KR840001008B1 - Process for preparing 3-vinyl-cephalosporin derivatives - Google Patents

Abstract

Title compds. I ≮n=0, l; R1=H, (II); R2=H, (III), t-butyl, methoxymethyl, benzhydryl, p-nitrobenzyl, p-methoxybenzyl; R3=(IV), (V); R4=H, protecting groups; R5=H, alkyl, cyanomethyl, tetrahydropyranyl, 2-methoxy, prop-2-yl; R8=alkyl, cyclohexyl; R9=H, alkyl, R3'=alkyl, trifluoromethyl, trichloromethyl, Ph, halo-, alkyl, nitro-; R3"=R3' or acylmethyl, 2-acylethyl, alkoxycarbonylmethyl, etc.≉ were prepd. Thus, 6.1g 2-benzhydryl- oxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-aza-bicyclo≮4.2.0≉ oct-2-ene in 75mL acetonitrile was treated with 3.49g p-toluene sulfonate in 25mL acetonitrile to give 4.7g 7-amino-2-benzhydryloxycarbonyl-8-oxo-3-(2-tosyloxy- vinyl)-5-thia-1-aza-bicyclo≮4.2.0≉ oct-2-ene.

Description

Method for preparing new 3-vinyl-cephalosporin derivative

The following general formula (I) relates to a process for the preparation of novel 3-vinyl-cephalosporins and salts thereof.

Compounds of the general formula (I) in which the value of n is 0 or 1 take the form of bicyclooct-2-ene or bicyclooct-3-ene (according to chemical abspact nomenclature) when n = 0. Or when n = 1, the substituent on the carbon atom at the 3-position of the bicyclooctene in the form of bicyclooct-2-ene represents a cis- or trans-stereoisomer form. a) Symbol R ₁ represents a hydrogen atom, a reactor of formula (II), symbol R ₂ represents a hydrogen atom, a reactor of formula (III) which can be easily removed by an enzyme, or a methoxymethyl tert-butyl group , Benzhydryl group, p-nitrobenzyl group or p-methoxybenzyl group, and the symbol R ₃ represents a reactor of general formula (IV) or general formula (V).

Wherein R ₄ is a hydrogen atom or (tert-butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, trityl group, benzyl group, dibenzyl group, benzyloxycarbonyl group, p-nitro Benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, formyl group or trifluoroacetyl group), and R ₅ is a hydrogen atom, an alkyl group, cyanomethyl group, or (trityl group, tetrahydropyranyl group, Or a protecting group such as 2-methoxy, prop-2-yl.

Food,

R ₈ represents an alkyl group or a cyclohexyl group,

R ₉ represents a hydrogen atom or an alkyl group.

Wherein R ₃ ′ represents an alkyl group, a trifluoromethyl group, a trichloromethyl group or a phenyl group which is unsubstituted or substituted by a halogen atom or an alkyl group or a nitro group, and R ₃ '' is the same as R ₃ ′ or an acylmethyl group , 2-acylethyl group, 2-acylpropyl group, alkoxycarbonylmethyl group, 2-alkoxycarbonylethyl group, or 2-alkoxycarbonylpropyl group.

The alkyl group or acyl group described above (or described in the future) refers to a straight or branched form containing 1 to 4 carbon atoms unless otherwise specified.

Also mixtures of bicyclooct-2-ene and bicyclooct-3-ene isomers and / or cis- and trans-isomers are within the scope of the present invention.

In the following description the trans-stereoisomeric forms are denoted by E and the cis-stereoisomeric forms are denoted by Z.

The -OR ₅ group in the reactor of formula II can also be in the syn- or anti-position, and such isomers or mixtures thereof are also within the scope of the present invention.

The syn-form is represented by general formula (IIa) and the anti-form is represented by general formula (IIb).

Among the meanings of R ₁ as described above, the following needs to be specifically mentioned. Namely, 2-methoxyimino-2- (2-tritylamino-thiazol-4-yl) -acetyl, 2-methoxyimino-2- (2-tert-butoxycarbonylamno-thiazole- 4-yl) -acetyl, 2-trityloxyimino-2- (2-tritylamino-thiazole-4-)-acetyl, 2-tetrahydropyranyloxyimino-2- (2-tritylamino- Thiazol-4-yl) -acetyl group

According to the present invention, R ₁ is as defined above in formula (II) but R ₄ is not a chloroacetyl group or a trichloroacetyl group, and R ₅ is as described above but does not represent a vinyl group. The compound of reacts the thiourea of formula (VI) to the compound of formula (V) or a mixture of isomers of the compound, and if appropriate reduces the sulfide oxides obtained (if n = 1), In this case, the protective group is removed.

In the formula, R ₄ is as described above.

Wherein R ₂ is as defined in a) above, R ₃ and n are as described above, R ₅ is as described above and Hal represents a chlorine or bromine atom.

The reaction is for example alcohol (methanol or ethanol), ketone (acetone), chlorinated solvent (chloroform or ethylene chloride), nitrile (acetonitrile), amide (dimethylformamide or dimethylacetamide), ether (tetrahydrofuran or di) In an aqueous solvent, an organic solvent or an aqueous organic medium, such as a solvent such as oxane), an ester (ethyl acetate), or an acid (acetic acid or formic acid), or a mixture of solvents such as sodium hydroxide, potassium hydroxide, alkali metal Carbonates, alkali metal bicarbonates, alkali metal salts of sodium carboxylate or sodium acetate), or in the presence of a base such as a tertiary amine (triethylamine, trimethylamine, or pyridine) or such base It is usually carried out at a temperature of -30 to 60 with no water.

If the reaction is carried out in the presence of a base, the intermediate of formula (VIII) may or may not be isolated depending on the nature and amount of introduction of the base, which is subsequently circulated in the acid medium.

[Wherein, R ₂ , R ₃ and n are as described above and R ₄ and R ₅ are also as described above.]

The reduction process of the sulfide oxide and the removal process of the furnace are carried out under the conditions described in the patent application No. 80 of 2007.

The compound of formula (VII) when R ₅ is an alkyl group or cyanomethyl group is selected from the acid halides of formula (VII), wherein R ₂ is 7-amino-three of formula (I) as defined in a) above. It is obtained by acting on palosporin, reducing the obtained sulfide oxide (if n = 1), and removing the protecting group, if appropriate.

[Wherein Hal and Hal 'are chlorine or bromine atoms, and R ₅ is an alkyl group or cyanomethyl group.]

This reaction may be carried out by alkali metal bicarbonate (e.g., in an aqueous organic medium such as, for example, water / ether (tetrahydrofuran or dioxane), water / ketone (acetone), or water / chlorinated solvent (chloroform or methylene chloride). It is generally carried out at temperatures of -40 to 40 ° C in the presence of alkaline condensing agents).

Compounds of formula (VII) are obtained by halogenating the compounds of formula (IV) by known methods used in the preparation of halogen derivatives that do not adversely affect other parts in the molecule.

[Wherein R ₅ and Hal 'are as described above.]

In order to obtain a compound of the general formula Hal represents a bromine atom, in the presence of a catalyst, that is, hydrobromic acid, hydrochloric acid, sulfonic acid (methylsulfonic acid, p-toluenesulfonic acid, or benzenesulfonic acid) Bromine may be used as the reactant by using the same acid catalyst or by using ultraviolet rays.

In order to obtain a compound of the general formula Hal represents a chlorine atom, chlorine may be used as a reactant in the presence of a catalyst as described above, or sulfuryl chloride may be used as a reactant.

The halogenation reaction is carried out in an organic solvent such as chlorinated solvent (eg methylene chloride, chloroform, carbon tetrachloride, dichloroethane, or trichloroethane), or ether (eg diethyl ether, or dioxane) or a mixture of these solvents. At a temperature between 40 ° C. and the reflux temperature of the reaction mixture.

Compounds of formula (X) are prepared from the corresponding ethers by the method described in French Patent Application No. 2,414,508.

This ester can be prepared by itself by the method Tetrahedrow, 34, 2233 (78) described by R. Bucourt and colleagues.

When R ₅ is a hydrogen atom, the compound of formula (VII) is treated with a nitrosilylating agent in a manner similar to that described in French Patent Application No. 2,399,418 and, if appropriate, after It is obtained by reducing and removing the protecting group.

[Wherein, R ₂ , R ₃ , Hal and n are as described above.]

The compound of the general formula (VI) when R ₅ is a protecting group is obtained by protecting the greed of the compound of the general formula (V) wherein R ₅ is a hydrogen atom.

Compounds of formula (VII) may be prepared by using the above conditions for condensing the compounds of formula (III) together with compounds of formula (I) or by a method analogous to that described in French Patent No. 2,399,418. Treatment with the compound of XII) yields R from 7-amino-cephalosporin of formula (I) as defined in a) above.

[Wherein Hal is as described above.]

The novel compounds of formula (I) are useful as intermediates for preparing 3-thiovinyl-cephalosporins of formula (XIII).

Food,

α) The symbol R is selected from the following meanings.

1) alkyl group, L-2-amino-2-carboxy-ethyl group and phenyl group,

2) pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl groups and their N-oxides

3) Pyrimidin-2-yl group: pyridazin-3-yl group substituted at the 6-position (by alkyl group, methoxy group, amino group or acylamino group)

4) 5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl group substituted at the 4-position according to a) -e) below: 1- each 1,3,4-triazol-5-yl or 2-alkoxycarbonyl-1,3,4-triazol-5-yl group substituted at the position

a) unsubstituted or substituted by an alkoxy, alkylthio, phenyl, formyl, carbamyl, alkylcarbamyl, dialkylcarbamyl, acyl, alkoxycarbonyl or thiazolidin-2-yl group By alkyl groups containing four carbon atoms

b) allyl group, 2,3-dihydroxypropyl, 1,3-dihydroxyprop-2-yl, 2-formyl-2-hydroxy-ethyl, 3-formyloxy-2-hydroxy By a -propyl, 2,3-bis-formyloxy-propyl or 1,3-bis-formyloxy-prop-2-yl group

c) hydroxyl group, carbacyloxy group (acyl moiety may be substituted by amino, alkylamino, or dialkylamino group), acyloxy group, alkylsulfinyl group, alkylsulfonyl group, amino group, alkylamino group, di Alkylamino group, sulfonamino group, alkylsulfonylamino group, sulfamoylamino group (acyl moiety optionally substituted by hydroxyl group, amino group, alkylamino group, or dialkylamino group), acylamino group, alkoxycarbonylamino group, ureido group , Substituted by an alkylureido group or a dialkylureido group, by an alkyl group containing 2-4 carbon atoms

d) by a reactor corresponding to one of the following general formulas (XIVa), (XIVb), (XIVc)

Food,

alk represents an alkylene group containing 1-4 carbon atoms,

X ^α and Y ^α are the same and represent an oxygen atom or a sulfur atom,

R ^α represents an alkyl group, or 1

When X ^α and Y ^{α represent the} same or different oxygen atoms or sulfur atoms,

R ^α together with these form an alkylene group containing 2-3 carbon atoms,

R ^β represents a hydrogen atom or an alkyl group containing 1-3 carbon atoms.

e) substituted by an alkoxyimino group or a hydroxyimino group by an alkyl group containing from 1 to 5 carbon atoms

5) 1,4-Dialkyl-5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl group, 1-alkyl-5,6-dioxo -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl group, or 2-alkyl-5,6-dioxo-1,2,5,6-tetrahydro-1, 2,4-triazine-3-yl

6) 1,3,4-triazol-5-yl, 1,2,3-triazol-5-yl, or 1-alkyl-1, substituted or unsubstituted at the 3-position by an alkoxycarbonyl group, 2,4-triazole-5-yl group

7) a. Alkyl group, trifluoromethyl group, alkoxy group, alkylthio group, hydroxyalkylthio group containing 2-4 alkyl atoms, alkylsulfonyl group, hydroxyl group, hydroxyalkyl group, carboxyl group, carboxyalkyl group, amino group , Alkylamino group, dialkylamino group, aminoalkyl group, alkylaminoalkyl group, dialkylaminoalkyl group, acylamino group, or acylaminoalkyl group, or

b. 1,2,4-thiamiazol-5-yl group substituted by an alkyl group or an alkoxy group

8) a. 1,3,4-oxadiazole-5-yl group substituted or unsubstituted by an alkyl group, trifluoromethyl group, phenyl group, aminoalkyl group, alkylaminoalkyl group, dialkylaminoalkyl group or acylaminoalkyl group or acylaminoalkyl group, or

b. Oxazol-2-yl group or 4-alkyl-oxazol-2-yl group

β) Symbol R represents an alkyl group or a phenyl group, symbol R ° ₁ is defined as R ₁ in b) above, symbol R ° ₂ is defined as R ₂ in b) above.

