DD234272A5 - NEW METHOD FOR PRODUCING A CEPHALOSPORIN - Google Patents

Abstract

The invention relates to a process for the preparation of a cephalosporin. The object of the invention is to provide an improved process by means of which the compound can be obtained in high yield and in high purity. According to the invention, a cephalosporin of the formula (I) or a salt thereof is prepared in which R 2 is a lower alkyl group, R 3 is a hydrogen atom or a carboxyl protective group and R 4 is a substituted or unsubstituted heterocyclic group which is linked to the exomethylene group in the Position of the cephem ring is linked via a carbon-nitrogen bond. Furthermore, according to the invention, a novel intermediate of the formula (IIa) in which R 2 is a lower alkyl group and a process for its preparation are available.

Description

wherein R ^{2 has} the meaning given in point 1, was obtained with boron trifluoride or a complex compound thereof, with a compound of formula (III):

(III)

wherein R ^3a and R ^{4 have} the meaning given in point 1, at -5O ⁰ C to O ⁰ C in an organic solvent and then at ^{0 0} C to 5O ⁰ C at a pH of 4.5-6.7 in one mixed solvent of water and an organic solvent.

Process according to item 10, characterized in that R ^{4 is} 2- (1,2,3,4-tetrazolyl), 1- (1,2,4-triazolyl), 2,3-dioxo-1,2,3,4 tetrahydropyrazinyl, 3,6-dioxo-1,2,3,6-tetrahydropyridazinyl, 6-oxo-1,6-dihydropyridazinyl, 2-oxo-1,2-dihydropyridazinyl, 6-oxo-1,6-dihydropyrimidinyl, 2 -Oxo-i, 2-dihydropyrimidinyl, 1,2,6-thiadiazine-1,1-dioxide-2-yl or isothiazolidine-1,1-dioxide-2-yl, which groups may be substituted with at least one substituent Halogen atoms, alkyl groups or alkylthio groups.

12. The method according to any one of items 10 or 11, characterized in that the pH of the reaction mixture is adjusted to 4.5-6.7 using a base and / or a buffer in the presence of a salt or using a base and / or a buffer.

Field of application of the invention

The invention relates to a novel process for the preparation of a cephalosporin, an intermediate for the cephalosporin and a process for the preparation of the intermediate.

Characteristic of the known technical solutions

It is already known that a cephalosporin (syn isomer) represented by the following formula (I) or a salt thereof:

SC - COHH, S V,

»« Il I

M ₁ A

(D

CH ₂ H

COOR

(Syn isomer)

wherein R ^{2 represents} a lower alkyl group; R ^{3 is} a hydrogen atom or a carboxyl-protecting group; and R ^{4 represents} a substituted or unsubstituted heterocyclic group attached to the exomethylene group in the 3-position of the cephem ring via a carbon-nitrogen bond, which is a highly useful antibacterial agent. such

Cephalosporins are the subject of various patent applications.

(Japanese Patent Laid-Open Nos. 99,592 / 82 and 93,085 / 84 and Japanese Patent Application Nos. 67,871 / 83,113,565 / 83 and 114,313 / 83.

Since then, the inventors have extensively studied to develop processes for producing the cephalosporin of the formula (I) or a salt thereof. It has been found by the inventors that a useful cephalosporin (syn isomer) of the formula (I) or a salt thereof can be easily obtained in high yield by reacting a compound (syn isomer) of the general formula (II):

- OQHHR

(ID

wherein R ^{1 represents} a hydrogen atom or a substituted or unsubstituted alkyl, aralkyl, aryl or heterocyclic group; and R ^{2 is} a lower alkyl group, with a compound of the formula (III):

CH ₂ R

(III)

COOR

3a

wherein R ^{3a represents} a carboxyl-protecting group and R ^{4 represents} a substituted or unsubstituted heterocyclic group linked to the exomethylene group in the 3-position of the cephem ring via a carbon-nitrogen bond in the presence of boron trifluoride or a complex compound thereof and below optionally removing the carboxyl-protecting group or converting the product to a salt.

Object of the invention

The object of the present invention is to provide a novel process which can easily obtain a useful cephalosporin (syn isomer) of the formula (I) or a salt thereof.

Explanation of the essence of the invention

The invention has for its object to provide a novel process for the simple preparation of a useful cephalosporin (syn isomer) of the formula (I) or a salt thereof, in which the desired product with high purity in

high yield is obtained.

It is a further object of the invention to provide a novel intermediate (syn-isomer) of the formula (II a) mentioned below. Finally, it is an object of the invention to provide a process for the preparation of the intermediate of formula (Ha)

create.

In the following the invention will be explained in more detail.

According to the invention, a process for producing a cephalosporin of the formula (I) or a salt thereof

created:

(D

j (syn-isomer)

wherein R ² , R ³ and R ^{4 have} the meaning given above. The process comprises reacting a compound of formula (II):

(ID

_ (Syn-isomer)

where R ¹ and R ^{2 have} the abovementioned meaning, with a compound of the formula (III):

(III)

CH ₂ R

COOR

wherein R ^3a and R ^{4 have} the abovementioned meaning, in the presence of boron trifluoride or a Kornp.lexverbindung thereof and then, if desired, the removal of the carboxyl-protecting group or the conversion of the product into

a salt thereof.

More specifically, therefore, a cephalosporin of the formula (I) or a salt thereof is easily obtained in a high yield by reacting an acid amide or a mono-substituted acid amide of the formula (II) having a free amino group in the 2-position of the thiazole ring a compound of formula (III) in the presence of boron trifluoride

or a complex compound thereof.

The invention also provides a novel intermediate of the formula (Na) for the preparation of a useful cephalosporin

created: .

U ^ G - GOHH ₂

I!

(Syn IsomeresJ

wherein R ^{2 has} the meaning given above. Furthermore, a process for the preparation of the intermediate of formula (IIa) is provided. The process involves the reaction of a compound of formula (IVa):

^ (Syn-isomer)

where X is a halogen atom and R ^{2 has} the meaning given above, with thiourea.

The invention will be explained in detail below. Unless otherwise stated, a straight or verzweigtkettigeCi_, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, in the present specification, the term "alkyl" z ₁₄ alkyl group. , Pentyl, hexyl, heptyl, octyl, dodecyl or the like. The term "alkenyl" means a C 2-20 alenyl group, e.g. Vinyl, allyl, isopropyl, butenyl, 2-pentenyl, etc. The term "aryl" means, for example, phenyl, ToIyI, naphthyl, indanyl or the like. The term "aralkyl" means, for example, benzyl, phenethyl, 4 Methylbenzyl, naphthylmethyl or the like The term "acyl" means a C ₁ ^ ₂ acyl group, e.g., formyl, acetyl, -propionyl, n-butyryl, isobutyryl, valeryl, pivaloyl, Pentancarbonyl, cyclohexanecarbonyl, benzoyl, naphthoyl, furoyl, thenoyl o. Like. The term "Halogen" means fluorine, chlorine, bromine, iodine or the like. Further, the term "lower" means 1 to 5 carbon atoms.

