 (System B) when TACA had an Rf of 0.35.

11

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Example 11

a) Diphenylmethyl- (6R, 7R, 2'R) -7- (2 / -t-butoxycarbonylamino-2'-phenylacetamido) -3- (2 [diphenylmethoxycarbonyl] methylthio] ethyl) -ceph-3- em-4-carboxylate The procedure of Example 7 (a) was repeated with the exception that thioglycolic acid diphenylmethyl ester, prepared by reacting thioglycolic acid with diphenyldiazomethane (t 2.65 (Ph, s), 3.05 (CHPh2, s), 6.68 (CH2, d, J8Hz), 8.02 (SH, t, J8Hz)) was used instead of 2-mercaptopyridine. The desired ester was isolated as a foam (33%); F = 85-95 ° C (dec.); [a1 -1.1 ° (c 1.01); Xmax. 257 nm (e 7500).

b) Trifluoroacetic acid salt of (6R, 7R, 2'R) -7- (2'-amino-2'-phenylacetamido) -3- (2- [carboxymethylthio] ethyl) -ceph-3-em-4-carboxylic acid Diphenylmethyl- (6R, 7R, 2 / R) -7- (2'-t-butoxycarbonylamino-2'-phenylacetamido) -3- (2- [diphenylmethoxycarbonylmethylthio] ethyl) -ceph-3-em-4- Carboxylate (980 mg, 1.11 mmol) in 1 ml anisole was shaken with 5 ml trifluoroacetic acid for 5 minutes. The volatile materials were evaporated in vacuo, the residue was dissolved in 15 ml of ethyl acetate and the solution was evaporated again. The remaining gummy substance was taken up in 15 ml of ethyl acetate and extracted with 5% aqueous trifluoroacetic acid (4 × 25 ml). The extracts were washed with ether, briefly rotary evaporated and freeze-dried and gave the desired salt as a white foam (572 mg, 83%); F = 104-117 ° C (dec.); [ajg1 +81 "(c 1.02, DMSO); Xmax. (pH6 phosphate buffer) 261 nm (e 8500); Rf 0.03 (system B), 0.02 (system C) if TACA Rf Had values of 0.34 and 0.40, respectively.

Example 12

a) Diphenylmethyl- (6R, 7R, 2'R) -7- (2 / -t-butoxycarbonylamino-2 / -phenylacetamido) -3- (2- [4-methylpyrimidin-2-ylthio] ethyl) - ceph-3-em-4-carboxylate triethylamine (800 mg, 8.0 mmol) was added to a suspension of 2-mercapto-4-methylpyrimidine hydrochloride (975 mg, 6.0 mmol) in 40 ml dichloromethane, the diphenylmethyl - (6R, 7R, 2 'R) -7- (2'-t-butoxycarbonyl-amino-2'-phenylacetamido) -3-vinylceph-3-em-4-carboxylate (2.50 mg, 4.0 mmol ) contained. The suspension was stirred at 20-25 ° C for 20 hours and then washed with 2N hydrochloric acid (20 ml, 10 ml). The organic layer was separated, dried and evaporated to a foam which was chromatographed on silica gel (90 g). Elution with dichloromethane containing 0 to 5% acetone gave the desired ester as a foam (1.32 g, 44%); F = 106-110 ° C; [a1 -41 ° (c 0.97); Xmax. 252 nm (s 18800); Xinfl. 273 nm (s 11300).

b) Di-trifluoroacetic acid salt of (6R, 7R, 2'R) -7- (2'-amino-2'-phenylacetamido) -3- (2- [4-methylpyrimidin-2-yl-thio] ethyl) -ceph-3-em-4-carboxylic acid After ester cleavage and removal of the protective group on the N atom, the product obtained from (a) gave the desired compound as a white, freeze-dried foam (87%, corrected for hydration); F = 59-67 ° (dec.); [afê, 0 + 34 ° (c 0.99, DMSO); Xmax. (pH6 phosphate buffer) 252 nm (s 18600); Rf 0.29 (System B), 0.15 (System C) when TACA had Rf values of 0.52 and 0.26, respectively.

