NO169231B - PROCEDURE FOR THE PREPARATION OF CARBOXYLIC ACID AMIDES. - Google Patents

Description

The present invention relates to a method for the production of carboxylic acid amides by acylation of amines with 2-benzothiazolyl thioesters of carboxylic acids, which method is characterized by bringing the amine into reaction in the form of an acid addition salt.

Acylation of amines with 2-benzothiazolyl thioesters is a method known per se for the production of carboxylic acid amides. In this method, amines are reacted in the form of the free base, whereby a further organic base, usually a tertiary amine, is often added to the reaction mixture in order to speed up the course of the reaction. In those cases when an acid addition salt of an amine was used as starting material, it was believed that at least one equivalent of an organic base, usually a tertiary amine, had to be added to the reaction mixture in order to transfer the acid addition salt in the reactive form, i.e. in the free base.

It was now surprisingly found that acid addition salts of amines can be reacted directly with 2-benzothiazolylthioesters of carboxylic acids, i.e. that it is not necessary to neutralize the acid addition salt of the amine with an organic base first, in order to release the reactive form, namely the free amine. As shown below in the examples, the method according to the invention is not limited to specific 2-benzothiazolyl thioesters or to specific acid addition salts of amines. Rather, it is generally applicable.

The method according to the invention is particularly of great advantage when the amine in the free base form is not particularly stable, which is often the case for 7-amino-cephalosporin derivatives. With the method according to the invention, 7-acylaminocephalosporin derivatives can be produced with good yield and high purity.

According to this, the object of the present invention is a method for the acylation of amines with the general formula

where R is the residue of a 7-aminocephalosporin or 6-aminopenicillin derivative or of a single aromatic

amine,

with 2-benzothiazolyl thioesters of carboxylic acids, characterized in that the amine is reacted in the form of an acid addition salt.

As previously mentioned, however, the method according to the invention is not limited to specific amines. For example, 6-amino penicillin derivatives or also simple aromatic amines, such as aniline, can also be successfully acylated.

The method according to the invention can be carried out in any inert organic solvent, in which the starting materials are at least partially soluble. Examples of solvents listed below include: Halogenated lower hydrocarbons, such as methylene chloride, chloroform and carbon tetrachloride, lower N,N-dialkyl fatty acid amides, such as N,N-dimethylacetamide and N,N-dimethylformamide, lower alcohols, such as methanol and ethanol, lower dialkyl ethers, such as diethyl ether, dimethyl ether, and t-butyl methyl ether, lower cyclic ethers, such as tetrahydrofuran and dioxane, lower mono- and dialkyl ethers of alkanediols, such as ethylene glycol diethyl ether, ethylene glycol monomethyl ether, and ethylene glycol monomethyl ether, lower dialkyl ketones, such as acetone and methyl ethyl ketone, dimentyl sulphoxide, mixtures of the aforementioned solvents and the like.

Preferred solvents are halogenated lower hydrocarbons, especially chlorinated lower hydrocarbons, lower alcohols and lower N,N-dialkyl fatty acid amides. A particularly preferred solvent is methylene chloride. The method according to the invention can be carried out in a wide temperature range. It can, for example, be carried out in a range from 0°C to 60°C. The reaction is preferably carried out in a temperature range from 15°C to 30°C, whereby, in a particularly preferred embodiment, work is carried out at room temperature.

As an acid addition salt, both salts with inorganic and organic acids come into consideration. Acid addition salts with aromatic or aliphatic sulphonic acids, or mineral acids are preferably used. In a particularly preferred embodiment, acid addition salts with p-toluenesulfonic acid or hydrochloric acid are used.

A compound of the general formula I is preferably used as amines

wherein R<1> means hydrogen or a for the blocking of the 4-carboxy group in cephalosporins common group, and R<2> means hydrogen or a for the 3-position in cephalosporins common group. In a particularly preferred embodiment, amines with the formula I are used, where R<1> means hydrogen or the group -A-OCOR where A means lower alkoxy, R means lower alkyl or lower alkylidene, R<2> means hydrogen, halogen, lower alkyl , lower alkenyl, lower alkanoyloxyalkyl, lower azidoalkyl, lower carbamoyloxyalkyl or the group -CH2-S-Q, -CH=CH-S-Q or -CH2-Q, Q is a heterocyclic group bonded over a carbon atom, and Q<1> is a over a nitrogen atom bound, N-containing heterocyclic group, where the heterocyclic groups are ordinary groups

in cephalosporins.