It should also be noted that when words such as "alkyl", "alkenyl", "aryl", "aralkyl" /, "acyl", "lower" and the like. in the various terms used in this specification, they each have the meaning given above, unless otherwise specified.

In the formula (II), R ^{1 represents} a hydrogen atom or a substituted or unsubstituted alkyl, aralkyl, aryl or heterocyclic group. The heterocyclic group specifically includes nitrogen-containing 5- or 6-membered heterocyclic groups such as pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl and the like. The substituents on R ¹ include, for. A halogen atom, a nitro group, an alkyl group, an aryl group, an alkoxy group, an alkylthio group, a cyano group, an amino group, an alkylamino group, a dialkylamino group, an acylamino group, an acyl group, an acyloxy group, an acylalkyl group, a carboxyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, a carbamoyl group, an aminoalkyl group, an N-alkylaminoalkyl group, a Ν, Ν-dialkylaminoalkyl group, a hydroxyalkyl group, a hydroxyiminoalkyl group, an alkoxyalkyl group, a carboxyalkyl group, a sulfoalkyl group, a sulfo group, a sulfamoylalkyl group, a sulfamoyl group, a carbamoylalkyl group, a carbamoylalkenyl group , an N-hydroxycarbamoylalkyl group and the like.

The above-mentioned alkyl, aralkyl, aryl or heterocyclic group for R ¹ may each be substituted with one or more of these substituents. Among these substituents, the carboxyl group may be protected with a carboxyl-protecting group, which will be explained below in connection with R ^3a and R ³ .

R ^3a represents a carboxyl-protecting group and R ³ represents a hydrogen atom or a carboxyl-protecting group.

The carboxyl-protecting group includes groups conventionally used as a carboxyl-protecting group in the field of penicillins and cephalosporins. These include, for example, alkyl; phthalidyl; diphenylmethyl; C 2-7 acyloxy C 1-5 alkyl such as acetoxymethyl, pivaloyloxymethyl, propionylpxymethyl, butyryloxymethyl, isobutyryloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 1-acetoxy-n-propyl, 1-pivaloyloxyethyl, 1-pivaloyloxy-n-propyl, benzoyloxymethyl, 1-benzoyloxyethyl and the like; .dgl .; oC ₂ -5 acyloxybenzyl such as a-pivaloyloxybenzyl, ot-acetoxybenzyl and the like. and other.

R ⁴ represents a substituted or unsubstituted heterocyclic group attached to the exomethylene group in the 3-position of the cephem ring via a carbon-nitrogen bond. The heterocyclic group includes, for. As tetrazolyl, triazolyl, (di- or tetra-hydro (pyrazinyl, (di- or tetra-hydro! -Pyridazinyl, dihydropyrimidinyl, and five- or six-membered cyclic groups of the formula

where w is a divalent group, ζ. 1,2,6-thiadiazine-1,1-dioxide-2-yl, isothiazolidine-1,1-dioxide-2-yl and the like.

The heterocyclic group specifically includes 1- (1,2,3,4-tetrazolyl), 2- (1,2,3,4-tetrazolyl), 1- (1,2,3-triazolyl), 2- (1, 2,3-triazolyl), 1- (1,2,4-triazolyl), 4- (1,2,4-triazolyi), 2,3-dioxo-1,2,3,4-tetrahydropyrazinyl, 3.6 Dioxo-1,2,3,6-tetrahydropyridazinyl, 6-oxo-1,6-dihydropyridazinyl, 2-oxo-i, 2-dihydropyrazinyl, 6-oxo-i, 6-dihydropyrimidinyl, 2-oxo-1,2 dihydropyrimidinyl, 1,2,6-thiadiazine-1,1-dioxide-2-yl, isothiazolidine-1,1-dioxide-2-yl and the like.

As substituents on the heterocyclic groups for R ⁴ , those substituents which have been explained in connection with R ¹ can be used. Among these substituents, the carboxyl-protecting group may be protected with the carboxyl-protecting group described in connection with R ^3a and R ³ .

The salts of cephalosporin of the formula (I) include salts of the basic groups as well as the acidic groups, namely those conventionally used in the field of penicillins and cephalosporins. The salts of the basic groups include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid and the like; Salts with organic carboxylic acids such as oxalic acid, succinic acid, formic acid, trichloroacetic acid, trifluoroacetic acid and the like; and salts with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid,

etc.. The salts of the acidic groups include e.g. Salts with alkali metals such as sodium, potassium and the like; Salts with alkaline earth metals such as calcium, magnesium and the like; Ammonium salts; and salts with nitrogen-containing organic bases such as triethylamine, trimethylamine, aniline, N, N-dimethylaniline, pyridine, dicyclohexylamine and the like. like.

Hereinafter, embodiments of the method according to the invention will be explained.

(a) A process for producing a cephalosporin of the formula (I) or a salt thereof.

(i) the cephalosporin of the formula (I) or a salt thereof can be obtained by reacting a compound of the formula (II) with a compound of the formula (III) in the presence of boron trifluoride or a complex compound thereof.

Then, if necessary, the carboxyl-protecting group is removed or the product is converted to a salt. The compound of the formula (III) is easily obtained by subjecting a 7-aminocephalosporanic acid to 3-position conversion in the presence of an acid (Japanese Patent Application Kokai (Laid-open) Nos. 99,592 / 82,93,085 / 84 and 98,089 / 84 and Japanese Patent Applications Nos. 67,871 / 83,113,565 / 83 and 114,313 / 83 and similar processes) and subsequently protects the carboxyl group in the 4-position by introducing a protective group.

The complex compound of boron trifluoride used in the present invention comprises ζ. Β. Complex compounds of boron trifluoride with a carboxylic acid ester such as ethyl formate, ethyl acetate or the like; with a dialkyl ether such as diethyl ether, diisopropyl ether or the like; with sulfolane; and with a nitrile such as acetonitrile, propionitrile or the like. Preferred are a sulfolane complex compound, an acetonitrile complex compound, a diethyl ether complex compound and a

Ethyl acetate complex of Bort ri fluoride. ,

According to the invention it is further preferred to carry out the reactions in an organic solvent. The usable organic solvents include, for example, nitroalkanes such as nitromethane, nitroethane, nitropropane and the like. Ethers such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, anisole and the like; Esters such as ethyl formate, diethyl carbonate, methyl acetate, ethyl acetate, diethyl oxalate, ethyl chloroacetate, butyl acetate and the like; halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane and the like; Nitriles such as acetonitrile, propionitrile and. etc .; Ketones such as acetone and the like; Sulfolane, etc. Preferred are nitroalkanes, esters, nitriles, halogenated hydrocarbons and sulfolane. It is also possible to use a mixed solvent of two or more of these organic solvents. Further, a complex compound which is formed between such an organic solvent and boron trifluoride can be used as a solvent.

The amount of the compound of formula (II) used is generally 0.7-5 moles, preferably 1-3 moles per mole of the compound of formula (III). The amount of boron trifluoride or its complex compound used is generally 1-3 moles per mole of the compound of formula (II).