Example 13 a) Diphenylmethyl- (4§, 6R, 7R, 2'R, l "§) -7- (2 / -t-butoxycarbonylamino-2'-phenylacetamido) -3- (2" -methylthio-ethylidene) - cepham-4-carboxylate methanethiol was slowly stirred with a solution of diphenylmethyl- (6R, 7R, 2'R) -7- (2'-t-butyoxycar-

bonylamino-2 / -phenylacetamido) -3-vinylceph-3-em-4-carb-oxylate (630 mg, 1.0 mmol) in 25 ml peroxide-free tetrahydrofuran and 25 ml 0.2m-pH-8-phosphate- Buffer passed for half an hour. The solution was then stirred for a further 4 to 5 hours at 20-250 ° C until the UV spectrum of an aliquot showed little absorption at about 295 nm, the characteristic of the starting vinyl ester. The mixture was purged with air to remove excess methanethiol, then poured into 50 ml of ethyl acetate and 50 ml of saturated saline. The mixture was shaken and the organic layer separated, dried and evaporated. The residue was chromatographed on silica gel (20 g) and dichloromethane containing 0 to 5% acetone was used as the eluent. The desired is ester was obtained as a foam (365 mg, 54%); F = 95-99 ° C; [a] i ° -109 ° (c 1.00); Xmax. 252 nm (e 2600) and 257 nm (s 2400).

b) Diphenylmethyl- (6R, 7R, 2 / R) -2- (2'-t-butoxycarbonylamino-2-phenylacetamido) -3- (2-methylthioethyl) -20 ceph-3-em-4-carboxylate

DiphenylmethyI- (4 |, 6R, 7R, 2 / R, r / |) -7- (2'-t-butoxycarbo-nylamino-2'-phenylacetamido) -3- (2 "-methylthio-ethylidene) -cepham- 4-carboxylate (1.46 g, 2.16 mmol) in 25 ml dry dichloromethane was stirred with tri-25-ethylamine (110 mg, 1.1 mmol) for 64 hours at 5 ° C. The solution was evaporated to a foam and the residue was chromatographed on silica gel (45 g) Elution with benzene containing from 0 to 15% ethyl acetate gave the desired ester as a foam (500 mg, 34%), F = 85-97 ° C (dec. ); [a1 -17 ° 30 (c 1.07); Xmax. 263 nm (s 6800).

Further elution gave mixtures of the ester mentioned in the heading, its ceph-2-em isomer, and the starting isomer (total 803 mg). By treating this material again with 50 mg of triethylamine 35 for 48 hours and then re-chromatographing, more of the desired ester was obtained than foam (415 mg, 28%); F = 94-99 ° C (dec.); [a] g '-21 ° (c 1.09); Xmax. 264 nm (e6900).

40 c) trifluoroacetic acid salt of (6R, 7R, 2'R) -7-

(2 / -Amino-2'-phenylacetamido) -3- (2-methylthioethyl) -ceph-3-em-4-carboxylic acid The product from (b) above was de-esterified and deprotected on the N atom according to the method Example 13 (b) and 45 gave the title compound as a foam (81%); F = 132-140 ° C (dec.); [<x] g> + 78 ° (c 0.98, DMSO); Xmax. (pH6 phosphate buffer) 263 nm (e 8500); Rf. 0.20 (System B), 0.06 (System C) when TACA had Rf values of 0.43 and 0.23, respectively.

50 Example 14

Diphenylimethyl- (6R, 7R) -7-formamido-3- (2- [pyrid-2-ylthio] ethyl) -ceph-3-em-4-carboxylate 2-mercaptopyridine (845 mg, 7.6 mmol) and Diphenylmethyl- (6R, 7R) -7-formamido-3-vinylceph-3-em-4-carboxylate 55 (1.60 g, 3.8 mmol) in 20 ml dichloromethane were at 20 to 25 ° C for 16 Stirred with triethylamine (190 mg, 1.9 mmol) for hours. The solution was washed with 10 ml of 2N hydrochloric acid and dried with 10 ml of saturated aqueous sodium bicarbonate and evaporated. The residue was chromatographed on Kie-60 selgel (75 g); elution with dichloromethane containing 0 to 15% acetone gave the title ester as a foam (520 mg, 26%); F = 78-90 ° C (dec.); Md1 + 28 ° (c, 1.00); Xmax. 250 nm (e 15.900) and 285 nm (e 9.500).

Example 15

Diphenylmethyl- (6R, 7R) -7-formamido-3- (2- [methoxycarbo-nylmethylthio] ceph-3-em-4-carboxylate. The procedure of Example 14 was repeated, using the

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Exception that methyl thioglycolic acid was used instead of 2-mercaptopyridine. The desired compound was obtained as a foam (24%); F = 56-64 ° (dec.); [a] j! + 19 ° (c 0.55); Xmax. 258 nm (e 6,900).