A compound of the general formula II is preferably used as 2-benzothiazolyl thioesters of carboxylic acids.

in which R<3> means lower alkyl, lower alkylene, lower alkanoyl or the group -A'-COOR', A' means lower alkylene, R<*> means a carboxy protecting group common in cephalosporin chemistry, and Q' means a heteroaromatic bonded over one carbon atom group, whereby the heteroaromatic groups are common groups in 7-oxyiminoacetylamino-cephalosporins. In a particularly preferred embodiment, a compound of formula II is used where R<3> means methyl or the group -A^COOR, 1 A<*> means methylene or 2,2-propylene, R' means t-butyl, and Q" means 2-amino-4-thiazolyl or 2-furanyl.

In the reaction by an acid addition salt of an amine of formula I with a compound of formula II, a compound of the general formula III is first formed.

in which R<1>, R<2>, R<3> and Q" have the meanings given above, or if there is an amino group which can form a salt, the corresponding acid addition thereof. With

these compounds are known compounds, which have antimicrobial properties or which can be transferred into antimicrobially effective compounds by known methods.

In the case of the antimicrobially active 7-acylamino-cephalosporin derivatives, which can be produced in a preferred embodiment according to the invention, it concerns the compound with the general formula IV,

where R 4 means hydrogen, lower alkyl, lower alkylene or the group -A<*> -COOH, and R 1 , R 2 , A' and Q have the meanings given above, and the pharmaceutically acceptable salts thereof.

In a particularly preferred embodiment, methylene-(6R, 7R)-7-amino-3-[(5-methyl-2H-tetrazol-2-yl)-methyl]-8-oxo-5-thia- l-azabicyclo-[4.2.0]oct-2-ene-carboxylate-pivalate and as benzthiazolylthioester (Z)-2-(2-amino-4-thiazolyl)-2(methoxyimino)-acetic acid-2-benzthiazolylthioester where an acid addition salt of (6R,7R)-7-[(Z)-2-(2-amino-4-thiolyl)-2-(methoxyimino)-acetamido]-3-[(5-methyl-2H-tetrazole) is prepared -2-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene carboxylate pivalate.

Within the scope of the present invention, the term "lower" denotes groups and compounds with up to 7, preferably up to 4, carbon atoms. The term "alkyl" taken by itself or, in combination as alkoxy, alkylene, alkylidene and azidaolalkyl, denotes straight or branched chain saturated hydrocarbon groups such as methyl, acetyl, isopropyl and t-butyl. The term "alkenyl" denotes straight and branched chain unsaturated hydrocarbon groups, such as allyl. The term "alkanoyl" denotes straight-chain or branched fatty acid groups

such as acetyl.

The term "heteroaromatic groups" preferably denotes monocyclic heteroaromatic groups which as heteroatoms preferably contain an oxygen or sulfur atom and/or 1-4 nitrogen atoms. They are preferably 5- or 6-jointed. They may possibly be substituted, whereby amino or lower alkyl groups can for example be used as substituents; 2-furanyl, 2-amino-4-thiazolyl and 5-methyl-1,3,4-thiadiazol-2-yl are examples of heteroaromatic groups.

The term "heterocyclic group" preferably denotes nonocyclic, especially 5- and 6-membered, partially unsaturated or aromatic heterocyclic groups, which heteroatom preferably contains oxygen or a sulfur atom and/or 1-4 nitrogen atoms, or bicyclic, especially 8-10 membered , partially unsaturated or aromatic heterocyclic groups, which as heteroatoms preferably contain oxygen or sulfur atoms and/or 1-5 nitrogen atoms. This group is preferably unsubstituted or substituted with hydroxy, also oxo, lower alkyl and/or lower oxoalkyl.

The term "N-containing heterocyclic group" preferably denotes saturated, partially unsaturated and aromatic heterocyclic groups, which contain up to 4 nitrogen atoms as heteroatoms. They are preferably 5- or 6-membered and may also carry a condensed 5- or 6-membered cycloalkane or benzene ring. It is preferably substituted with lower alkyl or carbamoyl. The nitrogen atom, over which the N-containing heterocyclic group is also attached, can also be quaternary substituted. 5-Methyl-2-tetrazolyl and pyridinium-1-yl are examples of N-containing heterocyclic groups.