The substituent at the 3-position of the bicyclooctene in the compound of formula (XIII) represents an E or Z stereoisomeric form, and if R ° ₁ is a reactor of formula (II), the reactor has a syn or anti form. Indicates. Compounds of general formula (XIII) also exist as mixtures of these isomeric forms.

The compound of general formula (XIII) is obtained from the compound of general formula (I) by the following process.

I °) 3-thiovinyl-cephalosporin of general formula (XIII) when R is as defined for α and β above but does not contain a substituent of general formula (XIVc) is represented by general formula (XV) A thiol of (or of an alkali metal salt or alkaline earth metal salt thereof) of which R is a reactor of formula (II) as described above and R ₂ has a corresponding significance, or R ₁ in b) R ₂ is obtained by acting on a cephalosporin derivative of formula (I) or a mixture of these isomers, where appropriate, reducing the obtained oxide and removing the protecting groups.

Wherein R is as described above (when R is to obtain cephalosporin of general formula (XIII) containing a formyl group or acylalkyl group) [In general formula (XIVa) and general formula (XIVb) As defined) is protected as acetal.

If reactor R of a compound of formula (XV) is susceptible to interference (especially when R contains amino, alkylamino, hydroxyl, or carboxyl groups), it does not adversely affect other parts of the molecule. It is desirable to protect this group by the methods described.

The protective step in the case of an amino group, an alkylamino group, or a carboxyl group is effectively carried out under the conditions described above.

The protection process in the case of the hydroxyl implementation is a case of protecting the greed and is effectively performed by the reactor described in Patent Application No. 80-2007, or a 2,3-dihydroxy-propyl group or a 1,3-di In the case of protecting the hydroxy-prop-2-yl group, it is effectively formed in the form of a cyclic acetal.

When R ₅ is a hydrogen atom, it is preferable to protect the oxime (under the conditions as described above).

Moreover, when reactor R in the compound of general formula (XV) contains a hydroxyl group or a sulfo group, it is preferable to use the compound of general formula (I) whose value of n is zero.

This reaction is usually carried out in the presence of a base such as a pyridine or tertiary organic base. For example, diisopropylethylamine or diethylamine is used.

Alkali of the thiol of formula (XV) does not necessarily have to be present with a metal salt or, if used, an alkali metal salt.

This reaction is advantageously carried out in an organic solvent such as dimethylformamide, tetrahydrofuran or acetonitrile or a mixture of solvents as described above.

If appropriate in the presence of water it is also possible to carry out in the presence of alkali metal bicarbonate in a solvent as described above.

The reaction is carried out at temperatures between -20 ° C. and the reflux temperature of the reaction mixture, depending on the thiol used for the temperature value to be selected. Likewise, the reaction time also varies from 5 minutes to 48 hours depending on the thiol used.

If appropriate, this reaction may be carried out in the presence of nitrogen.

When R ₁ represents a reactor of the general formula (II), it is preferable to use a compound in which R ₂ is not hydrogen when trying to use the bicyclooct-3-ene of the general formula (I).

Whether or not the protecting group is removed from R before or after reducing the oxide, and also before or after removing other protecting groups, is not important.

Reduction of oxides and removal of protecting groups are carried out according to the method described in patent application 80-2007. If the dihydroxypropyl group is protected in the form of a cyclic acetal, the protecting group is removed under addition decomposition (as trifluoroacetic acid, aqueous or non-aqueous formic acid, or P-toluenesulfonic acid).

If aqueous or non-aqueous formic acid is used, the vitrification of the hydroxyl groups protected in the form of cyclic acetals is at least partly directed to the corresponding formic acid monoester or ester, and separated by chromatography as necessary.

The removal of a group of formula (XIVa) or formula (XIVb) is carried out as follows (when R is to obtain a compound of formula (XIII) containing a form group or acylalkyl group). That is, in the presence of sulfonic acid (eg methanesulfonic acid or P-toluenesulfonic acid), in an organic solvent (eg acetonitrile or acetone), optionally in the presence of water and optionally acetone, glyoxylic acid, benzaldehyde or In the presence of an acetalizable reactant such as pyruvic acid, at a temperature between 20 ° C. and the reflux temperature of the reaction mixture, or R is 5,6-dioxo-1,4,5,6-tetrahydro In the case of the -1,2,4-triazine-3-yl group (preferably containing less than 10% water) by the action of aqueous formic acid, in the presence of silica or without silica, or By transition-acetalization in the presence of a reactant that can be acetalized.

The thiols of formula (XV) used in the form of tautomers are prepared by one of the following methods, depending on the meaning of reactor R.

That is, when R is a pyrid-3-yl group, the method J. Am. Described by H. M. Wuest and E. H. Salkal. Chem. SoC, 73,1210 (1951)): Method described by B. Blank and his colleagues when R is a pyrid-3-yl-1-oxide group. J. Med. Chem. 17,1065 (1974) by reference: the method described by RAYJones and its solutions when R is a pyrid-4-yl-1-oxide group J. Chem. Soc., 2937 (1960) When R is an alkyl group, a methoxy group, or a pyridazin-3-yl group substituted by an N-oxide derivative thereof, by the method described in Belgian Patent No. 787,635: R is an amino group, or In the case of a pyridazin-3-yl group substituted by an N-oxide derivative of the compound, the method described in Belgian Patent No. 787,635: R is an amino group or a pyridazin-3-yl group substituted by an N-oxide derivative thereof. In the case of, by the method described in Belgian Patent No. 579,291: when R is an acylamino group or a pyridazin-3-yl group substituted by an N-oxide derivative of the group, M. Kuagai and Peninsula ( Method described by M. Baudo) (see Japanese Chemical Magazine, 84,995 (1963)), Chem are the methods described by the leg (T.Horie) and weda (T.Ueda). Pharm. 5,6-dioxo-1,4,5,6-tetrahydro-, wherein R is then substituted at the 4-position by the reactor R selected in a) -e) by Bull., 11,114 (1963). M. Pesson and Antoin for 1,2,4-triazin-3-yl or 2-alkoxycarbonyl-1,3,4-triazol-5-yl groups substituted at the 1-position The presence of alkali metal alcoholates, such as sodium ethylate, or sodium methylate, or potassium tert-butyllayote, by the method described by M.Antoine Bull.SoC.Chim.France (1970), 1590 Under the reaction of alkyloxalate with thiosemicarbazide of formula (XVI):

Food,

AR is as defined in a) -e).

a) an allyl group or a compound containing 1-4 carbon atoms, an alkoxy group, an alkylthio group, a phenyl group, a carboamyl group, an alkyl carbamyl group, a dialkylcarbyl group, an acyl group, an alkoxycarbonyl group or a thia Alkyl group optionally substituted by zolidin-2-yl group

b) a 2,3-dihydroxy-propyl group or a 1,3-dihydroxy-prop-2-yl group optionally substituted in the form of a cyclic acetal

c) (containing 2-4 carbon atoms, with hydroxyl, carbamyloxy, dialkylamino, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, sulfamoylamino, optionally substituted yarn Alkyl group itself substituted by an amine group, an alkoxy carbonyl amino group, a ureido group, an alkylureido group, or a dialkylureido group

d) a reactor of formula (XIVa) or formula (XIVb)

e) hydroxyiminoalkyl group or alkoxyamino group

In order to use the compound for preparing the compound of general formula (XIII), it is not necessary to purify the obtained compound (and also to liberate a protecting group).

Thiosemicarbazide of formula (XVI) is described by K.A.Jensen and his colleagues [Acta.Chem. Scand., 22, 1 (1969)] or as described by Y. Kazarov and J.Y. Potovskii [Dokalady Acad. Nauk SSSR, 134,824 (1966), the latter being protected if R contains an amino group.

The protecting step of the amino group and the removing step of the protecting group are carried out by conventional methods which do not adversely affect other parts of the molecule. In particular, tert-butoxycarbonyl groups which can be removed by addition decomposition are preferably used.

1-position by R is an alkyl group, an allyl group, or an alkoxyalkyl group, or an alkyl group substituted as defined in a) above as defined above in a) as having 1-4 carbon atoms (excluding a thiazolidin-2-yl group) In the case of the 1,3,4-triazol-5-yl group substituted in the method described by M.pesson and M.Antoine [Bull. Soc. Chim. France 1590 (1970)]: Kanaoka when R is a 1,3,4-triazol-5-yl group substituted at the 1-position by a thiazolidin-2-yl-alkyl group or a hydroxyiminoalkyl group. 1-dialkoxyalkyl obtainable from 4-dialkoxyalkyl-thiosemicarbazide by the method described by M. kanaoka (see J. pharm. Soc. Japan, 75, 1149 (1955)). By reacting cysteamine or hydroxylamine with -5-mercapto-1,3,4-triazole, respectively: 1 wherein R is optionally protected in the form of a 2,3-dihydroxypropyl group or a cyclic acetal A 1,3,4-triazol-5-yl group substituted at the 1-position by a, 3-dihydroxysp-2-yl group or R is a reactor of formula (XIVa) or formula (XIVb) If indicated, by the method J.Pharm.Soc.Japa 75,1149 described by M.Kanaoka (see 1955: substitution at the 4-position by acyloxyalkyl optionally substituted with R; In the case of a 2-alkoxycarbonyl-1,3,4-triazol-5-yl or 1,3,4-triazol-5-yl group, as described, for example, by CGKruse and his colleagues According to the method (see Tet. Lett. 1725 (1976)), 5,6-dioxo-4-hydroxyalkyl-3-5-mercapto-1,3,4-triazole, in which the mercapto group is previously protected, Or acylation of 1-hydroxyalkyl-5-mercapto-1,3,4-triazole, respectively, by conventional acylation of alcohols that do not adversely affect other parts of the molecule, followed by mercapto groups in the acid medium. Liberating: a 5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl group wherein R is substituted at the 4-position by aminoalkyl or alkylaminoalkyl Or alkoxycarbonyl-1,3,4-triazol-5-yl or 1,3,4-triazol-5-yl or 1,3,4-triazole-5 substituted at the 1-position In the case of a -group, for example, by a tert-butoxycarbonyl group The ahminreul the corresponding compound glass by:

R is a 5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl group substituted at the 4-position by sulfoaminoalkyl, or at the 1-position In case of substituted 2-alkoxycarbonyl-1,3,4-triazol-5-yl group or 1,3,4-triazol-5-yl group, it is tertiary by a method similar to that described in Belgian Patent No. 847,237. From the corresponding compound substituted by a butoxycarbonyl aminoalkyl group: R is a 1,4-dialkyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl group or 1 In the case of a -alkyl-5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-riazin-3-yl group by the method described in Belgian Patent No. 830,455: R is 2 -Alkyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4, -triazin-3-yl group or 1-alkyl-3-alkoxycarbonyl-1,2,4 For the triazole-5-diary, the method described by M. pe sson and M. Antoine [CR Acad. Sci., Ser C, 267,25,1726 (1968): R and the method described by M. Kanoka for the 1,3,4-triazole-5- diary [J. .Pharm.Soc.Japan, 75,1149 (1955), wherein R is optionally substituted by alkyl, alkoxy, alkylthio, alkylsulfonyl, amino, alkylamino, dialkylamino or acylamino groups. In the case of a 3,4-thiadiazole-5-yl group, by the method described in Belgian Patent No. 830,821: 1, wherein R is substituted by hydroxyalkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl, In the case of a 3,4-thiadiazole-5-yl group, when R is a 1,3,4-thiadiazole-5-yl group substituted by a carboxyalkyl group by the method described in German Patent Application No. 2,446,254. By the method described in German Patent Application No. 1,953,861: where R is a 1,3,4-thiadiazole-5-yl group substituted by a trifluoromethyl group By the method described in Hei. Application No. 2,162,575: R is acyl by the method described in Japanese Patent Application No. 77 / 48,666 when R is a 1,3,4-thiadiazole-5-yl group substituted by a carboxyl group. In the case of the 1,3,4-thiadiazol-5-yl group substituted by an aminoalkyl group, 1,3, wherein R is substituted by a hydroxyalkylthio group by the method described in Japanese Patent Application No. 76/80875 In the case of a 4-thiadiazole-5-yl group, the method described by G.Nannini (see Arz. Forsch. 27 (2), 343 (1977)): R is substituted by alkyl or alkoxy. Or 1,2,4-thiadiazole-5-yl group, the method described in German Patent Application No. 2,806,226, or Chem. Ber. By the method described in 90,184 (1957): If R is the 1,3,4-oxadiazole-5-yl group described in the definition of general formula (XIII) at 8a, described by E. Hoggarth. By the method [see J. Chem. Soc. 4811 (1952)]: if R is an oxazol-2-yl group or a 4-alkyl-oxazol-2-yl group, By the described method [see J.Org.Chem.32,2079]: Belgian patent 830,821 for tetrazol-5-yl groups optionally substituted in the 1-position by alkyl, hydroxyalkyl or phenyl groups By the method described in the following paragraphs: when R is tetrazol-5-yl substituted at the 1-position by an alkoxyalkyl group, sodium azide isothiocyanatoalkoxyalkyl at the reflux temperature of the reaction mixture in an organic solvent such as ethanol. By addition reaction with derivatives: this isothiocyanatoalkoxyalkyl derivative is prepared by Schmidt and his colleagues. Is obtained by the method described (see Chem. Ber. 73, 286 (1940)).