The reaction generally proceeds at -10 ⁰ C to 50 ⁰ C in a period of 10 minutes to 20 hours completely. In this reaction, the order of addition of the compounds of formulas (II) and (III) and boron trifluoride (or a complex compound of boron trifluoride) is not critical. Preferably, however, first the compound of formula (II) is reacted with boron trifluoride or a Complex compound thereof and subsequently the reaction product is reacted with the compound of formula (III).

Further, a compound obtained by reacting the compound of the formula (II) with boron trifluoride and a complex compound thereof is preferably isolated, and the isolated compound is subsequently reacted with the compound of the formula (III). In this case, the amount of boron trifluoride or its complex compound used is two moles or more, preferably 2-3 moles, per mole of the compound of the formula (II). The compound obtained by the reaction of the compound of the formula (II) with boron trifluoride or a complex compound thereof is generally used in an amount of 1-2 moles (relative to the compound of the formula [N]) per mole of the compound of the formula (III) used, (ii) When using the method described below, even if one obtains the compound of formula (IN), which was obtained in the process for preparing the compound of formula (III) without isolation as a starting compound for the inventive method , as excellent results as when using an isolated compound of formula (III) as starting material: A compound (syn-isomer) of the formula (II-a):

C-CONH ₂ ;

(Syn isomer)

wherein R ^{2 has} the meaning given above, is reacted with boron trifluoride or a complex compound thereof. The compound thus obtained is reacted with the compound of the formula (III) at -50 ° C to 0 ° C in the above-mentioned organic solvent to prepare an intermediate (first reaction step),

COOR ^3a

wherein R ² , R ^3a and R ^{4 have} the meaning given above. Subsequently, the reaction mixture is further reacted at ⁰ ° C. to 50 ^° C. and at a pH of 4.5 to 6.7 in a mixed solvent of water and the organic solvent (second reaction step). This gives a cephalosporin of the formula (I) or a salt thereof of high purity and in high yield.

Even if the unisolated compound of the formula (III) is used as the starting compound, therefore, the above procedure (ii) can prevent decomposition of the intermediate and achieve the purpose of the present invention.

As the complex compound of boron trifluoride, the same compounds as mentioned above can be used in this reaction. The amount of the compound of the formula (III), the amount of boron trifluoride or its complex compound used, and the amount of the compound obtained by reacting the compound of the formula (II-a) with boron trifluoride or its complex are as mentioned above.

As the mixed solvent of water and an organic solvent, mixed solvents of water and the above-mentioned organic solvents may be used. In particular, mixed solvents are used

, preferred, which form a two-layer system. , -

If one carries out the reaction (second reaction stage) in a mixed solvent of water and an organic solvent at a pH of 4.5-6.7 at 0 ^c C to 5O ⁰ C, the pH is adjusted appropriately and legally kept within the above-mentioned pH range by use of a base and / or a buffer, with conventionally used agents are suitable. In this case, the reaction is preferably carried out at a pH of 6.2-6.5. If the reaction is carried out in a pH range of 4.5-6.0, the pH is preferably adjusted in the presence of a salt. The base used in this reaction comprises inorganic bases conventionally used to adjust a pH, e.g. Alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; Alkali metal hydrogencarbonates such as sodium hydrogencarbonate, potassium hydrogencarbonate and the like; Alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like. etc .; Alkali metal phosphates such as sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate; and alkali metal acetates such as sodium acetate, potassium acetate and. The buffers include buffer solutions conventionally used for pH adjustment, for example, buffer solutions using phosphoric acid, boric acid, acetic acid, tri (hydroxymethyl) aminomethane or the like. The salt used in the reaction includes inorganic salts such as sodium chloride and the like.

The first reaction step of the reaction at -50 ⁰ C to ⁰ ° C is carried out in an organic solvent is generally completed in a period of 10 minutes to 10 hours. In this case, the reaction proceeds with increasing reaction temperature in a shorter time and is completed at -5 ° C to 0 ⁰ C, generally within about 1 hour. The second reaction step, in which the reaction is carried out at 0 ⁰ C to 50 ⁰ C, is generally complete in a period of 10 minutes to 20 hours.

The cephalosporin of the formula (I) or a salt thereof obtained in this way can be isolated and purified by a conventional method, and subsequently, if desired, the compound of the formula (I) wherein R ^{3 is} a carboxyl group may be used. Protective group, are easily converted in known manner into a corresponding compound in which R ^{3 is} a hydrogen atom or in a salt thereof.

The invention further includes all optical isomers, racemic compound, and all crystal forms and hydrates of the compounds of formula (I) or a salt thereof.

(b) Process for the preparation of the compound of formula (II).

The compound of the formula (II) can be obtained, for example, according to the stated preparation processes.

Also included in the present invention are all solvates, adducts, crystal forms and hydrates of the compound of formula (II).

production method

CH ₃ COGH ₂ COOHHR

CHCOO COHHR ³ II

OH

Hitrosation 1

(V)

(VI)

CH 2 COC-COZ ³ II

\ m ²

(VIII) Syn isomer

-> - CH ₃ COC-COHHR

Alkylation 1

(VII) Syn isomer

halogenation

SCH ₂ COc-COHHR ^{1 1} U

(HH ₂ ) ₂ C = S

cyclization

(IV)

Syn isomer

C-COIHR H

(ID

χ Syn isomer ^X 0R ²

In this case, R ¹ , R ² and X have the abovementioned meaning; Z stands for a halogen atom or a group of formula -OR ¹ or -SR ¹ (wherein R ¹ is as defined hereinbefore); and the binding symbol rvrwvi means that the connection is a

Syn- or anti-isomer or as a mixture thereof.

(1) Preparation of the compound of the formula (VI)

A nitroso compound of the formula (VI) can be obtained by reacting a compound of the formula (V) with a

Nitrosating.

The reaction is generally carried out in a solvent. The usable solvents include those which are inert to the reaction, such as water, acetic acid, benzene, methanol, ethanol, tetrahydrofuran

u. The like. These solvents can be used as a mixture of two or more.

The preferred nitrosating agents for this reaction are nitrous acid and derivatives thereof, for example nitrosyl halides such as nitrosyl chloride, nitrosyl bromide and the like; Alkali metal nitrites such as sodium nitrite, potassium nitrite and the like; and alkyl nitrite such as butyl nitrite, pentyl nitrite and the like. If an alkali metal nitrite is used as the nitrosating agent, the reaction is preferably carried out in the presence of an inorganic or organic acid such as, for example, hydrochloric acid, sulfuric acid, formic acid, acetic acid or the like. If an alkyl nitrite is used as a nitrosating agent, the reaction is preferably carried out in the presence of a strong base, such as a

Alkali metal alkoxide.

This reaction proceeds at ⁰ C to 3O ⁰ C over a period of 10 minutes to 10 hours completely.

(2) Preparation of the compound of the formula (VII)

The compound of the formula (VII) can be obtained by reacting a compound of the formula (VI) with an alkylating agent.