European Patent Application No. 37,380 (filed October 7, 1981) describes a process for the preparation of 7-acylaminocephalosporin derivatives by acylating a 7-amino-cephalosporin derivative with a 2-benzothiazolylthioester in an inert organic solvent at a temperature from -40°C to 60"C. The amino component is reacted in the form of the free base. Similar methods are described in European patent applications no. 115,770 and 187,209 and in the international patent application with publ. no. WO 85/04659.

The difference between the present method and the known methods is thus that the amino component is reacted in the form of an acid addition salt and not in the form of the free base. It is worth noting that in the present improved process no base is added during the reaction.

It is well known in the art that amines in the form of the free base are reactive, nucleophilic compounds that easily undergo

various kinds of reactions such as acylation with reactive derivatives of carboxylic acids to give amides and condensation with ketones and aldehydes to give imines. On the other hand, it is also well known that amines are normally completely deactivated if they are converted to acid addition salts. For example, bifunctional compounds having a primary amino and a carbonyl function cannot be stored in the form of the free base due to self-condensation. However, self-condensation can be avoided by protonating the amino function with a strong acid. The amino group in the bifunctional compound is then present in the form of an unreactive acid addition salt, and the bifunctional compound can be stored in this form without problems.

In view of the fact that amines are known to be deactivated by protonation with strong acids, one skilled in the art would not expect a reaction to take place between a 2-benzothiazolyl thioester and an acid addition salt of carboxylic acids without the need to neutralize the acid addition salt with a base to release the reactive form, namely the free amine. The various examples in the present case show, and it is also surprising, that the present improvement is not limited to specific 2-benzothiazolyl thioesters or to specific acid addition salts of amines. It has a much wider application.

In order to substantiate the advantages of the method according to the invention, Example 1 below was compared with the example in European Patent Publication No. 187,209. The two methods differ mainly in the form of the amine to be acylated: In example 1 below, it is present as an acid addition salt (p-toluenesulfonate); the amine to be acylated is methylene-(6R,7R)-7-amino-3-methyl-8-oxo-5-thia-1-azobicyclo[4.2.0]oct-2-ene-2-carboxylate-pivalate-p -toluenesulfonate; and in the example from European patent publication 187,209 the amine to be acylated is present as a base, namely methylene-(6R,7R)-7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo-[4.2.0 ]oct-2-ene-2-carboxylate pivalate.

The comparison of yield and purity of the final product (in both cases methylene-(6R,7R)-7-[(Z)-2-(2-amino-4-thiazol-lyl)-2-(methoxyimino)-acetamido]-3 -methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate-pivalate-hydrochloride) showed the following:

However, the product from EPOS 187.209 is present at 4% as unwanted hydroiodide. Example 1 gives a clearly higher yield and, moreover, a uniform hydrochloride which is not contaminated with unwanted hydroiodide.

The following examples serve to elucidate the present invention in more detail.

Example 1

8.77 g of (6R, 7R)-7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-1-carboxylic acid are suspended in 60 ml of acetone, add during 15 minutes at 20 - 25°C with stirring 6.3 g of 1,8-diazabicyclo [5.4.=]undec-7-ene (DBU), add to the formed solution at 15°C 10.6 g pivaloyloxymethyl iodide and stir for 15 minutes without cooling. 250 ml of n-butyl acetate are then added, after which the crystallized DBU hydroiodide is suction filtered and washed with 50 ml of n-butyl acetate. The yellow filtrate is washed twice with 125 ml of saturated salt solution and filtered over a folding filter. 100 ml of the solvent is distilled off in a water jet vacuum at 35°C. The solution is filtered once more and 8.4 g of p-toluenesulfonic acid is added with stirring, whereby the product crystallizes out. After stirring for 30 minutes, it is suction filtered, washed with n-butyl acetate and n-hexane and dried overnight in a water jet vacuum at 35°C. 18.5 g (92.3 6%) of methylene-(6R,7R)-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2 are obtained -carboxylate-pivalate-p-toluenesulfonate as white crystals (C14H20N2°5S-C7H8SO3 '* MG: 500' 581).