In the case of a tetrazol-5-yl group substituted at the 1-position by this carboxyalkyl group, the method described in Belgian Patent No. 858,112: R is a tetrazol-5-yl group substituted at the 1-position by a sulfoalkyl group. In the case described in Belgian Patent No. 856,498, or by methods described by DABerges and his colleagues [J. Het. Chem. 15,981 (1978)]: When R is a tetrazol-5-yl group in the 1-position by an aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl group, by the method described in German Patent Application No. 2,738,711: When R is a sulfazylalkyl group, sulfamoylaminoalkyl group, or a tetrazol-5-yl group substituted at the 1-position by a sulfoaminoalkyl group, by the method described in Belgian Patent No. 856,636: R is an acylaminoalkyl group. In the case of a substituted tetrazol-5-yl group or a 1,3,4-thiadiazol-5-yl group substituted by a hydroxyl group, the method described in US Pat. No. 4,117,123: R is a ureidoalkyl group, In the case of a tetrazol-5-yl group substituted in the 1-position by an alkylureidoalkyl group or a dialkylureidoalkyl group, the aralimetal isoty from the corresponding compound substituted by the aminealkyl in which the mercto group is previously protected. Treatment with an occyanate, or with an alkylisocyanate, or with a dialkylcarboamyl halide followed by liberation of the mercapto group under the conditions described in Belgian Patent No. 847,237; When R is a tetrazol-5-yl group substituted in the 1-position by a carboxyalkylaminoalkyl group, by the method described in German Patent Application No. 2,715,597: R is 1-position by the 2,3-dihydroxypropyl group. In case of a tetrazol-5-yl group substituted in the case of tetrazol-5-yl group substituted in the 1-position by the method described in U.S. Patent No. 4,046,242: In the case of a tetrazol-5-yl group substituted at the 1-position by a 1,3-hydroxy-prop-2-yl group, sodium azide is substituted with 2,2-dimethyl-1,3-dioxolane-5- By addition reaction with one isothiocyanate (if appropriate then liberation with a hydroxyl group): a reactor of the general formula (XIVa) as defined in the definition of general formula (XIII) in 9e, or general To the reactor of formula (XIVb), or to the reactor defined in 9c for formula (XIII) In the case of the tetrazol-5-yl group substituted at the 1-position by the method described by Os O (REOrth) (see J. Pharm. Sci 52 (9), 909 (1963)). Zide is reacted with the corresponding isothiocyanate: if R contains hydroxyl substituents, or hydroxyiminoalkyl substituents, the alcohol or greedy function is protected if appropriate, for example by tetrahydropyranyl groups.

II °) 3-thiovinyl-cephalosporin of formula (XIII) when R does not contain a substituent of formula (XIVa) can also be obtained by the following method. That is, a compound of formula (I) [as defined in II to prepare a compound of formula (I) wherein R is a hydrogen atom or R ₁ is a hydrogen atom and R has the corresponding meaning; or A mixture of these isomers is treated with thiols of the general formula (XV) (or with one of its alkali metal salts or alkaline earth metal salts) and then the sulfooxides obtained (if n = 1) where appropriate. And if appropriate, the protecting group R is removed to give the compound of formula (XVII).

[Wherein n is as described above, R ₁ and R are as defined in II above, and R has a corresponding meaning.]

This reaction is carried out under the above conditions for obtaining compounds of formula (XIII) from compounds of formula (I) and from thiols of formula (XV).

Reactor R of thiols is protected (as appropriate) as described above, and the removal of the protecting groups is effected effectively under the conditions described in patent application 80-2007.

However, it is preferable not to remove the protecting group until the compound of general formula (XIII) is obtained.

It is preferable not to remove the protecting group until a compound of the general formula (XVIII) is obtained.

The compound of the general formula (XVIII) is prepared by removing R from the compound of the general formula (XVII) when R is not a hydrogen atom or, if appropriate, simultaneously removing the protecting groups R and R from this compound.

In formula, R <_1> , R <_2> and n are as above-mentioned.

This reaction is carried out under the above conditions necessary for preparing the compound of formula (I) when R ₁ is a hydrogen atom.

3-thiovinyl-cephalosporin of general formula (XIII), wherein R, R ₁ ° and R ₂ ° are as described above, wherein 7-amino-cephalosporin of general formula (XVII) is represented by general formula (XIX) It is prepared by acylating with an acid to be formed or with a reaction derivative of the acid, and then reducing the obtained oxide (in the case of n = 1) and removing the protecting group.

R ₁ ° OH (XIX)

[Wherein, R _1. Is as described above and is selectively protected when it contains a group that interferes with the reaction.]

The amino group, or alkylamino group, present in any reactor R must be protected, and the carboxyl, hydroxyl, formyl, or acylalkyl group contained in this reactor R may be protected.

The protecting and removing step of the protecting group and the reducing step of the oxide are carried out under the conditions described in patent application 80-2007.

Moreover, when R contains a hydroxyl group, a sulfo group, a sulfinyl group, or a sulfinyl substituent, it is preferable to use the compound of general formula (XVII) whose value of n is zero.

3-thiovinyl-cephalosporin of general formula (XIII) wherein III °) R does not contain a substituent of general formula (XIVc) is a thiol ester of general formula (XX) and a 7-amino of general formula (I) To cephalosporin, where R ₁ is a hydrogen atom and R ₂ has a corresponding meaning, followed by reduction of the sulfooxide obtained when n = 1 and removal of the protecting group if appropriate. Can be.

R ₁ ′-SR (XX)

Wherein R ₁ ′ represents a reactor of formula (II) or is defined as R ₁ in b, where R is as defined above.

In this case, when R contains an amino substituent or a substituent, this substituent must be protected. When R contains a hydroxyl substituent or a carboxyl substituent, this substituent may be liberated or protected, and R is formyl. If it contains a substituent or an acylalkyl substituent, the substituent must be protected in the form of an acetal of formula (XIVa) or formula (XIVb).

Easy to interfere with the reaction reactors R ₁ 'if it is contained in, the R _1' must protect the advance. This also applies to oximes when R ₁ ′ (when R ₅ is a hydrogen atom) represents a reactor of general formula (II). Preference is also given to using compounds in which R ₁ ′ does not contain a halogen substituent.

In the above-mentioned process, when R contains a hydroxyl group, a sulfo group, a sulfonyl group, or a sulfonyl substituent, it is preferable to use the compound of general formula (I) whose value of n is zero.

The protecting and removing process of the protecting group is carried out under the conditions described in patent application 80-2007.

The reaction of thiolo-ester with 7-amino-cephalosporin of general formula (I) is carried out in the presence of an acid acceptor such as a free base, in particular pyridine or a tertiary organic base (particularly triethylamine, N, N -Diisopropyl-N-ethylamine, diethylphenylamine, or N-methylmorpholine) in general.

This reaction can be carried out with amides (eg dimethylformamide, or dimethylacetamide), ethers (eg tetrahydrofuran, or dioxane), chlorinated solvents (eg chloroform, or methylene chloride), ketones (eg acetone), or It is advantageous to carry out in an organic solvent such as nitrile (eg acetonitrile) or in a mixture of these solvents. This reaction may also be carried out in the presence of one alkali metal bicarbonate in the solvent, optionally in the presence of water.

This reaction is carried out at a temperature between −20 ° C. and the reflux temperature of the reaction mixture. Alternatively this reaction may be carried out in the presence of nitrogen.

The reduction process of S-oxide is carried out under the conditions described in patent application 80-2007. The thioloester of general formula (XX) is reacted with an acid of general formula (XIXa) or a reaction derivative of this acid to a thiol of general formula (XV) (or an alkali metal salt or alkaline earth metal salt of this thiol), and then suitable In this case, the protective group is removed.

R ₁ '-OH (XIXa)

In the formula (XIXa) R ₁ 'is R ₄ and R ₅ represents a or the reactor in the formula (Ⅱ) other than hydrogen, or R ₁ is defined as R ₁ in b.

When attempting to prepare a mixture of general formula (XIII) containing this formyl group, the reactor R is protected in the form of acetyl.

When obtaining the compound containing this carboxyl group or a sulfonyl group, it is preferable to process corresponding thiol with the reaction derivative of acid R <_1>'OH.

When trying to obtain a thiolo-ester which represents a reactor of general formula (II) as defined in the case where R ₁ ′ is R ₁ °, a tertiary-part which protects the aminothiazole by treating it in an anhydrous medium Can also remove oxycarbonyl groups

Preference is given to carrying out the reaction at 0 ° -20 ° C. with trifluoroacetic acid. The trityl group protecting the oxime is removed by hydrolysis with, for example, trifluoroacetic anhydride or the like. If necessary, the trityl group protecting the hydroxy substituent of the thiolo-ester may be effectively removed under the above conditions necessary for vitrification of the oxime.

It is advantageous to only remove the protecting group after reacting thiolo-esder with a compound of formula (I) wherein R ₁ is a hydrogen atom.

IV °) R ₁ ° is as described above in formula (II). However, _3- thiovinyl-cephalosporin of general formula (XIII) which shows the reactor of general formula (II) when R <_5> does not represent a vinyl group and R does not represent a substituent of general formula (XIVc) Obtained by the same process. That is, the compound of formula (XXI) is prepared from the compound of formula (XVIII) or from the compound of formula (XXII) by the above method used to prepare the compound of formula (VIII).

Wherein R _5, R, R _2, Hal and n are as described above.

In the formula, Hal, R ₂ , n and R are as described above.

When the compound of the general formula (XXI) is prepared from the compound of the general formula (XVIII), when R contains an amino group or an alkylamino group, R is protected in advance, and a hydroxyl group, a carboxyl group, a formyl group, or an acylalkyl group If it contains glass or protect.

When the compound of formula (XXI) is prepared from a compound of formula (XXII), when R contains an amino group, an alkylamino group, or a formyl group, R is protected in advance, and a hydroxyl group, a carboxyl group, or an acyl If it contains an alkyl group, it is free or protected.

The protecting and removing process of the protecting group is effected effectively under the conditions described in patent application 80-2007. Urea sulfide of general formula (VI) is reacted with a compound of general formula (XXI) under the above conditions used when preparing a compound of general formula (I) from a compound of general formula (VII), and then The sulfooxide obtained is reduced and, if appropriate, the protecting group is removed.

When R is to obtain a compound of formula (XIII) containing a formylalkyl group or acylalkyl group, this reactor R is protected as an acetal in the form of a reactor of formula (XIVa) or formula (XIVb) as described above. do.

The reduction process of sulfooxide and the removal of protecting group are effectively performed under the above conditions.

Cephalosporins of the general formula (XXII) are prepared from cephalosporins of the general formula (XIX) by reacting the general formula (XX) according to the above methods used to prepare compounds of the general formula (XXI).

V °) is substituted by a carbamoxyoxy group or by an alkyl group having 2-4 carbon atoms substituted by an acyloxy group (acyl moiety is optionally substituted by amino, alkamino, or dialkylamino group). 1,3,4, -tria which represents a 5,6-dioxo-1.4.5.6-tetrahydro-1,2,3-triazin-3-yl group substituted at the -position or substituted at the 1-position A sol-5-yl group or 2-alkoxycarbonyl-1,3,4-triazol-5-yl group or a 2-alkoxycarbonyl-1,3,4-triazol-5-yl group and R ₁ ° and R ₂ ° represents the corresponding meaning, and R is a 5,6-dioxo-4-hydroxyalkyl-1,4,5,6-tetrahydro-1,2,4, -triazin-3-yl group. -R selected from among, 1-hydroxyalkyl-1,3,4-triazol-5-yl groups, or 2-alkyloxycarbonyl-1-hydroxyalkyl-1,3,4-triazol-5-yl groups the -alk'-OH, R ₁ ° and R ° ₂ is a function of the organic compound represented by the general formula (XⅢ) as described above 3-thiovinyl-cephalosporin of the chain formula (XIII) is obtained by the process used to prepare esters or carbamates from alcoholols without adversely affecting other parts of the molecule, and then as appropriate It is obtained from a compound of the general formula (XIII ′) by reducing the sulfooxide and removing the protecting group.