This reaction can be carried out according to conventional methods and generally proceeds at -20 ^c C to 6O ⁰ C over a period of 5 minutes to 10 hours completely.

Any solvents may be used provided that they do not adversely affect the reaction. Suitable solvents include, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane and the like. etc .; Alcohols such as methanol, ethanol and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; Esters such as ethyl acetate, butyl acetate and the like; Amides such as Ν, Ν-dimethylformamide, N, N-dimethylacetamide and the like. etc .; Water; and other. These solvents can also be used as a mixture of two or more.

The alkylating agents used in the reaction include, for example, lower alkyl halides such as methyl iodide, methyl bromide, ethyl iodide, ethyl bromide and the like; dimethyl sulfate; diethyl sulfate; diazomethane; diazoethane; Methyl p-toluenesulfonate; etc.. If an alkylating agent other than diazomethane or diazoethane is used in the reaction, the reaction is preferably conducted in the presence of an inorganic or organic base, e.g. As an alkali metal carbonate such as sodium carbonate, potassium carbonate o. Like., An alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or the like.; triethylamine; pyridine; Ν, Ν-dimethylaniline; or the like. by.

The compound of the formula (VII) can also be obtained by subjecting the compound of the formula (VIII) to a conventional amidation reaction using ammonia or a primary amine.

(3) Preparation of the compound of the formula (IV)

The compound of the formula (IV) can be obtained by reacting a compound of the formula (VII) with a halogenating agent.

The reaction is generally carried out in a solvent. Suitable solvents are those which do not adversely affect the reaction, for example halogenated hydrocarbons, such as methylene chloride, chloroform

u. etc .; organic carboxylic acids such as acetic acid, propionic acid and. etc .; Ethers such as diethyl ether, tetrahydrofuran, dioxane and the like. etc .; Alcohols such as methanol, ethanol, isopropanol and the like. and other. These solvents can also be used as a mixture of two or more.

The reaction is generally complete at ⁰ ° C. over a period of 30 minutes to 24 hours.

The usable halogenating agents include, for example, halogens such as bromine, chlorine and the like; Sulfuryl halides such as sulfuryl chloride and the like; hypohalous acids or alkali metal hypohalites such as hypochlorous acid, hypobromous acid, sodium hypochlorite and the like; N-halogenated imide compounds such as N-bromosuccinimide, N-chlorosuccinimide, N-bromophthalimide and the like; Perbromide compounds such as pyridinium hydrobromide perbromide, 2-carboxyethyltriphenylphosphonium perbromide and the like; and other

(4) Preparation of the compound of the formula (II)

The compound of the formula (II) can be obtained by reacting a compound of the formula (IV) with thiourea.

The reaction is generally carried out in a solvent. As a suitable solvent, any solvent is contemplated so long as it does not adversely affect the reaction. Suitable solvents include water; Alcohols such as methanol, ethanol and the like; Ketone such as acetone and the like; Ethers such as diethyl ether, tetrahydrofuran, dioxane and the like. etc .; Amides such as Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide and the like; N-methyl-α-pyridone and the like. These solvents can also be used as a mixture of two or more.

The reaction proceeds in some cases particularly smoothly by adding an acid-binding agent. Useful acid-binding agents include, for example, inorganic or organic bases such as alkali metal hydroxides, alkali metal hydrogencarbonates, triethylamine, pyridine, Ν, Ν-dimethylaniline and the like.

The reaction proceeds at 0 ° C to 100 ⁰ C generally in a period of 1 to 48 hours, preferably 1 to 10 hours completely.

The thiourea can be used in an amount of one to several moles per mole of the compound of the formula (IV).

As mentioned above, the syn-isomer (of the formula (II) can be selectively obtained in a high yield at a low cost.

embodiment

In the following the invention will be explained in more detail by means of examples, without limiting the invention.

example 1

(1) Dissolve 10.1 g of acetoacetamide in 35 ml of water. 6.9 g of sodium nitrite are added to the resulting solution with ice cooling. Subsequently, 25 ml of 4N sulfuric acid were added dropwise to the resulting mixture, under stirring at 0 ⁰ C to 5 ⁰ C for a period of 30 minutes. After completion of the dropping, the mixture is reacted at the same temperature for 30 minutes. The pH is then adjusted to 6.0 with saturated aqueous sodium bicarbonate solution.

After the insoluble portions are removed, water is removed by distillation under reduced pressure. The residue obtained is added with 20 ml of ethyl acetate and the resulting crystals are collected by filtration. This gives 8.6 g (yield 66.2%) of 2-hydroxyimino-3-oxobutyramide having a melting point of 96 to 97 ° C. IR (KBr) crrT ^ _Vc = oJ 670

NMR Cd _c -DMSO) £ 'value """""

2.26 C3H, s, CHCO-), 7.46 ClH, bs, -CON ^),

^JX H

7.62 ClH, bs, -C0N (:) # 12.60 ClH, s,

(2) In 20 ml of water is dissolved 6.5 g of 2-hydroxyimino-3-oxobutyramide and 5.6 g of anhydrous sodium carbonate at 20 ⁰ C. Further, at 20 to 25 ⁰ C 6.6 g of dimethyl sulfate to the resulting solution and sets the resulting mixture at the same temperature for 2 hours. The precipitate formed is collected by filtration and treated with 100 ml of methanol. Subsequently, the resulting mixture is stirred at 40 ⁰ C to 50 ⁰ C for 30 minutes. After removal of the insoluble matters, the solvent is removed by distillation under reduced pressure. The residue thus obtained is added to 20 ml of ethanol and the crystals formed thereby collected by filtration. 5.2 g is obtained (yield 72.2%) of 2- (syn) -methoxyimino-3-oxo-butyramide having a melting point of 156-157 ⁰ C.

IR (KBr) cm ' ¹ : v_ 1700, 1670

C = O

NMR (dg-DMSO) S value

2.26 (3H _7s , CH ₃ CO-), 3.96 (3H, s, -OCH ₃ ),

7.46 (IH, bs, -CON ^), 7.58 (IH, bs,

^X H

-CON ^)

(3) 7.2 g of 2- (Syn) -methoxyimino-3-oxobutyramide are suspended in 36 ml of tetrahydrofuran. To the suspension is added under stirring at 4O ⁰ C. 0.8 g of bromine. After caused by the bromine color disappeared, additional 7.2 g of bromine are the suspension under stirring at 25 to 3O ⁰ C added. After the suspension is reacted at the same temperature for 1 hour, the solvent is removed by distillation under reduced pressure. To the residue obtained are added 50 ml of ethyl acetate and 20 ml of water. The pH is then adjusted to 6.0 with saturated aqueous sodium bicarbonate solution. The organic layer is separated and washed with 20 ml of saturated sodium chloride solution. The organic layer is then dried over anhydrous magnesium sulfate and the solvent is removed by distillation under reduced pressure. To the obtained residue is added 20 ml of a mixed solvent of diisopropyl ether-ethyl acetate (1: 1). The crystals formed are collected by filtration. This gives 9.2 g (yield 82.1%) of 4-bromo-2- (syn) -methoxyimino-3-oxobutyramide having a melting point of 112-113 ° C.