Example 16

Diphenylmethyl- (6R, 7R) -7-phenoxyacetamido-3- [2- (pyrid-

2-ylthio) ethyl] ceph-3-em-4-carboxylate triethylamine (400 mg, 4.0 mmol) was converted into 2-mercaptopyridine (1.33 g, 12.0 mmol) and diphenylmethyl- (6R, 7R) -7-phenoxyacetamido-3-vinylceph-3-em-4-carboxylate (4.21 g, 8.0 mmol) in 30 ml dichloromethane. The solution was stirred for 16 hours and then evaporated to an oil which was chromatographed on silica gel (200 g). Benzene containing from 0 to 20% ethyl acetate was used as the eluent. The desired ester could not be separated from its ceph-2-em isomer by thin layer chromatography using benzene / ethyl acetate or dichloromethane / acetone as elution systems. The optical rotation of each fraction of the product from the column chromatography was therefore measured. The first fractions which had negative rotations were combined and evaporated and the residue was crystallized from ether containing some dichloromethane to give the desired ester as white crystals (935 mg, 18%); F = 68-73 ° C; [a1 -29 ° (c, 1.02); Xmax. 249nm (e 16500), 268nm (e 11200) and 275 nm (eil 100).

Example 17

Diphenylmethyl- (6R, 7R, 2'R) -7- [2 '- (2,2,2-trichloroethoxycarbonylamino) -2'-phenylacetamido] -3- [2- (pyrid-2-ylthio) -

ethyI] -ceph-3-em-4-carboxylate triethylamine (375 mg, 3.7 mmol) was added to a suspension of diphenylmethyl- (6R, 7R, 2'R) -7- [2 '(2,2,2 -trichloro-ethoxycarbonylamino) -2'-phenylacetamido] -3-vinylceph-3-em-4-carboxylate (2.59 g, 3.7 mmol) in 40 ml dichloromethane, the 2-mercaptopyridine (820 mg, 7.4 mmol) were given. The suspension was stirred and after 20 minutes the vinyl ester was completely dissolved. The solution was stirred for 20 hours and then evaporated to a foam. This was chromatographed on silica gel (50 g),

the column being eluted with benzene containing 15% ethyl acetate to give the desired dichloromethane / ether ester as white crystals (1.29 g, 43%); F = 168-170aC (dec.); [a] «= - 32 ° (c0.99); Xmax. 249 nm (£ 15800) and 283 nm (elOOOO).

Example 18

DiphenyImethyl- (6R, 7R) -7-amino-3- [2- (pyrid-2-ylthio) -

ethyl] -ceph-3-em-4-carboxylate, hydrochloride Phosphorus pentachloride (925 mg, 4.44 mmol) in 5 ml of dry dichloromethane was treated with pyridine (350 mg, 4.4 mmol) in 5 ml of dichloromethane. The white suspension was stirred for 5 minutes and then cooled to 0 ° C. Diphenylme-thyI- (6R, 7R) -3- [2- (pyrid-2-ylthio) ethyl] -7- (thien-2-ylaceta-mido) ceph-3-em-4-carboxylate (1,25 g, 2.0 mmol) in 10 ml dry dichloromethane was added dropwise over 10 minutes and the mixture was stirred and allowed to warm to 25 ° C over half an hour. The solution was added to 2 ml of dry methanol in 7 ml of dichloromethane at 0 "C and the mixture was stirred for one hour at 0 ° C. The solution was washed with aqueous sodium bicarbonate and brine, then dried and evaporated to an oil. This was dissolved in warm ethyl acetate, the solution deposited crystals of the desired compound on cooling (635 mg), F = 126-134 ° C (dec.); [a7--22 ° (c 1.06, DMSO); X max. (EtOH) 248 nm (e 15700) and 283 nm (e 9800).