In the formulas, R _{4 ,} R _5, R _2, R-ali'-OH and n are the same as described above _, except that they represent R ₄ hydrogen atoms.

The esterification reaction is carried out in an inert organic solvent such as ether (e.g. tetrahydrofuran), chlorinated solvent (e.g. methylene chloride) or at a mixture of these solvents at a temperature between -50 ° C and the reflux temperature of the reaction mixture. In the presence of a nitrogen-containing base such as dimethylamino-pyridine or triacylamine (triethylamine) or in the presence of an alkaline condensing agent (eg sodium bicarbonate), in particular an acid (or any other reaction derivative of diacid) Condensation of anhydrides of, for example, halides, followed by reduction of the S-oxides obtained if appropriate and removal of the protecting groups according to the methods described above.

Carbamates are obtained by known methods that do not adversely affect other parts of the molecule. In particular, in chlorosulfonyl isocyanate in an inert organic solvent such as tetrahydrofuran or acetonitrile, and at -80 ° C to 20 ° C. Or trichloroacetyl isocyanate, followed by removal of the protecting group.

VI °) R is an acylamino group, an alkoxycarbonyl amino group, a ureido group in which a sulfoamino group, an alkylsulfonylamino group, a sulfamoylamino group (acyl moiety is optionally substituted by a hydroxyl group, an amino group, an alkylamino group, or a dialkylamino group) 5,6-dioxo-1,4,5,6-detrahydro-1 substituted at the 4-position by an alkyl group having 2-4 carbon atoms substituted by an alkylureido group or a dialkyl ureido group 2,3-triazin-3-yl group, or 1,3,4-triazol-5-yl group or 2-alkoxycarbonyl-1,3,4-triazol-4-yl group substituted at the 1-position Or a 1,3,4, -oxadiazol-5-yl group represented by or substituted by an acylaminoalkyl group, or an acylamino group, sulfamoylamino group, sulfoamino group, ureido group, alkylureido group, or dialkylureido group Substituted in the 1-position by an alkyl group containing 2-4 carbon atoms And a substituted tetrazol-5-yl group, wherein R ₁ ° and R ₂ ° are as described above, and 3-thiovinyl-cephalosporin of general formula (XIII), which is a structural derivative of an amine corresponding thereto, Compounds of the general formula (XIII ′) are known by reducing the sulfooxide and removing the protecting groups, if appropriate, by known methods necessary to form amide, sulfamide, carbamate or urea groups without adversely affecting other parts of the molecule. Obtained from

Food,

-NH₂는 알킬부분이2-4개의 탄소원자를 함유하고 있는 아미노 알킬기에 의하여4-위치에서 치환된5,6-디옥소-1,4,5,6,-테트라하이드로-1,2,4-트리아진-3-일기, 또는1-위치에서 치환된1,3,4-트리아졸-5-일기 또는 2-4개의 탄소원자를 함유하는2-알콕시카르보닐-1,3,4-트리아졸-5-일기,또는 아미노알킬기에 의해 치환된1,3,4-옥사디아졸-5-일기, 또는 데트라졸-5-일기를 나타낸다.R _{4 ,} R _5, R ₂ and n are as described above, except that R ₄ represents a hydrogen atom-

-NH ₂ is 5,6-dioxo-1,4,5,6, -tetrahydro-1,2,4 wherein the alkyl moiety is substituted in the 4-position by an amino alkyl group containing 2-4 carbon atoms 2-alkoxycarbonyl-1,3,4-triazole containing a -triazin-3-yl group, or a 1,3,4-triazol-5-yl group substituted at the 1-position or 2-4 carbon atoms Or a 1,3,4-oxadiazol-5-yl group or a detrazol-5-yl group substituted by a -5-yl group or an aminoalkyl group.

It is preferable that the compound containing a sulfo group, sulfonyl group or sulfaamyl group is prepared from a compound of the general formula (XIII ′) in which the value of n is zero.

Moreover, when reactor R is to produce a compound containing an amino group or a hydroxyl group, it is necessary to protect this group R in the reactants used. Likewise, when R ₅ represents a hydrogen atom, it is necessary to protect the oxime.

Reactor R is intended to produce compounds of formula (XIII) containing alkylsulfonylamino substituents, sulfamoylamino substituents (substituted or unsubstituted), acylamino substituents, alkoxycarbonylamino substituents, or dialkoxyureido substituents When it is advantageous to carry out the reaction by treating with chlorosulfonyl, acid chloride, chloroformate or dialkylcarbamyl chloride compounds respectively.

When attempting to prepare a compound of general time (XIII) containing a reactor Rsulfoamino substituent, an alkylsulfonylamino substituent, or an (substituted or unsubstituted) acylamino substituent, it is preferable to carry out the reaction effectively by anhydrides of acids. .

An acid may be used when R intends to obtain a compound of general formula (VIII) containing an acylamino group (substituted or unsubstituted).

When R is to obtain a compound of the general formula (XIII) containing a ureido group or an alkylureido group, the corresponding compound of the general formula (XIII ′) may be prepared in an aqueous organic medium or an organic medium (eg, in tetrahydrofuran). Treatment with alkali metal isocyanates or alkyl isocyanates at temperatures between -20 ° C and 60 ° C, respectively.

The reduction process and the removal of the protecting group are carried out under the above conditions.

VII °) R is a thiazolidin-2-yl-ankyl group, a reactor of the general formula (XIVc), or a hydroxyiminoalkyl group or alkoxyiminoalkyl group wherein the aminoalkyl moiety contains 1-5 carbon atoms A 5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazol-3-yl group substituted at the 4-position, or a 1,3 substituted at the 1-position; Hydroxy imino which represents a 4-triazol-5-yl group or a 2-alkoxy-carbonyl-1,3,4-triazol-5-yl group or the iminoalkyl moiety contains 1-5 carbon atoms A tetrazol-5-yl group substituted at the 1-position by an alkyl group or an alkoxyimino alkyl group, wherein R ₁ ° and R ₂ ° are as described above, wherein a formylalkyl group wherein R is one of the heterocycle groups described above (Or its hydrate form), 3-thiovinyl-cephalosporin of the general formula (XIII) forms an addition reaction derivative of the carbonyl group. Used according to the known method required cysteamine, an alcohol-ol, respectively, hydroxyl addition reaction of hydroxylamine, or an alkoxy amine and the protective group was then hayeoseo mine is if appropriate is obtained from the compound represented by the general formula (XⅢ)

Food,

-alk'CHO는 -디옥소-4- 포름일알킬 -1,4,5,6-테트라하이드로-1,2,4-트리아진-3-일기,1-포름일알킬-1,3,4-트리아졸-5-일기,2-알콕시카르보닐-1-포름일알킬-1,3,4,-트리아졸-5-5일기,도는1-포름일알킬-테트라졸-5-일기를 나타낸다.R _2, R ₄ and R ₅ are as described above,

-alk'CHO is -dioxo-4-formylalkyl -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl group, 1-formylalkyl-1,3,4 A -triazol-5-yl group, 2-alkoxycarbonyl-1-formylalkyl-1,3,4, -triazol-5-5yl group, or FIG. 1 represents a 1-formylalkyl-tetrazol-5-yl group .

This reaction is generally carried out at temperatures between 20 ° C. and the reaction mixture at reflux in an organic solvent.

The organic solvent is selected according to the solubility of the compound. That is, when the compound of R ₄ and R ₂ singer small formula (XⅢ '), not been used as tetrahydrofuran, acetonitrile, to use a solvent such as alcohols ol or a ketone is advantageous that .R ₄ and R ₂ When a compound of the general formula (XIII ′) which is hydrogen is used, it is advantageous to carry out the reaction in a solvent such as pyridine, dimethylsulfooxide or dimethylformamide.

When reactor R is to produce a compound of formula (XIII) containing a substituent of formula (XIVc), the reaction is carried out in an acid medium.

VIII。) R _2。 represents a reactor of formula (V), wherein and when R ₉ is as described above, 3-thiovinyl-cephalosporin of formula (XIII) adversely affects other parts of the molecule. By a known method for producing an ester from an acid as a method which does not extend, R ₂ may be obtained by esterifying a compound of the general formula (XIII) in which the amine moiety is previously protected.

Isomers of compounds in general formula (VII), general formula (XI), general formula (XVIII), general formula (XXI), or general formula (XXII) where n has a value of 1 are determined by chromatography or crystallization. Can be separated.

The novel compounds according to the invention, and the compounds of general formula (XIII), may be optionally purified by physical methods such as crystallization or chromatography.

New compounds of formula (I) in which amino groups are present can be converted to addition salts with acids. According to the method indicated as follows, this compound can be obtained in the form of a solution of trifluoroacetate, para-toluenesulfonate, or formic acid. However, the compounds obtained in the form of salts can be liberated by conventional methods and converted to salts of other acids.

The compound of general formula (I) containing a carboxyl group can be converted into a metal salt or an addition salt with a nitrogen-containing organic base group according to a known method. These salts can be reacted with metal bases (such as alkali metal bases or alkaline earth metal bases) or by amines in the appropriate solvents such as alcohols, ethers, or water to the compounds of general formula (I) or exchanged with salts of organic acids. Can be obtained by reaction. This salt can be isolated by filtration or, depending on necessity, forming a precipitate after concentrating the solution as needed.

Examples of salts include alkyl metal salts (e.g., salts of sodium, sodium, or ricin), or alkaline earth metal salts, salts of nitrogen-containing bases (dimethylamine salts, diethylamine salts, diisopropylamine salts, dicyclohexylamine salts). , N-ethylpiperidine salts and N-methylmorphlin salts, and addition salts of inorganic acids (such as hydrochloride or hydrobromide), or addition salts of organic acids (such as formate, trifluoroacetate, p-toluenesulfonate, Naphthalenesulfonate or oxalate), and the like.

The cephalosporin derivatives of formula (XIII) and their pharmaceutically acceptable salts, as defined above in α), exhibit particularly valuable antibacterial properties. Their gram-positive and gram-negative bacteria show significant activity in vitro and in organisms. In vitro, they were 0.001-1 mg for Escherichia coli, Monod starin at concentrations of 0.5-15 mg / cc for strains of Staphylococcus sensitivity to penicillin G (staphylococcus aureusSmith). Activity was demonstrated at a concentration of / cc and at a concentration of 0.06-30 mg / cc for Klebsiella Penumoniae.

Moreover, some of these compounds have been demonstrated to be active at concentrations of 0.01-30 mg / cc for Proteus morganii and 0.1-30 mg / cc for Enterobacter age rogenes.

In living organisms, these compounds are administered to subcutaneous tissue at a dose of 0.2-13 mg / kg of Staphylococcus aurecress smith (sensitive to penicillin G) daily, and also Escherichia coli (monotransformation0 daily). Activity was demonstrated through experimental inoculation of mice administered to subcutaneous tissue at a dose of 0.001-10 mg / kg.

Furthermore, LD ₅₀ of the compound of general formula (XIII) is the value between the doses of greater than 1.5 g / kg and 2.5 g / kg in the rat subcutaneous tissue administration.

The antibacterial properties of the derivatives of cephalosporin of the general formula (XIII) as defined in β) above, as well as the compounds as intermediates for the preparation of antibacterial substances, are described in US Pat. No. 4,065,620. .