IR (KBr) cm ' ¹ : ν 1715, 1660

NMR (dg-DMSO) δ value

4.02 (3H, s, -OCH ₃ ), 4.58 (2H, s, BrCH ₂ CO-),

7.72 (2H, bs, -CONH ₂ ) ·

(4) 4.5 g of 4-bromo-2- (syn) -methoxyimino-3-oxobutyramide are suspended in 13.5 ml of ethanol. The suspension 1.5 g of thiourea was added and the resulting mixture is reacted at 20 to 30 ⁰ C for 1 hour. The precipitated crystals are collected by filtration, washed with ethanol and then suspended in 25 ml of water. The pH of the resulting suspension is adjusted to 6.0 with saturated aqueous sodium bicarbonate solution. Subsequently, the crystals thus formed are collected by filtration and recrystallized from 15 ml of a mixed solvent of water-methanol (1: 1). This gives 2.9 g (yield 71.8%) of 2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamide having a melting point of 208-209 ⁰ C.

IR (KBi ₄ ctT ¹ : v _{c = 0} 1665

NMR (dg-DMSO) δ _value

Nn-3.84 (3H, s, -OCH ₃ ), 6.75 (IH, S, _S / \ _H ) »

/H

7.26 (2H, bs, -NH ₉ ), 7.61 (IH, bs, -CON ^),

* ^X H

7.91 (IH, bs, -CON ')

^X H

Table. 1

-Ν - C-CONHR ¹

 -crt

^{S /} N

(Syn isomer)

OCH.

σ φ '

Q-

Ql CT CO

connection Melting point IR (KBr) 1:08 (3H, NMR (0, .- DMSO) & 0 value (2H, m, -CH ₂ CH ₃ ), rl 3.81 (3H, t, J = 7Hz 1 -CH ₀ CHq) 1 3.18 X · - 7.15 223-225 1640 (2H, bs, S, -OCH ₃ ), 6.71 (IH , -CONH-) -CH ₂ CH ₃ 3.95 (3H, -NH ₂ ), 8. 31 (IH, t, J = 6 Hz ^N Jl) S, HDCH ₃ ) , 6.93 (IH, S - H ^^ 7:11 to 7:50 (2H, bs, -NH ₂ ), 195-198 1655 7.65- (3H, m, 7.31 (IH, s, -CONH-) - {θ) (2H, m, - / 0)), 10.70 -7.88

3 (Q CD (Q

(D

Q.

(Q Φ

D. Φ

ql

Q:

3 '

3 "Φ

φ U) '

Q) cn -P

[ N .. O ^. kl * ί? kl O m kl I K to cn I H xl / K Il xl iH K I VO H I - 2 1-3 tö κ O CN K O CN ^ in O CQ ε tH in cn U K σ CN U Κ * CN I K 3 κ I I CN I O ° 0 ι cn K - ^ cn r-I CN B ^ * (O iH η co a CN ^w cn CN CN K CO κι - .- CN O co co " \ K • Z I CN VO 1  Η co Ψ ♦ In CN W H K p. CN U γ cn cn ". O VO r- I K m ~ CN JL / ^cl £ K K Oil I U S3 K K O I η co CN I · - » Xi "^  » T cl K in VO co CN • a co co η • I * - * co O CN CN 1-) CN • cn co • cn C

Example 2

(1) In 43 ml of methanol containing 3.6 g of hydrogen chloride, 14.4 g of 2- (Syn) -methoxyimino-3-oxobutyramide are suspended. To the resulting suspension is 16.0 g of bromine at 30 ° C over a period of 1 hour

dropwise. The suspension is reacted at the same temperature for further 30 minutes, and then 43 ml of 1,4-dioxane and 22 ml of water are added to the reaction mixture while being cooled with ice. Subsequently, the pH is adjusted to 3.0-4.0 with aqueous ammonia. Then, 7.6 g of thiourea are added to the mixture and the mixture was reacted at 3O ⁰ C for 2 hours in order, wherein the pH is maintained with aqueous ammonia in a range of 3.5-5.0. The reaction mixture is subsequently cooled to 5 ⁰ C and the pH is adjusted to 6.5 with aqueous ammonia. The resulting crystals are collected by filtration and washed with a mixed solvent of water-1,4-dioxane (1: 1). This gives 18.5 g (yield 64.2 &) of 1,4-Dioxanaddukts of 2- (2-aminothiazol-4-yl) -2- (syn) -methoxyimidoacetarnid having a melting point of 196-198 ⁰ C.

IR (KBr) cm ^-1 : v _{c = 0} 1690 NMR Cd DMSO) S

*>, 3.83 (3H, s,

.OCHO, 6.70 (IH, s, ~ T ~ ^} ' ⁷ · ^{16 (2H} '

bs, -NH ₂ ), 7.48 ClH, bs, -CON <->,

H '

7.77 ClH, bs, -

(2) 14.4 g of the 1,4-dioxane adduct of 2- (2-aminothiozol-4-yl) -2- (syn) -methoxy-iminoacetamide obtained in the above step (1) is recrystallized from a mixed solvent of 18 ml of methanol. This gives 8.6 g (yield 86.0) 2- (2-Arninothiazol-4-yl) -2- (syn) -methoxyiminoacetamide having a melting point of 208-209 ⁰ C.

The physical properties (IR, NMR) of this product are identical to those of the product obtained in Example 1- (4).

(3) 1 g of the above step (1) obtained 1,4-Dioxanaddukts of 2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamide are suspended in 5 ml of methanol at 40 ⁰ C. The resulting suspension is stirred at the same temperature for 1 hour.

, Subsequently, the suspension is cooled to room temperature and the crystals thus obtained are collected by filtration. Gives 2- (2-aminothiazol-4-yl) -2- (syn) -rnethoxyiminoacetamid having a melting point of 223.5 to 225 ⁰ C (yield 89.2%)

 The physical properties (NMR) of this product are identical to those of the product obtained in Example 1- (4).

Example 3

(1) A mixed solvent of 60 ml of sulfolane and 60 ml of anhydrous methylene chloride containing 30.6 g of boron trifluoride is added with 30.0 g of 2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamide. The mixture is reacted at room temperature for 1 hour.

The crystals formed are collected by filtration. The crystals are then suspended in 300 ml of ethyl acetate and collected by filtration after the resulting suspension is stirred for 1 hour. The crystals are washed with two 60 ml portions of ethyl acetate and dried. This gives 42.3 g of crystals.