10.02 g methylene-(6R,7R)-7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate-pivalate-p- Toluenesulfonate is dissolved in 100 ml of methylene chloride, after which 7.0 g of S-(2-benzothizolyl)-2-amino-4-thiazole-thio-glyosylate-(Z)-0-methyloxime are added, stirred for 1.5 hours at 20 - 25°C, and wash the resulting solution twice with 50 ml of 5% sodium acetate solution and once with 50 ml of water, filter over a pleated filter and evaporate in a water jet vacuum at 30°C. The residue is dissolved in 100 ml of isopropanol while adding 4.5 ml of 5.2 N-hydrochloric acid in isopropanol. One touches

for 15 - 20 minutes at 25°C, during which a strong crystallization occurs. While stirring, 100 ml of n-hexane is added dropwise over 30 minutes, and the crystallized material is filtered, washed with isopropanol/n-hexane (1:1) and n-hexane, and dried overnight in a water jet vacuum at 40°C. 10.25 g (93.5%) of methylene-(6R,7R)-7-[8Z)-2-(2-amino-4-thiazolyl)-2(methoxyimino)-acetamido]-3-methyl- 8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate-pivilate hydrochloride as colorless crystals. This material is dissolved at 40°C in 50 ml of ethanol. 30 ml of n-hexane is then added dropwise and allowed to crystallize over 15 minutes with stirring. After the dropwise addition of a further 20 ml of n-hexane, the precipitate is suction filtered, washed with ethanol/n-hexane (1:1) and n-hexane and dried in a water jet vacuum at 40°C. 8.9 g (86.8%) of the desired product is obtained.

(C20H25N5°7S2-HC1'" MG: 548.029).

Example 2

a) 22.3 g of (6R,7R)-7-amino-3-acetoxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid are suspended in 120

ml of acetone, after which 12.6 g of 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) are added during 15 minutes and with stirring at 20 - 25°C. To the solution formed, 21.2 g of pivaloylmethyl iodide is added at 15°C, and it is stirred for 15 minutes without cooling. Then 500 ml of n-butyl acetate is added, after which crystallized DBU hydroiodide is suction filtered and washed with 100 ml of butyl acetate. The yellow filtrate is washed 2 times with 250 ml of saturated salt solution and filtered over a folding filter. 200 ml of solvent is distilled off in a water jet vacuum at 35 °C. The solution formed is filtered once more and, while stirring, is added

16.8 g of p-toluenesulfonic acid, H 2 O, whereby the product crystallizes. After stirring for 30 minutes, the product is suction filtered, washed with butyl acetate and n-hexane and dried overnight in a water jet vacuum at 35°C. 38.7 g (86.6%) of methylene-(6R,7R)-3-(acetoxymethyl)-7-amino-8-oxo-5-thia-azabicyclo[4.2.0]oct-2-ene- 2-carboxylate-pivalate-p-toluenesulfonate as colorless crystals.

(C16<H>22<N>2°7S'C7H8S03: MG: 558' 617)

b) 5.58 g methylene-(6R,7R)-3-(acetoxymethyl)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate- pivalate-p-toluenesulfonate is stirred in 60 ml of methylene chloride together with 3.5 g of S-benzothiazolyl)-2-amino-4-thiazole-thioglyoxylate-(Z)-0-methyloxime for 2 hours at 20 - 25°C. The resulting solution is washed twice with 30 ml of 5% sodium acetate solution and once with 30 ml of water, filtered over a pleated filter and evaporated by water jet vacuum at 40°C. The residue is dissolved in 50 ml of ethyl acetate while adding 2.5 ml of 5.2N-hydrochloric acid in isopropanol. 100 ml of ether is added, whereby a resinous material precipitates. The supernatant liquid is decanted off, and the resin is dissolved in 50 ml of acetic acid and crystallized by slow addition of ether. It is suction filtered, washed with ether and petroleum ether and dried overnight in a water jet vacuum at 30°C. 3.7 g (61%) of methylene 3-(acetoxymethyl)-(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)2-(methoxymino)acetamido]8- are obtained oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate hydrochloride as beige crystals (C22<H>27N5°9S2-HC1' MG' 606,065).

Example 3

11.5 g of (6R,7R)-7-amino-3-azidomethyl-8-ozo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid are suspended in 250 ml of methylene chloride . 6.5 g of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) are added at 20 - 25°C with stirring. After stirring for 15 minutes, 10.9 g of pivaloylozymethyl iodide are added to the dark suspension and stirred for 20 minutes at 20 to 25°C. Now 200 ml of water is added, and the emulsion is filtered through a filtration aid. The organic phase is separated, washed with 200 ml of water and 250 ml of n-butyl acetate is added, after which 250 ml of solvent is distilled off in a water jet vacuum at 25°C. The solution is filtered over a folding filter and the filtrate is added with stirring to 7.6 g of p-toluenesulfonic acid -H2O. After stirring for 30 minutes, crystallized material is suction filtered, washed with methyl acetate and low-boiling petroleum ether and dried overnight in a water jet vacuum at 35°C. 11.5 g (53.10%) of methylene-(6R,7R)-7-amino-3-(azaidomethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2- ene-2-carboxylate-pivalate-p-toluenesulfonate as beige crystals.