Compounds of formula (I) in the same case of a) -b) are particularly useful. In other words,

a) symbol R ₁ is a hydrogen atom, a reactor of formula (II), a trityl group, a reactor of R ₆ CC- (wherein R ₆ is an alkyl group containing 1-2 carbon atoms optionally substituted by a phenyl group or a phenoxy group) Phenyl group), or a reactor of the general formula R ₇ OCC- (wherein R ₇ is an unsubstituted alkyl group), and symbol R ₂ represents a hydrogen atom, a benzhydryl group, or a P-nitrilebenzyl group, or

의 반응기(Q가 수소원자이며Ar온 티에닐기임) 또는 일반식 Ar

의 반응기 (Ak은 페닐기이며 B는 알콕시카르보닐기이에 의해 선택적으로 보호된 아미노기를 나타냄) 이며, 또한 기호 R₂는 수소원자 또는 벤즈히드릴기 또는P-니트로벤질기이며, 기호R₃'가 R₃'와 같이 정의되거나 혹은 아실메틸기이며, n의 값은 0또는1인 일반식 R₃'-SO₂C-또는 일반식 R₃'-COC-의 반응기를 나타내는 경우, 이 화합물중에서 일반식(I)의 특히 바람직한 화합물은 다음 a)- b)와 같은 경우의 것이다.b) symbol R ₁ is:

In which Q is a hydrogen atom and is an ar-on thienyl group, or

Is a phenyl group and B represents an amino group optionally protected by alkoxycarbonyl group, and the symbol R ₂ is a hydrogen atom or a benzhydryl group or a P-nitrobenzyl group, and the symbol R ₃ ′ is R ₃ Or a compound of formula R ₃ '-SO ₂ C- or general formula R ₃ ' -COC-, wherein the compound is defined as' or is an acylmethyl group and the value of n is 0 or 1, Particularly preferred compounds of) are those in the following cases a)-b).

a) Symbol R ₁ is a hydrogen atom, a reactor of the general formula (II) (R ₄ is a hydrogen atom or a protecting group such as trityl, R ₅ is an alkyl group, a vinyl group, or a cyanomethyl group) Trityl group, general formula R ₆ CC- reactor (with R ₇ being an unsubstituted alkyl group), or

CH₂CO-의 반응기이거나, Ar이 페닐기이며, B는 아미노기 또는 3급-부톡시카르보닐아미노기인 일반식

의 반응기이고, 기호 R₂는 상기 a)에서 정의된 바와 같으며, 기호 R₃'는R₃'가 토실기 또는 메틸기이며, R₃'가 아세틸기에 의해 선택적으로 치환된 메틸기의 일반식(IV)또는 일반식(V)의 반응기를 나타내고, n의 값은0또는1인 경우 그리고 특히 다음과 같은 화합물:b) symbol R ₁ is a general formula

A reactor of CH ₂ CO-, wherein Ar is a phenyl group, B is an amino group or a tert-butoxycarbonylamino group

Symbol R ₂ is as defined in a) above, symbol R ₃ ′ is a general formula (IV) of methyl group wherein R ₃ ′ is a tosyl group or a methyl group, and R ₃ ′ is optionally substituted by an acetyl group. Or when the value of n is 0 or 1 and in particular the following compounds:

2-benzhydryloxycarbonyl-7-tert-butoxycarbonyl-amino-8-oxo-3-(2-tosyloxy-vinyl) -5-thia-1-aza-bicyclo [4,2 , 0] octo-2-ene, E-form.

2-benzhydryloxycarbonyl-7-tert-butoxycarbonyl-amino-8-oxo--5-oxide-3- (2-tosyloxy-vinyl) -3-thia-1-aza-bi Cyclo [4,2,0] octo-2-ene, Z-form.

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-trityl-amino-thiazol-4-yl) acetamido] -3-oxo-3- (2-tosyl Oxy-vinyl) -3-thia-1-aza-bicyclo [4,2,0] octo-2-ene, syn isomer, E-form.

2-Dizhydryloxycarbonyl-7- [2-methoxyimino--2- (2-tritylamino-thiazol-4-yl) -acetamido] -8-oxo-5-oxide-3 -(2-tosyloxy-vinyl) -5-thia-1aza-bicyclo [4,2,0] oct-2-ene, syn isomer, E-form.

7-amino-2-benzhydroxycarbonyl-3-oxo-3- (2-tosyloxy-vinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene, E-form.

The following examples illustrate how the invention is practiced, and do not limit the invention thereto. In these examples, the compounds were named according to the chemical abstract nomenclature. All compounds are partially general formula

It is named to indicate the stereochemistry attributable to

Example 1

2-benzhydryloxycarbonyl-7-tert-butoxycarbonyl-amino-8-oxo-3- (2-oxo-ethyl) -5-oxide-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (52.4 mg) was dissolved in pyridine (2CC). This solution was cooled to -15 and P-toluene sulfonyl chloride (21 mg) was added. The reaction mixture was stirred at -15 ° C for 5 minutes, and then at -15 ° C-0 ° C for 1 hour. This was then poured into distilled water (50 cc). The mixture was extracted with ethyl acetate (50cc) and the organic phase was washed with 0.1N hydrochloric acid (2x50cc) and then again with distilled water (2x50cc) which was dried over sodium sulphate and filtered and temperatured at 30 ° C. The solvent was evaporated under reduced pressure (20 mmHg).

2-benzhydryloxycarbonyl-7-tert-butoxycarbonylamino-8-oxo-3-5oxide-3- (2-tosyloxy-vinyl) -3-thia-1-aza-bicyclo Z- and E-form mixtures (66 mg) of [4,2,0] oct-2-ene were obtained in the form of orange bubbles. Preparative chromatography was carried out on a silica gel chromatography plate where cyclohexane and ethyl acetate were used. Using a mixture having a volume ratio of 50:50 as a solvent] The two forms were separated from each other. Z-shape:

Infrared spectrum (CHBr ₃ ): characteristic band at 3420,1800,1720,1505,1380,1370,1195,1180,1050,1010 and 730 (cm ⁻¹ ).

) :7.77 (d,J= 9,2H, 토실기의 오르도-위치에 H). E-형태(40mg):Quantum Hex Resonance Spectrum (350MHz, CDCl ₃ , δ in ppm, J in Hz): 1.49 (s, 9H, -CONH-): 5.81 (dd, J = 4.5 and 9.1,7-position): 6.42 (d, J = 19,2H, -SCH _2- ): 4.44 (d, J = 7,1H, = CH ₂ -OSO _2- ): 6.89 (s, 1H-COOCH

): 7.77 (d, J = 9,2H, H in the ortho-position of the tosyl group). E-form (40 mg):

Infrared spectrum (CHBr ₃ ): characteristic bands in 3420,1800,1720,1505,1308,1370,1195,1180, 1075,935 and 745 (cm ⁻¹ ).

Quantum hex resonance spectrum (350 MHz, CDCl ₃ , δ is in ppm, J is in Hz): 1.48 (s, 9H, (CH ₃ ) ₃ C-): 2.46 (s, 3H, -CH ₃ ): 3.16 and 3.81 (2d, J = 18,2H, -SCH _2- ): 4.46 (d, J = 4.51H, H at C-position): 5.73 (d, J = 9,1H, -CONH-): 5.8 (dd , J = 9 and 4.51H, H in 7-position: 6.83 (s, 1H, COOCH): 7.08 (d, J = 13.1H, = CH-OSO _2- ): 7.73 (d, J = 9,2H , Ortho-ortho-at position H)

2-Benzhydryloxycarbonyl-7-tert-butoxycarbonyl-amino-8-oxo-3- (2-oxo-ethyl) -5-oxide-5-thia-1-aza bicyclo [4 , 2,0] oct-2-ene can be prepared by the following method.

2-Benzhydryloxycarbonyl-7-tert-butoxycarbonyl-amino-3- (2-dimethylamino-vinyl) -3-oxo-5-thia-1-aza-bicyclo [4,2 , 0] oct-2-ene (E-form) (2.7 g) was dissolved in tetrahydrofuran (54 cc). Distilled water (27 g) and pure formic acid (2.7 cc) were added successively, and the reaction mixture was stirred at 25 ° C. for 40 minutes. The reaction mixture was partially concentrated under reduced pressure (20 mmgh) at 30 ° C., then ethyl acetate (200 cc) was added to separate the organic phase and washed with saturated brine solution (2 × 100 cc). The organic phase was then dried over magnesium sulphate in the presence of decolorized charcoal, filtered and concentrated to dryness under reduced pressure (200 mmHg) at 30 ° C., whereby an orange foam (2.3 g) was obtained, which was subjected to no further purification. It can be used.

A solution (1.02 g) of the foam thus obtained was dissolved in methylene chloride (100 cc) was cooled to a temperature between −5 ° C. and 0 ° C. A methylene chloride (40 cc) solution of 85% pure meta-chloroperbenzoic acid (0.35 g) was added dropwise for 20 minutes. After completion of the dropwise addition, the reaction mixture was stirred for 10 minutes at a temperature between -5 ° C and 0 ° C, washed with a semisaturated aqueous sodium bicarbonate solution (50cc), and then again with distilled water (3 x 500c). The solvent was dried over sodium sulphate, filtered and evaporated to dryness under reduced pressure (20 mmHg) at 30 ° C. The residue at this time was redissolved in methylene chloride (25 cc). Silica (0.56-0.2 mm) (5 g) was added.

The mixture was evaporated at 30 ° C. and 400 mm Hg until it was dried, and the obtained powder was premixed so that the volume ratio of cyclohexane and ethyl acetate was 80:20, and the column (column height of 25 g) = 21 cm, diameter = 2 cm). The volume mixing ratio of cyclohexane and ethyl acetate was continuously eluted as the following mixture. That is, an aliquot of 60 cc was collected at 80:20 (100 cc), 70:30 (200 cc), 60:40 (400 cc), 50:50 (400 cc), and 40:60 (400 cc). The 10-21 aliquots were concentrated to dryness at 30 ° C. under reduced pressure (20 mmHg). 2-benzhydryloxycarbonyl-7-3-grade--butoxycarbonylamino-3-oxo-3- (2-oxo-ethyl) -5-oxide-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (0.2 g) was obtained as an orange bubble.

Rf = 0.32: silica gel chromatography plate: eluent: cyclohexane and ethyl acetate in a volume ratio of 80:20.

Infrared spectra (CHBr ₃ ): characteristic band in 2720, 1800, 1720 and 1050 (cm ⁻¹ ).

Quantum nuclear magnetic resonance spectra (350 MHx, CDCl ₃ δ in ppm): 1.47 (s, 9H, (CH ₃ ) ₃ CO-): 3.37 and 3.57 (2d, AB J = 19 Hz, 2H, -CH ₂ CHO) 3.60 and 4.20 (2d, AB, J = 18 Hz, 2H: -SO-CH _2- ); 4.46 (d, J = Hz, 1H, H at 6); 5.44 (d, J = 10, Hz, 1H -CONH-); 5.82 (dd, J = 10Hz and 4Hz, 1H, 7-position H): 6.87 (S, 1H, -CH (C ₆ H ₅ ) ₂ : 7.2-7.5 (Hump 10H, directional) : 9.55 (d, J = 1Hz, 1H, CHO)

2-benzhydryloxycarbonyl-7-tert-butoxycarbonyl-amino-3amino-3- (2-dimethylamino-vinyl) -3-oxo-5-thia-1-aza-bicyclo [ 4,2,0] octene (E-form) is prepared by the following method.

That is, a solution obtained by dissolving dimethoxydimethylaminomethane in anhydrous N, N-dimethylformamide (12cc) at 25 ° C., 2-benzhydryloxycarbonyl-7-tert-butoxycarbonylamino-3-methyl-8 Oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (2.4 g) dissolved in anhydrous N, N-dimethylformamide (12 cc) in a dry nitrogen atmosphere. Was added. The reaction mixture was heated at 80 ° C. for 3 hours 20 minutes and poured into a mixture of ethyl acetate (150 cc) and distilled water (150 cc). The aqueous phase was poured gently and extracted with ethyl acetate (100 cc). The combined organic solution was washed with distilled water (2 × 100 cc), then dried over magnesium sulfate and filtered. The solvent was evaporated under 30 ° C. dark (20 mmHg) to give a brown foam (2.7 g). Thin membrane Chromatographica gel: cyclohexane A mixture of 60:40 with a volume ratio of ethyl acetate and ethyl acetate was used as the eluent and infrared spectra showed that the impurities were mainly 2-benzhydryloxycarbonyl 7-tert-butoxycarbonylamino-3- (2- It was found that dimethylamino-vinyl) -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (E-form).

Rf = 0.29: silica gel chromatography plate A mixture of cyclohexane and ethyl acetate having a volume ratio of 50:50.