IR (KBr) Cm " ¹ : 1680, 1650, 1620, 1200-1000

(2) In 41 ml of ethyl acetate are dissolved 4.10 g of pivaloyloxymethyl-7-amino-3- (5-methyl-1,2,3,4-tetrazol-2-yl) methyl-A ³ -cephem-4-carboxylate , 3.36 g of the crystals obtained in the above step (1) are added to the solution. Subsequently, the solution is reacted at room temperature for 3 hours. Subsequently, 41 ml of water are added to the reaction mixture and the pH is adjusted to 4.5 with sodium bicarbonate. The organic layer is separated, washed with 20 ml of water and dried over anhydrous magnesium sulfate. Subsequently, 2.4 g Mesityiensulfonsäuredihydrat to the organic layer. The resulting mixture is reacted at room temperature for 1 hour. The crystals formed are collected by filtration and washed with 5 ml of ethyl acetate. This gives 7.18 g (yield 90.5%) of the mesitylene sulfonic acid salt of pivaloyloxymethyl-7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- (5-methyl-1-ytetrazoate ^ -methyl-A ^ cephem ^ -carboxylate with a melting point of 218-220 ° C (decomposition).

IR (KBr) cm ^-1 : v _c = o 1782, 1745, 1680

Example 4

(1) 29.8 g of 7-amino-3- (5-methyl-1,2,3,4-tetrazol-2-yl) methyl-A ³ -cephem-4-carboxylic acid are suspended in 88.8 ml of acetone. Subsequently, 1b, 2 g!, S-diazabicyclo [alpha] 1-aldecene are added dropwise to the resulting suspension at 5 ° C. After the resulting mixture is reacted at 5 ° C to 10 ⁰ C for 30 minutes, the reaction mixture is cooled to 0 ⁰ C and treated with 24.2g Pivaloyloxymethyliodid. Subsequently, the mixture is reacted at 15 ⁰ C to 17 ° C for 20 minutes. After 385 ml was added dropwise to the reaction mixture, 3.37 g of pyridine are added to the mixture

added and the resulting mixture is stirred for 5 minutes. After removal of the insoluble constituents formed by filtration, the filtrate is cooled to -5 ° C. To the cooled filtrate is added 33.6 g of the crystals obtained in Example 3- (1). The resulting mixture is reacted at -5 ° C to 0 ° C for 1 hour.

(2) The reaction mixture obtained in the step (1) is added to the solution previously prepared by adding 19.6 g of 85% by weight phosphoric acid to 207 ml of water and adjusting the pH to 6.5 with 30 % aqueous sodium hydroxide solution. The resulting mixture is reacted at 25 to 27 ° C for 3 hours while maintaining the pH in a range of 6.2-6.5 with 20% aqueous potassium carbonate solution. Subsequently, the pH is adjusted to 3.0, with hydrochloric acid. The insoluble components are removed by filtration. Then the organic layer is separated and washed with 148 ml of water. To the obtained organic layer is added 21.3 g of mesitylenesulfonic acid dihydrate. The mixture is stirred at 20-22 ⁰ C1 hour. The precipitated crystals are collected by filtration, washed with three 44 ml portions of ethyl acetate and then dried. This gives 61.9 g (yield 78.0%) of the mesitylenesulfonic acid salt of pivaloyloxymethyl-7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- (B-methyl-1) ^ Atetrazole ^ -dimethyl ^ -cephem ^ -carboxylate with a melting point of 218-22O ⁰ C (decomposition).

[R (KBr) cnr ^1: v _c = o 1782 Ϊ745J680 Example 5

The reaction mixture, which was obtained in the same manner as in Example 4- (1), is placed in a solution previously prepared by adding 19.6 g of 85% by weight phosphoric acid and 88.8 g of sodium chloride to 266 ml of water and adjusting the pH to 5.3 with 30% aqueous sodium hydroxide solution. The resulting mixture is reacted at ⁰ C for 3 hours 25-27, wherein the pH value with 20% aqueous potassium carbonate solution keeps in a range of 4.8-5.0. Subsequently, the pH is adjusted to 3.0 with hydrochloric acid. The insoluble components are removed by filtration. Subsequently, the organic layer is separated and washed with 149 ml of water. To the resulting organic layer is added 21.3 g Mesitylensulfonsäuredihydrat and the mixture is stirred at 20-22 ⁰ C for 1 hour. The precipitated crystals are collected by filtration, washed with three 44 ml portions of ethyl acetate and then dried. This gives 61.9 g (yield 78.0%) of Mesitylensulfonsäuresalzes of pivaloyloxymethyl-7- [2- (2-aminothiazol-4-yD ^ -lsynl-methoxyiminoacetamidol-S-iö-methyl-i ^^^ - tetrazole ^ - yDmethyl-Acephem ^ -carboxylate with a melting point of 218-22O ⁰ C (decomposition).

IR (KBr) cm ^-1 : v _{c = o} V782, J 745, 1 680

Example 6

(1) To the reaction mixture obtained in the same manner as in Example 4- (1) is added 200 ml of ice water and the resulting mixture is stirred under ice-cooling for 3 minutes. The organic layer is separated and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure. 200 ml of diethyl ether are added to the residue obtained. The crystals formed are collected by filtration and then washed with diethyl ether. This gives 59.5 g of crystals.

The physical properties of the obtained crystals are as follows:

IRCKBr) on " ¹ : v _{c = Q} 1780, 1750

TLC Rf value: 0.6 9

Developing solvent:

Benzene: ethyl acetate: methanol = 10: 10: 3 plate: Merck TLC plate No. 5715

(2) In the solution, which was prepared by adding 19.6 g of 85% by weight of phosphoric acid to 207 ml of water and adjusting the pH to 30 with 30% aqueous sodium hydroxide solution to give the solution, which by dissolving of 59.5 g of the crystals obtained in the above step (1) was formed in 385 ml of ethyl acetate. The mixture is reacted at 25-27 ⁰ C for 2 hours, keeping the pH of the mixture with 20% aqueous potassium carbonate solution at 6.2-6.5. Subsequently, the pH is adjusted to 3.0 with hydrochloric acid. The insoluble components are removed by filtration. Then the organic layer is separated and washed with 148 ml of water. Then, 21.3 g Mesitylensulfonsäuredihydrat to the resulting organic layer and the mixture is stirred at 20-22 ⁰ C for 1 hour. The precipitated crystals are collected by filtration, washed with three 44 ml portions of ethyl acetate and getrock-v. This gives 55.5 g of Mesityiensulfonsäuresalzes of pivaloyloxymethyl-7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- (5-methyl-1,2,3,4-tetrazol-2-yl) methyl-A ³ -cephem-4-carboxylate having a melting point of 218-220 ° C (decomposition) ,

IR (KBr) cm " ¹ : v _{c = o} 1 782, 1 745, 1 680

Example 7

(1) In 13 ml of anhydrous methylene chloride is suspended 6.0 g of 2- (2-aminothiazol-4-yl) -2- (syn) -methoxy-iminoacetamide. To the resulting suspension is added 10.3 ml of a mixed solution ausSulfolan and anhydrous methylene chloride (1: 1 by volume) with a Gehaltan 2,72g boron trifluoride, specifically at 15-20 ⁰ C. The resulting mixture is reacted for 10 minutes at the same temperature , 13 ml of anhydrous methylene chloride containing 4.10 g of pivaloyloxymethyl-7-amino-3- (5-methyl-1,2,3,4-tetrazol-2-yl) methyl-A ³ -cephem acid are then added to the mixture. 4-carboxylate, and sets the resulting mixture at 30-35 ⁰ C, 2,5 hours to get. The reaction mixture is subsequently poured into 15 ml of ice-water and the pH is adjusted to 5.5 with saturated aqueous sodium bicarbonate solution. After removal of the insoluble constituents, the organic layer is separated, washed with 15 ml of saturated aqueous sodium chloride solution and