(C14<H>19<N>5°5S-C7H8SO3' MG: 541' 594).

b) 5.42 g methylene-(6R,7R)-7-amino-3-(azadomethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate- pivalate-p-toluenesulfonate is suspended in 50 ml of methylene chloride, after which 3.5 g of S-(2-benzothiazolyl)-2-amino-4-thiazole-thioglyoxylate-(Z)-o-methyloxime are added and stirred for 2 hours at 20 - 25°C. The resulting solution is washed twice with 50 ml of 5% sodium acetate solution and once with 50 ml of water and filtered over a pleated filter.

The residue is dissolved in 50 ml of ethyl acetate with the addition of 2.5 ml of 2N hydrochloric acid in isopropanol. While stirring, 150 ml of ether is added, whereby amorphous precipitated material is suction filtered. A solution of the material formed in 50 ml of acetic acid is poured with stirring into 150 ml of ether. The amorphous precipitated material is suction filtered, washed with ether and low-boiling petroleum ether and dried overnight in a high vacuum at 30°C. 5.0 g (84.75%) of methylene-(6R,7R)-7[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyimino)acetamido-3-(azidomethyl)- 8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate pivalate hydrochloride as a beige amorphous solid.

(C20<H>24<N>8°7S2-HC1; MG: 589.042).

Example 4

15.6 g of 7-amino-3[[(5-methyl-1,3,4-thiadiazol-2-yl)-thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0 ]oct-2-ene-2-carboxylic acid is suspended in 250 ml of methylene chloride, after which, with stirring at 20 - 25°C, 6.5 g of 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU ). After 15 minutes of stirring, 10.9 g of pivaloyloxymethyl iodide are added. Stir for 20 minutes at 20 - 25°C, add 250 ml of water and filter the emulsion through a filter aid. The organic phase is separated, washed with 250 ml of water and 500 ml of n-butyl acetate is added, after which one evaporates in a water jet vacuum at 35°C to a volume of 400 ml, filters and adds to the filtrate 7.6 g of p-toluenesulfonic acid, H20 while stirring After stirring for 30 minutes, the crystallized material is suction filtered, washed with n-butyl acetate and low-boiling pertrol ether and dried overnight in a water jet vacuum at 35° C. The material formed (12.0 g beige crystals) is dissolved in 100 ml methylene chloride. 250 ml of acetic acid and evaporate the solution in a water jet vacuum at 30°C to a volume of 150 ml. The crystallized material is suction filtered, washed with acetic acid and boiling petroleum ether and dried

overnight in a water jet vacuum at 3 <C>C. 8.2 g (32.5%) of methylene-(6R,7R)-7-amino-3[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8 are obtained -oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate-p-toluenesulfonate as white crystals, (C17H22<N>4°5<S>3-<C>7H8SO3' MG: 630,764).

b) 6.3 g methylene-(6R,7R)-7-amino-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo- 5-thia-1-azabicyclo[4.2.0]-oet-2-ene-2-carboxylate-pivalate-p-toluenesulfonate is dissolved in 60 ml of methylene chloride. 3.5 g of S-(2-benzothiazolyl)-2-amino-4-thiazole-thioglyoxylate-(Z)-O-methyloxime are added, stirred for 2 hours at 20 - 25°C, the solution is washed 2 times with 50 ml of 5% sodium acetate solution and 1 time with 50 ml of water, filter over a pleated filter and evaporate by water jet vacuum at 30°C. The residue is dissolved in 100 ml of vinegar. While stirring, 2.5 ml of 5.2 n-hydrochloric acid in isopropanol is added, the precipitated hydrochloride is suction filtered, and washed with vinegar and low-boiling petroleum ether and dried overnight in a water jet vacuum at 30°C. The material obtained (6.2 g dissolved in 30 ml of acetone). While stirring, 150 ml of ether is poured, the amorphous precipitated material is suction filtered, washed with ether and petroleum ether and dried overnight in a high vacuum at 40°C. 5.0 g (73.7%) of methylene-(6R,7R) are obtained -7-[(Z)-2-(2-amino-4-thiazolyl)-2-(meth-oxyimino)acetamido]-3[[(5-methyl-1,3,4-thiadiazol-2-yl) thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate pivalate hydrochloride as a beige amorphous solid, (C23H27<N>7°7S4'HC1 ' MG: 678,212).