2-benzhydryloxycarbonyl-7-tert-butoxycarbonyl-amino-3-methyl-8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-2- The yen is produced by the following method. In other words,

Diphenyl diazomethane (116.5 g) in acetonitrile (800 cc) was dissolved in 7-tert-butoxycarbonylamino-2-carboxy-3-methyl-8-oxo-5-thia-1-aza- A solution of bicyclo [4,2,0] oct-2-ene (188.6 g) in acetonitrile (2100 cc) was added dropwise at a temperature of 25 ° -30 ° C for 45 minutes. The reaction mixture was stirred at 22 ° C. for 16 hours and then concentrated to dryness under reduced pressure of 40 ° C. (20 mmHg). The residue was redissolved in ethyl acetate (2 liters) and the solution was dissolved in 2N hydrochloric acid (700 cc). After washing with, it was again washed with saturated aqueous sodium bicarbonate solution (700cc) and saturated brine solution (700cc). The solution was dried over sodium sulphate, treated with turquoise charcoal, filtered and concentrated to dryness under 40 ° C. (20 mmHg). This residue was redissolved in boiling ethyl acetate (600 cc). Cyclohexane (1 liter) was added and the mixture was heated to reflux, left to cool. The crystals shown at this time were filtered off, washed with diethyl ether (3 × 250 cc) and dried. 2-benzhydryloxycarbonyl-7-3-tert-butoxycarbonylamino-3-methyl-8-oxo-5-thia-1-aza-bicyclo [4,2,0] -oct-2 -Ene (191 ° C) was obtained in the form of white crystals (mp = 179 ° C). The mother liquor was concentrated to 500 cc to obtain a second aliquot of the compound (32.6 g, m.p = 178 ° C).

7-tert-butoxycarbonylamino-2-carboxy-3-methyl-8-oxo-5-thia-1-aza-bicyclo [4,2,0] -oct-2-ene is That is obtained by the method

7-amino-2-carboxy-3-methyl-8-oxo-5-thia-1-aza-bicyclo- [4,2,0] -oct-2ene- (371 g) was dissolved in sodium bicarbonate ( 307 g) is dissolved in an aqueous solution to a mixture of distilled water (2 liters). A solution of di-tert-butyl-carbonate (421 g) in dioxane (2 liters) was added for 10 minutes. The reaction mixture was stirred at 25 ° C. for 48 hours. The resulting suspension was concentrated at 50 ° C. (20 mmHg) to a residual volume of about 2 liters, and then diluted with ethyl acetate (1 liter) and distilled water (2 liters). It was. The aqueous phase was poured gently and washed with ethyl acetate (500 cc), then acidified to pH = 2 with 6N hydrochloric acid in the presence of ethyl acetate (1500 cc). The aqueous phase was extracted with ethyl acetate (2x1 liters). The combined organic phases were washed with saturated brine solution (2 × 250 cc) and then dried over sodium sulphate. After filtration was completed, the solvent was evaporated under reduced pressure (20 mmHg) at 50 ° C. to form 7-tert-butoxycarbonylamino-2-carboxy-3-methyl-3 in the form of yellow crystals (mp = 190 ° C., decomposition). -Oxo-3-thia-1-aza-bicyclo [4,2,0] oct-2-ene (486 g) was obtained.

Example 2

2-benzhydryloxycarbonyl-7-tert-butoxycarbonylamino-3- (2-oxoethyl) -8-oxo-5-thia-1-aza-bicyclo [4,2,0] A solution of oct-2-ene (10 g) and p-toluenesulfonyl chloride (4.57 g) in methylene chloride (100 cc) was stirred at 20 ° C. Triethylamine (3.1 cc) dissolved in methylene chloride (10 cc) was added to the solution for 5 minutes. The mixture was further stirred at 20 ° C. for 1 hour. The solution was then washed with saturated aqueous sodium bicarbonate solution (2x150cc) and water (2x150cc). The organic phase was dried over magnesium sulphate and concentrated to dryness under 40 ° C. pressure (20 mmHg). At this time, a brown residue (14.2 g) was obtained and chromatographed on a column (silica = 24 cm) containing silica gel (60 g). Elution was carried out with a mixture (1000 cc) having a volume ratio of ethyl acetate and cyclohexane of 3: 7 to collect an aliquot of 100 cc. Concentrated to dryness. At this time, a mixture of the following four compounds was obtained.

A: 2-benzhydryloxycarbonyl-7-tert-butoxycarbonylamino-8-oxo-3- (2-tosyloxy-vinyl) -5-thia-1-aza-bicyclo [4, 2,0] oct-3-ene, E-form.

A: 2-benzhydryloxycarbonyl-7-tert-butoxycarbonylamino-8-oxo-3- (2-tosyloxy-vinyl) -5-thia-1-aza-bicyclo [4, 2,0] oct-2ene, E-form.

A: 2-benzhydryloxycarbonyl-7-tert-butoxycarbonylamino-8-oxo-3- (2-tosyloxy-vinyl) -5-thia-1-aza-bicyclo [4, 2,0] oct-3-ene, E-form.

A: 2-benzhydryloxycarbonyl-7-tert-butoxycarbonylamino-8-oxo-3- (2-tosyloxy-vinyl) -5-thia-1-aza-bicyclo [4, 2,0] oct-2ene, E-form.

The quantum nuclear magnetic resonance spectra of these four compounds (350 MHz CDCl ₃ , δ is ppm unit, J is Hz unit) to investigate the characteristics of these four compounds are as follows.

CH=(벤즈하이드릴),C):6.85(S,

CH-(벤즈하이드릴), D):6.87(S,CH(벤즈하이드릴), A):6.88(d, J=12, -CH=CH-O-,B) : 6.90(S,CH(벤즈ㅏ이드릴), B): 6.95(d,J=12, -CH=CH-O-, B): 7.20-7.45 및 7.65-7.85(2m, 방향성).A: 40, B: 35%, C: 15%, D: 10%, 1.48 (S, (CH ₃ ) ₃ C-, A + B + C + D): 2.41 (S, -CH ₃ (tosyl) , B + D) 2.43 (S, -CH ₃ (tosyl), A + C): 3.39 and 3.47 (2d, J = 18-SCH _2- , B); 5.54 (d, J = 7, -CH = CH -O-, C) 5.25-5.40 (m, H ₇ , A + C, -NH-, A + B + C + D) 5.55 (dd, J = 7, -CH = 5.62 (dd, J = 4 and 9, H ₇ , B) 5.91 (d, J = 12, -CH = CH-O-, A): 6.14 (d, J = 7, -CH = CH-OD): 6.21 (S, H ₄ , D ): 6.42 (dJ = 7 -CH = CH-O-, A): 6.80 (S,

CH = (benzhydryl), C): 6.85 (S,

CH- (benzhydryl), D): 6.87 (S, CH (benzhydryl), A): 6.88 (d, J = 12, -CH = CH-O-, B): 6.90 (S, CH ( Benzhydride), B): 6.95 (d, J = 12, -CH = CH-O-, B): 7.20-7.45 and 7.65-7.85 (2m, directional).

2-benzhydryloxycarbonyl-7-tert-butoxycarbonylamino-8-oxo-3- (2-oxoethyl) -5-thia-1-aza-bicyclo [4,2,0] Oct-2-ene is prepared by the following method. In other words,

2-benzhydryloxycarbonyl-7-tert-butoxycarbonylamino-3- (2-dimethylamino-vinyl) -8-oxo-5-thia-1-aza-bicyclo [4,2, 0] Oct-2-ene (E-form) (5.5 g) (obtained as described in Example 1) in pure formic acid (40 cc) was kept at 0 ° C. for 3 minutes and ethyl acetate (300 cc) After dilution with, the compound was treated with distilled water (100 cc). The organic phase was poured gently and this organic phase was washed successively with distilled water (100 cc), saturated aqueous sodium bicarbonate solution (100 cc) and saturated salt (100 cc), dried over magnesium sulfate and filtered. Evaporation under reduced pressure gave an orange-brown foam (5.1 g), the characteristic of which was the same as that of the compound obtained in Example 4 of Patent Application No. 2007 of 1980.

Example 3

2-benzhydryloxycarbonyl-7-tert-butoxycarbonylamino-3- (2-tosyloxyvinyl) -5-thio-1-aza-bicyclo [4,2,0] oct-2 To a solution of p-toluenesulfonic acid hydrate (3.49 g) in acetonitrile (25 cc) was added dropwise for 25 minutes to a 35 ° C. solution of -ene (E-form) (6.1 g) dissolved in acetonitrile (75 cc). The mixture was stirred at 35 ° C. for 45 minutes, which was extracted with saturated sodium bicarbonate, carbonate solution (500 cc), the organic phase was washed with water (100 cc), dried over sodium sulfate, filtered and 20 ° C. 20 mm Hg (2.7 kPa) and concentrated to dryness. Thus 7-amino-2-benzhydryloxycarbonyl-8-oxo-3- (2-tosyloxyvinyl) -5-thia-aza-bicyclo [4,2,0] oct-2-ene (E-form) (4.7 g) was obtained in the form of a brown foam.

Rf = 0.18 Silica gel chromatography plate: A mixture in which the volume ratio of cyclohexane and ethyl acetate is 50:50 is used as the eluent.

2-benzhydryloxycarbonyl-7-tert-butoxycarbonylamino-8-oxo-3- (2-tosyloxy-vinyl) -5-thia-1-aza-bicyclo [4,2, 0] oct-2-ene (E-form) is prepared as described in Example 5 below.

Example 4

7-amino-2-benzhydryloxycarbonyl-8-oxo-3- (2-tosyloxy-vinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (E-form) (4.7 g) was dissolved in acetone (50 cc), water (5 cc) and sodium bicarbonate (2.8 g) and 4-bromo-2-methoxyimino in a solution cooled to -10 ° C. A solution of 3-oxo-butyryl chloride (syn isomer) (2 g) in acetone (10 cc) was added over 7 minutes. The mixture was stirred at −10 ° C. for 1 h and concentrated to dryness at 20 ° C., 20 mm Hg (2.7 kPa).

Crude 2-benzhydryloxycarbonyl-7- (4-bromo-2-methoxyimino-3-oxo-butyrylamino) -3-oxo-3- (2-tosyloxy-vinyl) -5 -Thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, E-form) (11 g) was obtained.

The crude compound (5 g) thus obtained was dissolved in tetrahydrofuran (25 cc) and poured into a solution of thiourea (0.5 g), water (50 cc) and ethanol (25 cc) at 20 ° C. for 5 minutes. The mixture was stirred at 20 ° C. for 30 minutes and concentrated to dryness at 20 ° C., 20 mm Hg (2.7 kPa). The residue is collected in ethyl acetate (150 cc), the organic phase is poured gently, washed with water (2 x 100 cc) and saturated brine solution (100 cc), dried over sodium sulphate and filtered, then dried at 20 <0> C under 20 mmHg. Concentrated. The compound thus obtained was chromatographed on a column of Merck silica gel (0.04-0.06 mm) (120 g) (diameter = 4 cm, height = 20 cm).

50 cc) of an aliquot was collected by elution with a mixture (2 liters) with a volume ratio of cyclohexane and ethyl acetate of 30:70. An aliquot of 16-38 was concentrated at 20 ° C. at 20 mmHg (2.7 kPa) to give 7-2- (2-amino-thiazole-vinyl) -5-thia- (aza-bicyclo [4,2,0] octo- 2-ene (syn isomer, E-form) (0.75 g) was obtained in the form of a cream solid.

7-amino-2-benzhydryloxycarbonyl-8-oxo-3- (2-tosyloxy-vinyl) -5-thia-1-aza-bacyclo [4,2,0] oct-2-ene (E-form) is prepared as described in Example 3.

4-Bromo-2-methoxyimino-3-oxo-butyryl chloride (synd isomer, E-form) (0.75 g) was obtained in creamy form.

7-amino-2-benzhydryloxycarbonyl-8-oxo-3- (2-tosyloxy-vinyl) -5-thia-1-aza-bacyclo [4,2,0] oct-2-ene (E-form) is prepared as described in Example 3.

4-Bromo-2-methoxyimino-3-oxo-butyryl chloride (syn isomer) can be prepared by the following method. That is, two drops of dimethylformamide were dropped into a 20 ° C. solution of 2-methoxy imino-3-oxo-butyl acid (syn isomer) (0.48 g) in diethyl ether (50 cc), followed by ethyl ether (50 cc). Oxalyl chloride (2cc) dissolved in) was added dropwise over 15 minutes. The mixture is stirred at 20 ° C. for 1 hour, 1 drop of dimethylformamide is added and the reaction is continued for 15 minutes. The compound is concentrated to dryness at 20 ° C., 20 mmHg (2.7 kPa), and the residue is collected in petroleum ether (2 × 30 cc) and the solvent is increased each time at 20 ° C., 20 mmHg (2.7 kPa).