Pressure removed. To the residue obtained, 60 ml of ethyl acetate are added to form a solution. This is then mixed with 2.36 g Mesitylensulfonsäuredihydrat. The resulting mixture is stirred for 30 minutes and the precipitate formed is collected by filtration. This gives 6.37 g (yield 80.2%) of the mesitylene sulfonic acid salt of pivaloyloxymethyl-7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- (5-methyl-1, 2,3,4-tetrazol-2-yl) methyl-a ³ -cephem-4-carboxylate having a melting point of 218-220 ⁰ C (decomposition).

IR (KBr) cm " ¹ : ^ = o 1 782, 1 745, 1 680

(2) The process of the above step (1) is repeated. However, the reaction conditions given in Table 2 are used. The mesitylene sulfonic acid salt of pivaloyloxymethyl-7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamidol-S-f S -methyl-1-yl] atetrazole -dimethyl-cephem-1-carboxylate is obtained.

The physical properties (melting point, IR) of this product are identical to those of the product obtained in the above step (1).

Table 2

No. \ 2- (2-amino-thiazol-4-yl) -2- (syn) -methoxy-iminoacetamide (g) P i va1oy1oxymethyl 7-amino-3- (5-methyl-1,2,3,4-tetrazol-2-yl) -methyl-A3-cephem-4-carboxylate (g) BF3 / (g> / / ^ solutions Reaction solvent Reaction tempera ture ( ⁰ C) reactionH time (hour) s- · - .. quantity. Product / (g) / / Aus / loot (%) 1 4.0 4.1 2.04 / sulfolane Methylene chloride 30 8 5.94 / 74.8 2 6.0 4.1 2.72 / acetonitrile acetonitrile 50 5 6.3 / 79.4 3 6.0 4.1 2.72 / sulfolane + methylene chloride nitromethane 30 3 6.4 / 80.6 4 6.0 4.1 2.72 / ethyl acetate Methylene chloride + ethyl acetate 30 3 6.4 / 80.6

Note: * This solvent is one such,

in which BF _{3 is} dissolved or which forms a complex with BF-

(3) The above step (1) is repeated. However, the starting compounds given in Table 3 are used instead of 2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamide. The mesitylene sulfonic acid salt of pivaloyloxymethyl-7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido) -3- (5-methyl-1,2,3,4-tetrazol-2-yl ) methyl-A ³ -cephem-4-carboxylate.

The physical properties (melting point, IR) of this product are identical to those of the product obtained in the above step (1).

Table 3

starting compound Yield κ * ι 1 N-ethyl-2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamide 75.0 2 N-phenyl-2- (2-aminothiazol-4-yl) -2- (syn) -methoxy-irineaoacetamide 80.2 3 Np ⁱ -nitrophenyl-: 2- (2-aminothiazol-4-yl) -2- (syn) -methoxy) aminoacetamide 82.0 4 N-Cpyridin-4-yl) -2-C 2 -aminothiazol-4-yl) -2-Csyn) -methoxyiminoacetamide 65.8

Example 8

(1) In 13mg of anhydrous methylene chloride is suspended 6.0 g of 2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamid. To the resulting suspension is added 10.3 ml of a mixed solution of sulfolane and anhydrous methylene chloride (1: 1 by volume) containing 2.71 g of boron trifluoride at 15-2O ⁰ C. The mixture is reacted at the same temperature for 10 minutes , 10 ml of anhydrous methylene chloride containing 4.62 g of diphenylmethyl-7-amino-3- (5-methyl-1,2,3,4-tetrazol-2-yl) methyl-A ³ are then added to the mixture. cephem-4-carboxylate. The resulting mixture is reacted at 30-35 ⁰ C for 3 hours. The reaction mixture is poured into 50 ml of water and the pH is adjusted to 5.5 with sodium bicarbonate. After removing the insoluble matters, the organic layer is separated, washed with 20 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure, and the residue obtained is purified by a column chromatography (Wako Silica Gel C-200, eluent: chloroform-methanol). This gives 4.2 g (yield 65.1%) of diphenylmethyl-7- [2- (2-aminothiazol-4-yl) -2- (syn) methoxyiminoacetamido] -3- (5-methyl-1,2,3 , 4-tetrazol-2-yl) methyl-A ³ -cephem-4-carboxylate with a melting point of 102-105 ° C (decomposition).

IK (KBr) cm ^-1 : v _{c = 0} 1778, 1720, 1660 The compounds shown in Table 4 are obtained in a similar manner.

CN m 33 S3 Z U O U κ ' 13 C / 2 Y Z CN 33

Φ • - Φ ε •H ο U cn O H 1 ι I C <4-4 -H cn 4 C pa

CN

φ 82.0 80.0 O Il CJ ->> fQ ·· "HHO 1781, 1725, 1672 1780, • 1720, 1680, 1640 Melting point rc) 155-157 (decomposition) 166-167 (decomposition) connection α ζ Cj ι UD S CN ti OI

(2) Dissolve 6.45 g of diphenylmethyl-7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- (5-methyl-1) in a mixed solvent of 35 ml of trifluoroacetic acid and 10 ml of anisole , 2,3,4-tetrazol-2-yl) methyl-A ³ -cephem-4-carboxylate. The resulting mixture is reacted at room temperature for 1 hour. The solvent is removed by distillation under reduced pressure, and diethyl ether is added to the obtained residue. The resulting crystals are collected by filtration, washed sufficiently with diethyl ether and then dried. This gives 5.46 g (yield 92.1%) of the trifluoroacetic acid salt of 7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- (5-methyl-1SiO) . ^ -tetrazole -yOmethyl-a ^ ^ cephem-carboxylic acid having a melting point of 123-125 ⁰ C (decomposition) IR (KBr) cm ^"1: v _{c = 0} 1790.1720-1635

Example 9 Table 5

H ₀ N

OCH ₃ COOR

(Syn isomer)

connection R ³ r4 Melting point ( ⁰ C) IR (KBr) ^cm " ^{1: v} c = o * -CH ₂ OCOC (CH ₃ ) ₃ -N I 144-146 (Zers.). 1780, 1745, 1660 * -CH ₂ OCOC (CH ₃ ) ₃ ^ SCH -N Γ I ^ -N 135-137 (Zers.) 1785, 1745, 1672 -CH ₂ OCOC (CH ₃ ) ₃ -N ^. I> *.! ^CH 3 127-128 (Zers.) 1780, 1743, 1675 -CH ₂ OCOC (CH ₃ ) ₃ -N I 130-132 (Zers.) 1780, 1745, 1665 -CH ₂ OCOC (CH ₃ ) ₃ "Ν I> = N Cl 118-122 (Zers.) 1780, 1745, 1670 -CH ₂ OCOC (CH ₃ ) ₃ -N ^ N-CH ₂ CH ₃ 145-147 1780, 1740, 1675, 1640

Table 5 (cont

-CH ₂ OCOC

-N-134-137 (Zers.)