Example 5

a) 12.15 g of (6R,7R)-7-amino-3-(5-methyl-2H-tetrazol-2-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct- 2-ene-2-carboxylic acid

suspended in 60 ml of acetone. 6.3 g of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) are added during 15 minutes at 20 - 25°C with stirring, to the resulting solution at 15°C 10.6 g pivaloyloxymethyl iodide and stir for 15 minutes without cooling. 250 ml of n-butyl acetate are then added. 250 ml of n-butyl acetate is suction filtered from the crystallized and washed with 50 ml of n-butyl acetate. The yellow filtrate is washed twice with 125 ml of saturated salt solution and filtered over a folding filter. In a water jet vacuum, 100 ml of solvent are distilled off at 35°C. The solution is filtered again and 8.4 g of p-toluenesulfonic acid are added with stirring. The crystallized material

filtered with suction after stirring for 30 minutes, and washed with n-butyl acetate. The material obtained is suspended in 200 ml of butyl acetate and, with stirring, 20 ml of 5.2 hydrochloric acid in isopropanol is added, whereby a slurry is formed. The solution is stirred for 1 hour, during which crystallization occurs. Mon

The crystallized hydrochloride is suction filtered, washed with n-butyl acetate and n-hexane and dried overnight in a water jet vacuum at 35°C. 13.9 g (77.75%) of methylene-(6R,7R)-7-amino-3 -[5-methyl-2H-tetrazol-2-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate-pivalate hydrochloride as white crystals,

(C16<H>22N6°5S-HCl/ MG: 446.91).

b) 4.46 g methylene-(6R,7R)-7-amino-3-[(5-methyl-2H-tetrazol-2-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2 .0]oct-2-ene-2-carboxylate pivalate hydrochloride is dissolved in 50 ml of methylene chloride. 4.79 g of S-(2-benzothiazolyl)2-amino-a-[(Z)-(1-butoxycarbonyl-1-methylethoxy]imino]-4-thiazole-thioacetate are added, stirring for 3 hours at 20 - 25 °C, evaporate the solution in a water jet vacuum at 30°C and dissolve the residue in 50 ml of acetic acid. While stirring, add 200 ml of ether, whereby a resin is precipitated. The above liquid phase is decanted. The resin is dissolved in 50 ml of acetic acid, after which while stirring, pour into 300 ml of ether. The amorphous precipitated material is suction filtered, washed with ether and low-boiling petroleum ether, and dried overnight in a water jet vacuum at 35° C. 6.55 g (86.4%) of methylene-(6R,7R )-7-[(Z)-2-(2-amino-4-thiazolyl)-2[[1-(t-butoxycarbonyl)-1-methylethoxy-]imino]acetamido]-3[(5-methyl-2H -tetrazol-2-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylate pivalate hydrochloride as a beige amorphous solid,

(C29H39<N>9°9S2-HC1; MG:758,266)

Example 6

4.46 g methylene-(6R,7R)-7-amino-3[(5-methyl-2H-tetrazol-2-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0] oct-2-ene-2-carboxylate pivalate hydrochloride is dissolved in 60 ml of methylene chloride. 4.5 g of S-(2-benzothiazolyl)-2-amino-4-thiazole-thioglyoxylate (Z)-0-[(t-butoxycarbonyl)-methyl]oxime are added and stirred for 3 hours at 20 - 25°C . The solution evaporates in a water jet vacuum at 30°C. The remainder is dissolved in 50 ml of vinegar. While stirring, 200 ml of ether is added, amorphous precipitated material is suction filtered and washed with ether. The material obtained is dissolved in 30 ml of vinegar. While stirring, pour in 300 ml of ether. The amorphous precipitated material is suction filtered, washed with ether and low-boiling petroleum ether, and dried overnight in a water jet vacuum at 40°C. 6.2 g is obtained

(84.9%) methylene-(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2[[t-butoxycarbonyl)methoxy]imino]-acetamido]-3- [5-Methyl-2H-tetrazol-2-yl)methyl]-8-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate pivalate hydrochloride as a beige amorphous solid, (C27 <H>35N909S2.HC1: MG: 730,212).