The 2-methoxyimino-3-oxo-butanyl chloride (syn isomer) thus obtained was dissolved in methylene chloride (50 cc), and 5.4 N solution (0.2 cc) and bromine (1.14 cc) in which hydrogen chloride was dissolved in ether were dissolved at 20 ° C. This solution is added at. The mixture was stirred at 20 ° C. for 20 hours and concentrated to dryness at 20 ° C., 20 mmHg, and then brown oil (5.42) consisting mainly of 4-bromo-2-methoxyimino-3-oxo-butyrenechloride (syn isomer) g) is obtained.

Quantum nuclear magnetic resonance spectrum (350 MHz, CDCl ₃ , δ in ppm J in Hz): 4.25 (S, 3H, -OCH ₃ ); 4.34 (S, 2H, -CH ₂ -)-2-methoxyimino-3-oxo-butyl acid (syn isomer) is prepared by the following method. In other words

A mixture of ethyl 2-methoxyimino-3-oxo-butyrate (syn isomer) (52 g), ethanol (300 cc) and sodium hydroxide solution of 1 (330 cc) is heated at reflux for 15 hours. Ethanol is evaporated at 20 ° C., 20 mmHg (2.7 kPa) and the residue is extracted with methylene chloride (150 cc). The aqueous phase is treated with charcoal (1 g), filtered, saturated with brine, cooled to 4 ° C. and acidified to pH = 2 by addition of 2N hydrochloric acid in the presence of methylene chloride (200 cc). The aqueous phase is reextracted with the same solvent (2 × 100 cc) as before, followed by ethyl acetate (6 × 200 cc). The organic phases are dried over sodium sulphate and concentrated to dryness separately at 20 ° C., 20 mm Hg (2.7 kPa). The residue is combined and treated with diisopropyl ether (80 cc) for 4 hours with very vigorous stirring. The obtained crystals were filtered off and dried to yield 2-methoxyimino-3-oxo-butyl acid (syn isomer) (8.9 g).

Infrared spectra (CHCl ₃ ): characteristic bands of 3400, 2830, 2300, 1730, 1695, 1370 and 1035 (cm ⁻¹ ).

Quantum nuclear magnetic resonance spectrum (60 MHz, CDCl ₃ , δ in ppm J in Hz): 2.48 (S, 3H, CH ₃ CC−): 4.18 (S, 3H, —OCH ₃ ); 11.2 (S, 1H, -COOH).

Ethyl-2-methoxyimino-3-oxo-butyrate (syn isomer) is prepared by the method of R. Bucurt and his colleagues (Terahedrch 34, 2233 (1978)).

Example 5

2-benzhydryloxycarbunyl-7-tert-butoxycarbonylamino-8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicychloride ( 75 cc) and dimethylacetamide (4.62 cc) and reduced to phosphorus trichloride (2.03 cc) as described in Korean Patent Application 2007/1980 Example 24. Chromatography on silica gel using a mixture of cyclohexane and ethyl acetate in a volume ratio of 50:50 as an eluent results in 2-benzhydryloxycarbonyl-7-tert-butoxycarbonyl-amino-8- Oxo-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (E-form) (6.1 g) was obtained.

Infrared spectrum (CHBr ₃ ): characteristic bands in 3425,1780, 1720, 1505, 1370, 1190, 1180, 1075 and 760 (cm ⁻¹ ).

);6.90(d, J=12, 1H, =CHS-).Quantum nuclear magnetic resonance spectrum (350 MHz, CDCl ₃ , δ in ppm J in Hz): 1.50 (S, 9H, -C (CH ₃ ) ₃ ); 2.42 (S, 3H, -CH ₃ ); 3.35 and 3.42 (2d, J = 18, 2H, -SCH _2- ); 4.92 (d, J = 4, 1H, H in 6-position); 5.59 (ddm J = 5 and 9, 1H, H in the 7-position); 6.84 (d, J = 12, 1H, -CH = CHS-); 6.88 (S, 1H, -C00CH

; 6.90 (d, J = 12, 1H, = CHS-).

According to the invention the following compounds can also be prepared. 2-benzhydryloxycarbonyl-7-2-methoxyimino-2-2) -trityl-amino-thiazol-4-yl) -acetamino-8-oxo-3- (2-tosyloxy (E-form) [nuclear magnetic resonance spectrum (350 MHz, CDCl ₃ , δ in ppm) of -vinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene And 3.49 (AB, J = 19 Hz, 2H, -S-CH ₂ -cepem); 5.07 (d, J = 4 Hz, hydrogen at 6 positions); characteristic at 5.092 (dd, J = 4 and 9 Hz, hydrogen at positions 7)].

2-benzhydryloxycarbunyl-7-tert-butoxycarbonylamino-2- (2-tritylamino-thiazol-4-yl) -acetamido-8-oxo-3- (2- E-form [Nuclear Magnetic Resonance Spectrum (350MHz, CDCl ₃ , δ is ppm) -5.07 (of tosyloxy-vinyl) -5-thia-1-aza-bicyclo [4,2,0] oct-3-ene Hydrogen at S, 1H, 2); 5.32 (d, J = Hz, hydrogen at position 6); 5.68 (dd, J = 4 and 9 Hz, hydrogen at position 7); Characteristic at 6.19 (S, 1H, hydrogen at position 4)].

2-benzhydryloxycarbunyl-7- [2-methoxy-iandno-2- (2-tritylamino-thiazol-4-yl) -acetamido-3- (2-dimethylamino- Vinyl) -8-oxo-5-thia-1-aza-bicyclo [4,2,0] oct-3-ene.

Rf = 0.18 [silica gel chromatography: mixture of cyclohexane and ethyl acetate with a volume ratio of 50:50 is used as the eluent].

Infrared spectrum (CHBr ₃ solution): Characterized at 1765 cm ⁻¹ (carbonyl group of β-lactam) and 1610 cm ⁻¹ (double bond of enamine).

Nuclear magnetic resonance spectra (350 MHz, CDCl ₃ , δ are in ppm: 2.87 (S, 6H, (CH ₃ ) ₂ N-); 2.98 and 3.15 (AB, J = 14 Hz, 2H, -S-CH ₂ -cepem) ; 4.08 (S, 3H, = NOCH ₃ ); 5.12 (d, J = 4 Hz, 1H, hydrogen at position 6); 5.51 (dd, J = 4 and 8 Hz, hydrogen at position 1H, 7 position); 6.42 and 6.54 ( AB, J = 14 Hz, 2H, H, trans-vinyl); 6.83 (ring of S, 1H, thiazole ring); 6.14 (s, 1H, -COOCH (C ₆ H ⁹ ) ₂ ); 7.01 (s, broad, 1H, (C ₆ H ₅ ) ₃ NH); 7.10-7.50 (15H, aromatic); 6.53 (d, J = 8 Hz, 1H, -CONH-).

2-benzhydryloxycarbunyl-7- [2-methoxyimino-2- (2-tritylamino-thiazol-4-yl) -acetamido-8-oxo-3- (2-oxo- Syn isomer of et) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene.

Rf = 0.35 [silica gel chromatography: mixture of cyclohexane and ethyl acetate having a volume ratio of 50:50 as an eluent].

Infrared spectrum (KBr): 1780 cm ⁻¹ (carbonyl of β-lactam); 1720 cm ⁻¹ (carbonyl of covalent ester group); 1680 cm ^-1 (carbonyl group of amide group).

Nuclear magnetic resonance spectra (350 MHz, CDCl ₃ , δ in ppm) 3.26 and 3.57 (AB, J = 19 Hz, 2H, —SCH ₂ -sepam); 3.51 and 3.67 (AB, J = 14 Hz, 2H, CH ₂ CHO); 4.08 (S, 3H, = NOCH ₃ ); 5.08 (d, J = 4Hz, 1H, hydrogen at position 6); 5.09 (dd, J = 4 and 9 Hz, 1H, hydrogen at position 7); 6.73 (s, 1H, hydrogen to riazole ring; 6.83 (d, J = 9Hz, -CON H- ); 6.85 (s, 1H, -COCCH (C ₆ H ₅ ) ₂ ); 6.99 (s, broad range, 1H, (C ₆ H ₅ ) ₃ (N H ); 7.02-7.45 (15H, aromatic); 957 (s, 1H, -CHLO).

2-benzhydryloxycarbonyl-3-oxo-3- (2-tosyl-oxy-vinyl)-[2- (2-tritheramino-thiazol-4-yl) -2-vinyloxy-amino- Beige powder of acetamido] -5-thia-1-aza-bisaclot [4,2,0] oct-2-ene and -oct-3-ene (a mixture of E- and Z-forms) .

Infrared spectrum (KBr): characteristic band (cm ⁻¹ ) in 1790, 1725, 1690, 1640, 1525, 1495, 1450, 1195, 1180, 1075, 1005, 950, 755 and 705.

) ; 4.77(dd, J=2 및 16, 1H,

); 5.09(d, J=4, 1H, 6위치에 수소0: 5.94(dd, J=4 및 9,1,7위치에 수소); 6.81(s,1H, 리아졸의 수소); 6.91(s, 1H,

); 7.07(dd, J=6 및 16, 1H, -CH=CH₂); 7.74(d, J=8, 2H, 설포닐기의 수소).Proton nuclear magnetic resonance spectra (350 MHz, CDCl ₃ , δ in ppm, J in Hz) 2.45 and 3.55 (2d, J = 18,2H, —SCH ₂ −); 4.27 (dd, J = 2 and 6, 1H,

); 4.77 (dd, J = 2 and 16, 1H,

); 5.09 (d, J = 4, 1H, hydrogen at 6 position 0: 5.94 (dd, J = 4 and hydrogen at 9, 1, 7 position); 6.81 (s, 1H, hydrogen of riazole); 6.91 (s, 1H,

); 7.07 (dd, J = 6 and 16, 1H, -CH = CH ₂ ); 7.74 (d, J = 8, 2H, hydrogen of sulfonyl group).

2-benzhydryloxycarbonyl-3- (2-oxo-eryl) -8-oxo-7- [2- (2-tritylamino-riaazol-4-yl-2-vinyloxyimino-acetami FIG.] Syn isomer, which is a dark blue foam of -5-ria-1-aza-bicyclo [4,2,0] oct-2-ene.

Infrared spectra (KBr): characteristic band (cm ⁻¹ ) at 1785, 1725, 1685, 1640, 1350, 1495, 1450, 1000, 950, 755 and 700.

) ; 4.78(dd, J=2 및 17, 1H,

) ; 5.12(d, J=4, 1H, 6위치에 수소); 6.0(dp, J=4 및 9, 1H, 7위치에 수소); 6.8(s, 1H, 티아졸의 수소): 6.90(s, 1H, -COOCH); 7.08(dd, J=6 및 17 , 1H, -CH=CH₂) ; 9.55(s,1H, -CHO).Proton nuclear magnetic resonance spectra (350 MHz, CDCl ₃ , δ for ppm, J for Hz); 3.26 and 3.58 (2d, J = 18, 2H, -SCH _2- ); 3.53 and 3.69 (2d, J = 18, 2H, -CH _2- ); 4.28 (dd, J = 2 and 6, 1H,

); 4.78 (dd, J = 2 and 17, 1H,

); 5.12 (d, J = 4, 1H, hydrogen at position 6); 6.0 (dp, J = 4 and 9, 1H, hydrogen at position 7); 6.8 (s, 1H, hydrogen of thiazole): 6.90 (s, 1H, -COOCH); 7.08 (dd, J = 6 and 17, 1H, -CH = CH ₂ ); 9.55 (s, 1 H, -CHO).

2-benzhydryloxy-carbonyl-3- (2-dimethylamino-vinyl) -8-oxo-7- [2- (2-trityl-amino-thiazol-4-yl) -2-vinyloxy Syn isomer, E-form, which is the brown foam of -amino-acetamido] -5-thia-1-aza-bisaclot [4,2,0] oct-2-ene.

Infrared Spectrum (KBr): Characteristic band (cm ⁻¹ ) at 1770, 1670, 1635, 1610, 1530, 1495, 1450, 1000, 945, 755 and 7000.

); 4.73(dd, J=2 및 14, 1H,

: 5.18(d, J=4, 1H, 6위치에 수소): 5.60(dd, J=4 및 9, 1H, 7위치에 수소 ; 6.53 및 6.75(2d, J=16, 2H, -CH=CH-): 6.88(s, 1H, COOCH〈); 7.10(dd, J=7 및 14,1H, =NOCH=).Proton nuclear magnetic resonance spectra (350 MHz, CDCl ₃ , δ for ppm, J for Hz); 2.90 (s, 6H, -N (CH ₃ ) ₂ ): 4.25 (dd, J = 2, 1H,

); 4.73 (dd, J = 2 and 14, 1H,

5.18 (d, J = 4, 1H, hydrogen at 6-position): 5.60 (dd, J = 4 and 9, 1H, hydrogen at 7-position; 6.53 and 6.75 (2d, J = 16, 2H, -CH = CH -): 6.88 (s, 1 H, COOCH &lt;); 7.10 (dd, J = 7 and 14,1 H, = NOCH =).