178O ₇ 1750, 1680

1650

-CH ₂ OCOCCCH ₃ )

^CH 3

141-142 (Zers.)

1775, 1740, 1650

-CH ₂ OCOC (CH ₃ )

CH ₃

156-159

1775, 1740, 1670

1640

-CH ₂ OCOC (CH ₃ J ₃

151-153 (Zers.)

1780, 1745, 1660

-CH ₂ OCOC (CH ₃ J ₃

-ty

124-125 {dec.)

1780, 1745, 1680, 1670

-CH ₂ OCOC (CH ₃ J ₃

160-164 (Zers.)

1785, 1750, 1665

-CH ₂ OCOCCCH ₃ )

-N CH 139-141 (Zers.)

1780, 1740, 1690

1660

-CH ₂ OCOC (CH ₃ )

-N

CH-

116-118 (Zers.)

1780, 1745, 1670

Table 5 (continued)

-CH ₂ OCOC (CH ₃ )

: s-

N v

112-113

1780, 1750, 1675

CH.

, N = N

-ν;

154 (Zers.)

CH ₃

1785, 1730, 1655

(CH ₂ )

0 0

-NN-CH-CH. N f 2 3

139-144 (Zers.)

1780, 1720, 1680, 1640

CHOCOC (CH ₃ ) ₃

-ν:

, N = N

^ N

127-130 (Zers.)

CH-

1780, 1740, 1675

CHOCOC (CH ₃ J ₃ CH.

-N Cl

145-147

1780, 1745, 1670

CHOCOC (CH ₃ ) CH.

-NJI-CH ₃

198-201 (Zers.).

1780, 1740, 1680

1640

CHOCOC (CH ₃ ) CH.

O 0

-N N-CK ₂ Cll ₃

148-150

1780, 1740, 1680, 1640

Table 5 (cont

-CHOCOC (CH-,)

i CH,

0 139-141 (Zers.) '

1783, 1740, 1680, 1640

CHOCOC CH,

-N N- (CH ₂ ) ₅ CH ₃

145-150 (Zers.)

1780, 1740, 1685, 1645

-CHOCOC (CH -) -

I ³ CH.,

-NN- (CHO) ₇ CH-, 170-172 (Dec.)

1780, 1740, 1680, 1640

-CHOCOC (CH-), I ³ CH.,

V? ⁰

-N N- (CH ₂ J ₁₁ Ch ₃ 153-158 (Zers.)

1780, 1745, 1675, 1640

-CHOCOC (CH ₃ ) ^[ 3

CH-

-N. 143-145 (Zers.)

1780, 1740, 1655

-CHOCOC (CH)

CH,

N = N 'S 112-116 (Zers.)

1780, 1740, 1660

-CHOCOC (CH ^) -

1 ³ CH,

CH-118-121 (Zers.)

1780, 1740, 1660

Table 5 (continued)

-CHOCOC (CH-) -

^{3 3}

CH,

-ν:

.Ν = ϋ

"N

150-160 (Zers.)

1793, 1742, 1675

N-

166-168 (Zers.)

1775, 1745, 1665

-NN-CH ₉ CH-> 200

1780, 1680, 1640

-CH ₂ OCOCH ₃

-N,

'Ν

121-124 (Zers.)

1780, 1745, 1670

-N '

N = N

107-108

1780, 1760, 1670

-CHOCOC (CH ₃ )

T ²

CHO

.N = N

-N

140-142 (Zers.)

1785, 1745, 1675

-CHOCOC (CH ₃ )

N = N

-N

153-157 (Zers.)

1785, 1745, 1680

Table 5 (continued)

-CHOCO- / 0 / CH ₃ CH ₃ 125 (Zers.) 1780, 1740, 1675

Note: * Hydrochloride (The hydrochlorides are

obtained in a conventional manner). ** Diastereomer

Claims (10)

Invention claim: (Syn-isomers q ) wherein R ^{2 is} a lower alkyl group; R ^{3 represents} a hydrogen atom or a carboxy-protecting group; and R ^{4 is} a substituted or unsubstituted heterocyclic group linked to the exomethylene group at the 3-position of the cephem ring via a carbon-nitrogen bond, characterized by reacting a compound of the formula (I) (Syn isomer) where R ^{1 is} a hydrogen atom or a substituted or unsubstituted alkyl, aralkyl, aryl or heterocyclic group and R ^{2 has} the abovementioned meaning, with a compound of the formula (III) (III) wherein R ^{3a is} a carboxy-protecting group and R ^{4 is} as defined above, reacting in the presence of boron trifluoride or a complex compound thereof and subsequently, if desired, the carboxy-protecting group removed or converts the product into a salt. 2. The method according to item 1, characterized in that R ^{1 is} a hydrogen atom. 3. The method according to item 1, characterized in that R ^{1 is} an unsubstituted alkyl group. 4. The method according to item 1, characterized in that R ^{1 represents} a substituted or unsubstituted aryl group. 5. The method according to any one of items 1 to 4, characterized in that one carries out the reaction in the presence of an organic solvent. 6. The method according to item 1, characterized in that a compound which is obtained by reacting a compound of formula (II) _ _ IT C ^ -COMR ' (ID / Τ OR (syn isomer) wherein R ¹ and R ^{2 have} the meaning given in point 1, with boron trifluoride or a Kompiexverbindung thereof was obtained, with a compound of formula (111) (III) where R ^3a and R ^{4 have} the meaning given in point 1, implements. 7. The method according to item 6, characterized in that R ^{1 is} a hydrogen atom. 8. The method according to item 7, characterized in that R ^{4 is} 2- (1,2,3,4-tetrazolyl), 1- (1,2,4-triazolyl), 2,3- (dioxo-1, 2 , 3,4-tetrahydropyrazinyl, 3,6-dioxo-1,2,3,6-tetrahydropyridazinyl, 6-oxo-1,6-dihydropyridazinyl, 2-0x0-1,2-dihydropyrazinyl, 6-oxo-1,6 dihydropyrimidinyl, 2-oxo-i, 2-dihydropyrimidinyl, 1,2,6-thiadiazine-1,1-dioxide-2-yl or isothiazolidine-1,1-dioxide-2-yl, which groups may be substituted by at least one substituent of halogen atoms, alkyl groups or alkylthio groups. 9. The method according to any one of the items 6 to 8, characterized in that the reaction in the presence of an organic Performs solvent. 10. The method according to item 7, characterized in that a compound which is obtained by reacting a compound of formula (II-a) C-COH ₂ N (syn-isomer)