Example 19

Diphenylmethyl- (6R, 7R ~ 7-amino-3- [2- (pyrid-2-ylthio) -

ethyl] ceph-3-em-4-carboxylate phosphorus pentachloride (2.09 g, 10.0 mmol) in 25 ml dichloromethane was treated dropwise with pyridine (790 mg, 10.0 mmol) in 5 ml dichloromethane; the resulting white suspension was stirred at 25 ° C for 15 minutes, then cooled to 0 ° C and with diphenylmethyl- (6R, 7R) -7-phenoxyacetamido-3- [2- (pyrid-2-ylthio) ethyl] ceph -3-em-4-carboxylate (2.54 g, 3.98 mmol) in 30 ml of dichloromethane, which was added dropwise with stirring. The resulting solution was stirred at 0 ° C for 30 minutes, then at 25 ° C for 30 minutes, and finally cooled to - 20 ° C and added dropwise to a mixture of 10 ml of methanol and 10 ml of dichloromethane, which was violent at - 20 ° C were given. The mixture was stirred at 0 ° C for 30 minutes, then 40 ml of saturated aqueous sodium bicarbonate was added and stirring continued at 0 ° C for a further 30 minutes. The organic layer was separated, washed with brine, dried and evaporated. Chromatography on silica gel, using benzene / ethyl acetate mixtures for elution (5: 1, 3: 1 and 1: 1 in succession), gave the desired compound as a light yellow foam (1.45 g) F = 100-108 ° C (dec.); [cx] d -34 ° (c 1.01, CHCb), Xmax. (EtOH) 249 nm (e 14900) and 285 nm (e 9900).

Example 20

Diphenylmethyl- (6R, 7R) -7-amino-3- [2- (pyrid-2-ylthio) -

ethyl] ceph-3-em-4-carboxylate, dihydrochloride phosphorus oxychloride (370 mg, 0.22 ml, 2.4 mmol) became diphenylmethyl- (6R, 7R) -7-formamido-3- [2-pyrid-2 -ylthio) ethyl] -ceph-3-em-4-carboxylate (420 mg, 0.79 mmol) in 5 ml of methanol and 5 ml of ether at 5 ° C.

The solution was stirred at 5 ° C for one hour and a white solid separated out. More ether (20 ml) was added; the mixture was stirred at 5 ° C for 5 minutes, then the white solid was filtered off, washed with ether and dried to give the title compound (320 mg), M = 115-127 ° C (dec.); [a7 + 43 ° (c 1.05, DMSO), Xmax. (EthOH) 247 nm (e 16100) and 285 nm (e 9700).

Example 21

a) Diphenylmethyl- (2'R, 6R, 7R) -7- (2 -dichloroacetoxy-2'-phenylacetamido) -3- [2- (pyrid-2-ylthio) ethyl] ceph-3-em-4-carboxylate Diphenylmethyl- (6R, 7R) -7-amino-3- [2- (pyrid-2-ylthio) ethyl [ceph-3-em-4-carboxylate (1.52 g, 3.0 mmol) with propylene Oxide (DL-2-methyloxirane, 1.5 ml) in dichloromethane was treated at 5 ° C with (2'R) -2'-dichloroacetoxy-2'-phenylacetyl chloride (3.25 mmol) in 12 ml dichloromethane, which was added dropwise during Was added for 10 minutes. The solution was stirred for 3/4 hour at 25 ° C, then cooled to 0 ° C and treated with 10 ml of 0.2 M pH 8 phosphate buffer. The mixture was stirred at 0 ° C for 15 minutes, then the organic layer was separated, dried and evaporated. The residue was chromatographed on silica gel, which was eluted with dichloromethane containing from 0 to 2.5% acetone. The fractions containing the main product were combined and evaporated to a gummy substance. This material was added to a little ethyl acetate, with stirring, to petroleum ether (boiling range 40-60 ° C.), and the resulting precipitate was filtered off, washed with petroleum ether and dried, and gave the desired ester as a brown powder (1.79 g) 60-88 ° C (dec.); [a] è7 -37 ° (c 1.0, CHCb); Xmax (EthOH) 248 nm (e 16400) and 284 nm (e 9500).

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615 186

b) (2'R, 6R, 7R) -7- (2 / -hydroxy-2 / -phenylacetamido) -3- [2- (pyrid-2-ylthio) ethyl] ceph-3-em-4-carboxylic acid Das Product according to example a) above (1.65 g, 2.2 mmol) with 1.5 ml of anisole was shaken with 5 ml of trifluoroacetic acid for 5 minutes. The solution was evaporated in vacuo at 40 ° C and the residue in 10 ml of ethyl acetate was stirred with saturated aqueous sodium carbonate for 74 hours. The organic layer was separated, washed with hydrochloric acid, dried and evaporated to give crude (2'R, 6R, 7R) -7- (2'-dichloroacetoxy-2 / -phenylacetamido) -3- [2-pyrid-2- ylthio) ethyl] -ceph-3-em-4-carboxylic acid (530 mg).