2-benzhydryloxycarbonyl-3-oxo-5-oxide-3- (2-tosyloxyvinyl) -7- [2- (2-tritylamino-thiazol-4-yl) -vinyloxyimino -Acetamido] -5-thia-1-aza-bicyclo 4,2,0-oct-2-ene (syn isomer, E-form).

Infrared spectrum (KBr): characteristic band (cm ⁻¹ ) in 1800, 1725, 1690, 1635, 1520, 1495, 1450, 1195, 1180, 1070, 1050, 1000, 945, 740 and 700.

);4.62(d,J=4,1H,6위치에 수소);4.76(dd,J=2 및 13, 1H,

) ;6.20(dd, J=4 및 9,1H, 7위치에 수소); 6.80(s,1H,티아졸의 H); 6.90(s,1H, -COOCH=);6.92 및 7.10(2d, J=12,2H, -CH=CH-) : 7.05(dd, J=6 및 13, 1H, =NOCH=); 7.73(d,J=8,2H, -OSO₂-기의 오르토-위치에 수소).Proton nuclear magnetic resonance spectra (350 MHz, CDCl ₃ , δ for ppm, J for Hz); 2.45 (s, 3H, -CH ₃ ): 3.19, 3.77 (2d, J = 18, 2H, -SCH _2- ); 4.27 (dd, J = 2 and 6, 1H,

;; 4.62 (d, J = 4, 1H, hydrogen at position 6); 4.76 (dd, J = 2 and 13, 1H,

); 6.30 (dd, J = 4 and 9,1H, hydrogen at position 7); 6.80 (s, 1H, H of thiazole); 6.90 (s, 1H, -COOCH =); 6.92 and 7.10 (2d, J = 12,2H, -CH = CH-): 7.05 (dd, J = 6 and 13, 1H, = NOCH =); 7.73 (d, J = 8,2H, hydrogen at the ortho-position of the -OSO ₂ -group).

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-tritylamino-thiazol-4-yl) -acetamido] -8-oxo-5 in the form of a cream foam. -Oxide-3- (2-tosyloxyvinyl-5-thia-1-aza-bicyclo [4,2,0] -oct-2-ene (a mixture of syn isomer E-form and Z-form). Isomers

Infrared spectrum (CHBr ₃ ): characteristic band (cm ⁻¹ ) in 3380, 1800, 1720, 1680, 1510, 1375, 1190, 1175, 1000, 735.

Proton nuclear magnetic resonance spectra (350 MHz, CDCl ₃ , δ for ppm, J for Hz); 2.03 (s, 3H, C ₆ H ₄ -CH ₃ ): 3.36 and 4.07 (2d, J = 19,2H, -SCH ₂ ); 4.09 (s, 3H, -OCH ₃ ); 4.52 (d, J = 4,1H, hydrogen at position 6); 6.16 (dd, J = hydrogen at position 4 and 9,1H, 7 position); 6.43 (AB, J = 8,2H, CH = CH-): 6.86 (s, 1H, &gt;CHOCO-); 6.71 (s, 1H, hydrogen at position 5 of thiazole); 7.75 (d, J = 9,2H, hydrogen at the ortho-position of the tosyl group).

E-isomer

Infrared spectrum (CHBr ₃ ): characteristic band (cm ⁻¹ ) in 3380, 800, 1725, 1685, 1515, 1380, 1190, 1180, 1070, 1050, 755 and 735.

Proton nuclear magnetic resonance spectra (350 MHz, CDCl ₃ , δ for ppm, J for Hz); 2.45 (s, 3H, C ₆ H ₄ CH ₃ ): 3.19 and 3.77 (2d, J = 18, 2H, -SCH ₂ ); 4.08 (s, 3H, -OCH ₃ ) 4.6 (hydrogen at d, J = 4,6): 6.18 (hydrogen at dd, J = 4 and 9,7): 6.72 (s, 1H, 5 of thiazole Hydrogen at position); 6.93 (d, J = 12, 1H, -CH = CH-OSO _2- ): 7.11 (d, J = 12 1H, -CH = CH-OSO _2- ): 6.90 (s, 1H, -COOCH <): 7.73 (d, J = 9,2H, hydrogen at the ortho-position of the tosyl group).

[2-Benzhydryloxycarbonyl-7-2-methoxyimino-2- (2-trityl-amino-thiazol-4-yl) -acetamido] -8-oxo-5 in the form of an orange powder -Oxide-3- (2-tosyloxy-vinyl) -5-thia-1-aza-bisaclo [4,2,0] oct-2-ene (syn isomer, Z-type).

Rf = 0.35 [silica gel chromatography plate; A mixture having a volume ratio of cyclohexaneethyl acetate of 50:50 is used as the eluent.

2-benzhydryloxycarbonyl-7- [2-methoxyimomo-2- (2-tritylamino-thiazol-4-yl) -acetamido] -3- (2-tosyloxyvinyl)- 8-oxo-5-thia-1-aza-bicyclo [4,2,0] oxo-2-ene (syn isomer, E-form).

Rf = 0.35 [silica gel chromatography; Using a mixture having a volume ratio of cyclohexaneethyl acetate of 50:50 as the eluent.

2-benzhydryloxycarbonyl-7- [2-methoxyimino-2- (2-trityl-amino-thiazol-4-yl) -acetamido] -3- (2-tosyloxyvinyl) -8-oxo-5-thia-1-aza-bisaclo [4,2,0] oct-2-ene (syn isomer, E-form).

Rf = 0.52 [silica gel chromatography using an eluent having a volume ratio of 50:50 of cyclohexane and ethyl acetate].

Infrared spectrum (CHBr ₃ ): characteristic band (cm ⁻¹ ) at 3400, 1790, 1725, 1685, 1520, 1375, 1190, 1180, 1075, 1050, 755 and 740.

Proton nuclear magnetic resonance spectra (350 MHz, CDCl ₃ , δ in ppm, J in Hz); 2.42 (s, 3H, -CH ₃ of tosyl group); 3.33 and 3.42 (AB, J = 19, 2H, -SCH _2- ): 4.07 (s, 3H, -OCH ₃ ); 5.03 (d, J = 4,1H, hydrogen at position 6); 5.87 (dd, J = 4 and hydrogen at position 9,1H, 7); 6.71 (hydrogen at position 5 of s, thiazole): 6.87 (s, 1H, -CO ₂ CH <): 6.87 (d, J = 10,1H,- CH = CH-OSO _2- ): 7.0 (s, rum, 1H, NH- of thiazole); 7.78 (d, J = 9,1H, -CONH-).

7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-8-urea-3- (2-tosyloxyvinyl) -5-thia -1-aza-bicyclo [4,2,0] -oct-2-ene (syn isomer, E-form).

Rf = 0.57 [silica gel chromatography; Using a mixture of ethyl acetate, acetone, water and acetic acid in a volume ratio of 50: 20: 10: 10 as eluent.

Infrared Spectrum (KBr): Characteristic band (cm ⁻¹ ) at 3400, 3340, 3000, 2820, 2200, 1775, 1320, 1670, 1630, 1370,1190,1165 and 1071.

Proton nuclear magnetic resonance spectra (350 MHz, DMSO d ₆ , δ in ppm, J in Hz); 2.42 (s, 3H, -CH ₃ of tosyl group); 3.55 and 3.78 (AB, J = 19, 2H, -SCH _2- ): 3.83 (s, 3H, -OCH ₃ ); 5.14 (d, J = 4,1H, hydrogen at 6 position); 5.75 (dd, J = 4 and hydrogen at position 9,1H, 7): 6.65 (dd, J = 12,1H, -CH = CH-OSO _2- ): 6.73 (s, 1H, hydrogen at position 5 of thiazole): 7.18 ( s, broad, NH ₃ ): 9.58 (d, J = 9, 1H -CONH-).

Yellow powdery form 7- [2- (2-amino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-carboxy-8-oxy-3- (2-tosyloxy-vinyl ) -5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, E-form).

Infrared spectrum (KBr): characteristic band (cm ⁻¹ ) in 3360, 3200, 3100, 2000, 1770, 1670, 1630, 1530, 1370, 1190, 1175, 1070, 1045, 925 and 810.

2-wire nuclear magnetic resonance spectra (350 MHz, DMSO d ₆ , δ for ppm, J for Hz); 2.45 (s, 3H, -CH ₃ ): 3.58 and 3.80 (2d, J = 18, 2H, -SCH _2- ): 3.88 (s, 3H, -OCH ₃ ); 5.18 (d, J = 4, 1H, Hydrogen at 6-position); 5.78 (dd, J = 4 and 9,1H, hydrogen at 7-position): 6.68 and 7.20 (2d, J = 12, 2H, -CH = CH-): 6.74 (s, 1H, thia Hydrogen of the sol): 7.20 (s, 2H, -NH ₂ ): 7.51 and 7.88 (2d, J = 8, 4H, tosyl); 9.58 (d, J = 9, 1 H, -CONH-).

7-2- (2-amino-thiazol-4-yl) -2-methoxyamino-acetamino-2-benzhydryloxycarbonyl-8-oxo-3- (2-tosyloxy in the form of a cream solid -Vinyl) -5-thia-1-aza-bicyclo- [4,2,0] oct-2-ene (syn isomer, E-form).

Infrared spectrum (CHBr ₃ ): characteristics at 3480, 3390, 3340, 3210, 1780, 1725, 1680, 1620, 1600, 1530, 1495, 1455, 1445, 1360, 1190, 1180, 1075, 1050, 925, 810 and 760 Di (cm- ¹ ).

Proton Nuclear Magnetic Resonance Spectrum (350MHz, DMSO d ₆ , δ is ppm unit, J is ppm unit): 2.43 (s, 3H, -CH ₃ ): 3.61 and 3.85 (2b, J = 18, 2H, -SCH ₂ ) 3.86 (s, 3H, -OCH ₃ ); 5.22 (d, J = 4, 1H, hydrogen at position 6); 5.85 (dd, J = 4 and hydrogen at position 9, 1H, position 7): 6.44 and 7.38 ( 2d, J = 12,2H, -CH = CHS-: 6.75 (s, 1H, hydrogen of thiazole): 6.88 (s, 1H, -COOH <): 7.20-(s, 2H, -NH ₂ ): 7.50 and 7.84 (2d, J = 8, 4H, tosyl); 9.62 (d, J = 9, 1 H, -CONH-).

Claims (1)

3- of formula (I) consisting of reacting thiourea of formula (II) with a cephalosporin derivative of formula (III) or a mixture of isomers thereof, or removing a protecting group in the resulting compound A process for preparing a mixture of vinyl-cephalosporins and isomers thereof or salts thereof.

Popular [syn- or anti-form, R ₄ being a hydrogen atom or a protecting group which is not a chloroacetyl and trichloroacetyl group, and R ₅ is a hydrogen atom, an alkyl group, a cyanomethyl group, or a protecting group]; R ₅ is a structural formula that can be easily removed by hydrogen atoms, appeal

(R ₉ is an alkyl group or a cyclohexyl group, R ₉ is a hydrogen atom or an alkyl group), methoxymethyl group, tertiary butyl group, benzhydryl group, p-nitrobenzyl group, or p-methoxybenzyl group ego; R ₃ is a group of the formula R ₃ ′ -SO ₂ C- or R ₃ ″ -COO, wherein R ₃ ′ is substituted by an alkyl, trifluoromethyl, or trichloromethyl group, or by a halogen atom or an alkyl or nitro group An unsubstituted phenyl group, R ₃ ″ is the same as R ₃ or an acylmethyl, 2-acylmethyl, 2-acylpropyl, alkoxycarbonylmethyl, 2-alkoxycarbonylethyl, or 2-alkoxycarbonyl group; All the alkyl moieties, acyl moieties, alkyl groups and acyl groups mentioned above are straight or branched chains of C ₁ -C ₄ unless otherwise specified; Hal is chlorine or bromine atom; The compound of formula (I) is in the form of bicyclooct-2-ene or bicyclooct-3-ene when n = 0, in the form of bicyclooct-2-ene when n = 1, 3 The substituent in position is the E-type or Z-type.