Example 7

26.1 g methylene-(6R,7R)-7-amino-3-[(5-methyl-2H-tetrazol-2-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0 ]oct-2-ene-2-carboxylate pivalate hydrochloride is dissolved in 2 60 ml of methylene chloride. 20.44 g of S-(2-benzothiazolyl)-2-amino-4-thiazole-thioglyoxylate-(Z)-O-methyloxime are added, the solution is stirred for 2 hours at 20 - 25°C and then evaporated in a water jet vacuum at 30° C. The residue is dissolved in 350 ml of acetone. It is allowed to crystallize for 1.5 hours with stirring, suction filtered, washed with acetone and n-hexane and dried overnight in a water jet vacuum at 35°C. The material obtained (33.15 g of colorless crystals) is dissolved in 100 ml of methanol, after which 100 ml of ethanol and then 130 ml of n-hexane are added, allowed to crystallize for 30 minutes at 20 - 25°C, 70 ml of n-hexane are added dropwise while stirring for about 30 minutes, suction filter and wash the material obtained with ethanol/n-hexane (1:1), and n-hexane and dry overnight in a water jet vacuum at 35°C. 29.5 g (80.16%) of methylene-(6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-[ 5-Methyl-2H-tetrazol-2-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate-pivalate hydrochloride as white crystals, (C22 <H>27<N>9°7S2'HC1; MG: 630.095).

Example 8

3.25 g of methylene-(2S,5R,6R)-6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate-pivalate-hydrochloride are dissolved in 30 ml of methylene chloride, after which 3.1 g of S-(2-benzothiazolyl)-2-amino-4-thiazole-thioglyoxylate (Z)-0-methyloxime are added, stirred for 2 hours at 20 - 25°C and filtered obtained resolution over a folding filter. The filtrate is poured with stirring into 200 ml of isopropyl ether.

The amorphous precipitated material is suction filtered, washed with isopropyl ether and dissolved in 250 ml of n-butyl acetate. In a water jet vacuum at 30°C, it is then evaporated to a volume of 100 ml. While stirring, 100 ml of ether is added, the precipitated material is suction filtered, washed with ether and low-boiling petroleum ether and dried overnight in a high vacuum at 40°C. You obtain 3.7 g (76%) methylene-(2S,5R,6R)-6-[(z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-acetamido]-3,3-dimethyl-7 -oxo-5-thia-1-azabicyclo[3.2.0]-heptane-2-carboxylate pivalate hydrochloride as a yellow amorphous solid.

Example 9

1.3 g of aniline hydrochloride is suspended in 50 ml of methylene chloride. 3.5 g of S-(2-benzothiazolyl)-2-amino-4-thiazole-thioglyoxylate-(Z)-O-methyloxime are added and stirred for 1.5 hours at 20 - 25°C, whereby a solution is obtained from which the desired product is crystallized. It is suction filtered, washed with methylene chloride and dried in a water jet vacuum at 3CC. The material obtained (3.1 g of beige crystals) is dissolved in 31 ml of methanol while heating. It is cooled to 20°C, 30 ml of ether is added, the crystallized material is suction filtered, washed with methanol/ether, (1:1) and ether and dried overnight

in high vacuum at 4 0°C. 2.35 g (75.1%) of 2-amino-4-thiazoleglyoxylanilide-(Z)-O-methyloxime hydrochloride are obtained as beige crystals (C12H12N402S.HC1 '* MG: 312.775)

Example 10

3.64 g 1-[[(6R,7R)-7-amino-2-carboxy-8-oxo-5-thia-1-azabi-cyclo[4.2.0]oct-2-en-3-yl] methyl]pyridinium hydroxide inner salt dihydrochloride is dissolved in 250 ml of methanol. 5.74 g of S-(2-benzothiazolyl)2-amino-a-[(Z)-[1-(t-butoxycarbonyl)-1-methylethoxy]imino]-4-thiazole-thioacetate and 150 ml of methylene chloride are then added and stir for 2 hours at 20 - 25°C. The yellow solution formed is evaporated by water jet vacuum at 30°C, and the residue is stirred with 100 ml of acetone. The solid is suction filtered, washed with acetone and dried in a vacuum at 25°C. The material formed (5.6 g of beige amorphous solid) is distributed between 50 ml of water and 50 ml of methylene chloride. The aqueous phase is separated, washed twice with methylene chloride, and freeze-dried overnight in high vacuum. 4.2 g (62.2%) of 1-[[(6R,7R)-7-[(Z)-(2-amino-4-thiazolyl)-2-[[1-(t-butoxycarbonyl) are obtained -1-methylethoxy]imino]acetamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en -3-yl]methyl]pyridinium hydroxide inner salt dihydrochloride as a beige lyophilisate (C26H30<N>6O7S2•2HC1; MG: 675,603).