This material (490 mg) in 20 ml acetone and 10 ml water was stirred with 5 ml saturated aqueous sodium bicarbonate for 1 hour. The acetone was evaporated and the residue was taken up in 10 ml dichloromethane and acidified to pH 2 with concentrated hydrochloric acid. The aqueous layer was evaporated and extracted with more dichloromethane and the combined extracts were dried and evaporated to give the title acid as a brown foam (270 mg) F = 56-83 ° C (dec.); [ajg * + 66 ° (c 0.98, DMSO); Xmax. (EthOH) 249 nm (e 14800) and 274 nm (e 8700).

Example 22

a) Diphenylmethyl- (6R, 7R) -7 - [(2E) -2-hydroxyimino-2- (thien-2-yl) -acetamido] -3- [2- (pyrid-2-ylthio) ethylceph-

3-em-4-carboxylate Diphenylmethyl- (6R, 7R) -7-amino-3- [2- (pyrid-2-ylthio) ethyl] -ceph-3-em-4-carboxylate hydrochloride 1.32 g , 2.44 nmol) with 1 ml of propylene oxide in 10 ml of dry dichloromethane was stirred at 0 ° C. and with (2E) -2-dichloroacetoxy-imino-2- (thien-2-yl) acetyl chloride (3.5 mmol) in 10 ml of dichloromethane treated for 5 minutes. The solution was stirred and allowed to warm to 25 ° C over half an hour. 10 ml of water and 10 ml of saturated aqueous sodium bicarbonate were added and the mixture was stirred vigorously for 1/4 hour. The organic layer was separated, washed with water, dried and evaporated. The crude product was purified by column chromatography on silica gel, using dichloromethane containing 0-5% acetone for the elution. This gave the title ester as a white foam (1.25 g), F = 90-102 ° C (dec.); [ate? + 1.4 ° (c 1.06, CHCb); Xmax. (ÄthOH) 250 nm (e 22500) and 285 nm (e 18500).

b) (6R, 7R) -7 - [(2E) -2-hydroxyimino-2- (thien-2-yl) acetamido [-3- [2- (pyrid-2-ylthio) ethyl] ceph-3- em-4-carbon

acid

The product according to example a) above (1.11 g, 1.69 mmol) with 1 ml of anisole was shaken for 4 minutes with 4 ml of trifluoroacetic acid. The volatile materials were in the

Evaporation in vacuo at 40 ° C and the residue in 15 ml of ethyl acetate was extracted with saturated aqueous sodium bicarbonate / water (1: 1 v / v, 3 X20 ml). The combined aqueous extracts were acidified with concentrated hydrochloric acid under 20 ml of ethyl acetate. The aqueous layer was separated and extracted with more ethyl acetate (3 X 20 ml); the combined organic extracts were dried and concentrated. The resulting crystals were filtered off and recrystallized from chloroform / ethyl acetate and gave the desired acid (705 mg), F = 116-132 ° C (dec.), [«] Gf + 52 ° (c 1.03, DMSO); Xmax. (pH 6 phosphate buffer) 252 nm (e 19400) and 277 nm (ë 16100).

Example 23

a) Diphenylmethyl- (6R, 7R) -7 - [(2Z) -2-phenoxyimino-

2-phenylacetamido] -3- [2- (pyrid-2-ylthio) ethyl] ceph-3-em-4-carboxylate

Diphenylmethyl- (6R, 7R) -7-amino-3- [2- (pyrid-2-ylthio) ethyl] -ceph-3-em-4-carboxylate (1.26 g, 2.5 mmol) in 20 ml of dichloromethane was treated sequentially with DL-dicyclohexylcar-bodiimide (515 mg, 2.5 mmol) and (2Z) -2-phenoxyimino-2-phenylacetic acid (605 mg, 2.5 mmol), each of these compounds in 10 ml of dichloromethane was added dropwise with stirring. The mixture was stirred at 20 ° C for 2 hours, held at 5 ° C for 16 hours and finally evaporated. The residue was stirred with 20 ml of ethyl acetate and the suspension was evaporated again. The resulting solid was extracted with ethyl acetate (5x10 ml) and the combined extracts were evaporated to an oil. Chromatography on silica gel, using dichloromethane containing 0-2% acetone as the eluent, gave the desired ester as a foam (1.46 g), M = 110-118 ° C. (dec.); [a] ^ 7 = 15 ° (c 1.00, CHCb); Xmax. (EtOH) 249 nm (e 25700), 267 nm (e 20100) and 286 nm (e 19600).

b) (6R, 7R) -7 - [(2Z) -2-phenoxyimino-2-phenylacetamido] -

3- [2- (pyrid-2-ylthio) ethyl] ceph-3-em-4-carboxylic acid hydrochloride

The product according to (a) above (1.31 g, 1.8 mmol) was subjected to ester cleavage using the method of Example 22 b). The solid residue from the ethyl acetate extracts was redissolved in ethyl acetate and the solution evaporated again. This residue in 20 ml of ethyl acetate was washed with saturated aqueous sodium bicarbonate (3 X 20 ml); by adding 2N hydrochloric acid to the organic phase, pale crystals were deposited. The mixture was filtered and the crystals were washed thoroughly with ethyl acetate and dried to give the desired compound (875 mg), M = 123 to 126 ° C (dec.); [a] k7 + 48 ° (c 1.06, DMSO); Xmax. (ÄthOH) 251 nm (e 24600), 269 nm (e 20300) and 285 nm (e 19100).

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Claims (3)

615 186 2. The method according to claim 1, characterized in that the compounds of formula II with a) a compound of formula V. 35 R3 R 'S s1 N \ R6 (V) wherein R3, R4, R5 and R6, which are identical or different, each represent hydrogen or an aliphatic, alicyclic, aromatic, araliphatic or heterocyclic group or at least two of the radicals R3, R4, R5 and R6 form one or more polyvalent groups and / or at least one of the radicals R4 and R6 of a group 45 50 Ni5 corresponds and the remaining groups have the meanings given; b) a compound of formula VI R wherein R10 represents a hydrogen atom or a hydroxy, lower alkyl or lower alkoxy group. 5. The method according to claim 2, characterized in that a compound of formula VII, wherein R3 'unsubstituted or mono- or polysubstituted by amino, hydroxy, carboxy, esterified carboxy or aryloxy substituted lower alkyl; unsubstituted or mono- or polysubstituted by halogen, lower alkyl, lower alkoxy, nitro, halo-alkyl, cyano, carboxy, esterified carboxy, hydroxy, acyl, acyloxy or optionally substituted amido, substituted phenyl or naphthyl; Aryl-lower alkyl; C5-C7 cycloalkyl; or a 5- or 6-membered heterocyclic group having at least one heteroatom from the group consisting of oxygen, nitrogen or sulfur. 6. The method according to claim 1, characterized in that a base from the group consisting of tri-lower alkylamines, aromatic heterocyclic nitrogen bases, alkali metal carbonates, hydrogen carbonates or phosphates and anion exchange shear resins is added to the reaction medium. 7. The method according to claim 1, characterized in that an electrophilic compound from the group consisting of mercury (II) - or silver perchlorate, nitrate, trifluoroacetate and tetrafluoroborate and Lewis acids are added to the reaction medium as an activating agent. 8. The method according to claim 1, characterized in that an intermediate cepham compound of the formula IV y R -Ç — N i v (VI) wherein R7 and R8, which are the same or different, each represent an aliphatic, alicyclic, aromatic, araliphatic or heterocyclic group and R7 also represents a hydroxyl or esterified hydroxyl group and R9 represents an aliphatic or araliphatic group or together (IV) CH-CH -Y COOK 2nd PATENT CLAIMS 1. Process for the preparation of a cephem compound of formula I. men forms a bivalent group with R7 and / or R8; or c) a compound of formula VII R3'-SH (VII) CH2-CH2-Y comi (i), wherein R1 is a free or protected amino group; and Y is the residue of a thiourea bonded via sulfur, which may be substituted, means thioamides, thiols or thiophenols, it also being possible for the compounds to carry substituents in the 2- or 7-position, characterized in that a compound of the formula II wherein R3 'represents an aliphatic, alicyclic, aromatic, araliphatic or heterocyclic group. 3. The method according to claim 2, characterized in that a compound of formula VI, wherein R9 is a lower alkyl or aryl-lower alkyl group or together with R7 and / or R8 a lower alkylene, alkenylene, alkadienylene, alkylidene or alkenylidene group forms, said groups may be interrupted by an oxygen, nitrogen or sulfur atom, and the remaining radicals R7 or R8 have the meaning given. 4. The method according to claim 2, characterized in that as a compound of formula VI, a compound of formula VIII CH = CH, N (VIII), (II) 10th COOH optionally with intermediate protection of the 4-carboxyl group, with a thiourea, substituted thiourea, thioamide, thiol or thiophenol. 3rd 615186 isolated and then converted into the corresponding ceph-3-em compound by treatment with a base.