Example 11

3.09 g of (6R,7R)-7-amino-3-acetoxymethyl-8-oxo-5-thia-1-azabi-cyclo[4.2.0]oct-2-ene-2-carboxylic acid hydrochloride are dissolved in 50 ml N,N<1->dimethylacetamide. 4.2 g of S-(2-benzothiazolyl)-2-amino-4-thiazole-thioglyoxylate-(Z)-O-methyloxime are added, the solution is stirred for 30 minutes at 20 - 25°C, and then evaporated in high vacuum at 35°C. The residue is dissolved in 25 ml of acetone. While stirring, 200 ml of ether is poured in, the precipitated material is filtered, washed with ether and dried in a water jet vacuum at 30°C. The material obtained (6.5 g of yellow amorphous solid) is stirred in 100 ml of isopropanol while adding 2 ml of 5N hydrochloric acid in isopropanol for 1 hour at 25°C, whereupon crystallization occurs. The crystals are suction filtered, washed with isopropanol and low-boiling petroleum ether, and dried overnight in high vacuum at 30°C. 3.55 g (72.15%) of (6R,7R)-3-(acetoxymethyl)-7-[2-(amino-4-thiazolyl)-2-(methoxyimino)acetamido]-8-oxo-5 -thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid hydrochloride as beige crystals (C16<H>17<N>507S2.HC1.0,3 isopropanol; MG: 509.95) .

Example 12

3.75 g of (6R,7R)-amino-3-methyl-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid hydrochloride are dissolved in 75 ml of N, N'-dimethylacetamide, after which 6.3 g of S-(2-benzothiazolyl)-2-amino-4-thiazole-thioglyoxylate-(Z)-O-methyloxime are added, stirred for 30 minutes at 35°C and evaporated in high vacuum at 20 - 25°C. The residue is stirred with 500 ml of methylene chloride. The precipitated material is suction filtered, washed with methylene chloride and ether and dried by water jet vacuum at 25°C. The material obtained (6.3 g of almost colorless amorphous solid) is stirred in 100 ml of isopropanol while adding 3 ml of 5N hydrochloric acid in isopropanol for 2 hours at 20 - 25°C, whereby crystallization occurs. The crystals are suction filtered, washed with isopropanol and ether and suspended in 40 ml of ethanol. The suspension is stirred for 30 minutes at 50°C. It is then cooled to 20°C, and the solid is suction filtered, washed with ethanol and n-hexane and dried overnight in a high vacuum at 30°C.

2.4 g (37%) of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-methyl-8 are obtained -oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid hydrochloride as colorless crystals (C14H15N505S2.HC1; MG: 433.885).

Example 13

2.23 g methylene-(6R,7R)-7-amino-3-[5-methyl-2H-tetrazol-2-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0] oct-2-ene-2-carboxylate pivalate hydrochloride is dissolved in 50 ml of methylene chloride, after which 2.71 g of (S)-(2-benzothiazolyl)-thiobenzoate is added, stirring for 24 hours at 20 - 25°C , and evaporates the solution in a water jet vacuum at 30°C. The residue is stirred for 1 hour with 25 ml of ether. Filter with suction and wash with ether. The material is dissolved in 40 ml of methylene chloride, 80 ml of isopropenyl ether is added and the solvent is distilled off in a water jet vacuum at 30°C, whereby the product crystallizes. The crystals are suction filtered, washed with isopropyl ether and dried overnight in high vacuum at 30°C. 1.2 g (46.7%) of methylene-(6R,7R)-7-benzamido-3-[(5-methyl-2H-tetrazol-2-yl)methyl]-8-oxo-5-thia are obtained -1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate-pivalate as white crystals (C23H26N606S; MG: 514.557).

Claims (2)

1. Procedure for the acylation of amines with the general formula where R is the residue of a 7-aminocephalosporin or 6-aminopenicillin derivative or of a single aromatic amine, with 2-benzothiazolyl thioesters of carboxylic acids, characterized in that the amine is reacted in the form of an acid addition salt. 2. Method according to claim 1, characterized in that an acid addition salt with p-toluenesulfonic acid or hydrochloric acid is used.