CS216507B2 - Manufacturing process for derivatives of 7- +l2-/2-aminothiazol-4-yl/-2-oximinoacetamido +p -ceph-3-em-4-carboxylic acid - Google Patents

Description

It is known that compounds of formula I

containing an oxyimine moiety of the formula —C — CO—,

II

N

AND

OR _t may exist in the form of syn- and antia that their biological activities are different.

Furthermore, it is known that the syn-oxyiminoether is converted very readily to the anti-compounds due to the different reaction conditions, so that special methods must be used to avoid this isomerization and to obtain uniform products in the form of the syn-.

Thus, for example, it is known from DOS 2 702 501 that compounds of the formula I in which the R10 group is in the syn position are formed when the acylation is carried out with symmetrical 2-alkoxyiminoacetic anhydride.

This rearrangement has the disadvantage that 2-alkoxyiminoacetic acid must be added in twice the amount of the acylated amino compound.

It is further known from DOS 2,223,375 and 2,256,534 that the chlorides of the compounds of formula II can be prepared in admixture with their anti-compounds using the sodium salt of the corresponding carboxylic acid with oxalyl chloride using a catalytic amount of dimethylformamide or free acid with phosphoropentachloride. . Furthermore, in DOS No. 2,556,736, it is described for aminothiazolyl compounds that the use of oxalyl chloride as the acid chloride-forming agent from the sodium salt gives a compound whose NMR spectrum shows that it is an anti-compound.

son Η anti Η

6.75 (D ₂ O)

7.58 (D ₂ O)

DOS 2 702 501 DOS 2,556,736

Finally, it is described in the literature that, when dimethylformamide and phosphorus oxychloride, thionyl chloride or phosgene are used, acylation of the 7-amino-cephem compound with 2- (2-amino-thiazolyl) alkoxyiminoacetic acid proceeds well. In-house research shows that products produced in this way are produced in moderate amounts and in poor purity. As further described in the literature, ultimately, purification by chromatography is necessary to obtain a pure product.

In addition, it is known in the literature that diimethylformamide with thionyl chloride forms a compound which is not very stable and which can decompose rapidly with traces of Fe ³⁺ .

Surprisingly, it has now been found that the use of a compound of formula (IV) gives rise to reaction products of higher stability upon addition of an acid halide-forming agent such as phosgene, oxalyl chloride, phosphoropentachloride or phosphorus oxychloride. These reaction products form active complexes with the carboxylic acids of the formula II, which surprisingly react with the 7-amino-cephem compounds of the formula II in an unexpectedly excellent yield and high purity to the derivatives of the formula I. It is surprisingly emphasized that the acylation proceeds without rearrangement. an oxyiminoether moiety from the syn to the anti-form.

carboxy, C 1 -C 4 alkoxycarbonyl, phenyl, C 1 -C 4 alkylphenyl or halophenyl, C 2 -C 6 alkenyl which may still be substituted by halogen, phenyl, C 1 -C 4 alkylphenyl in the alkyl moiety and hailoigenphenyl, R 2 denotes an aminothiazolyl in which the amino group is optionally substituted. protected by up to β 19 carbon atoms, cleavable by acid hydrolysis or hydrogenolysis, and

B denotes acetoxymethyl, carbamoylmethyl or the group —CH2 S — Het, wherein Het represents a five-membered ring in which 1-4 carbon atoms are replaced by sulfur and / or nitrogen atoms, or 1-methyl-tetrazol-2-yl or 2-methyl-1 A 3,4-thiadiazol-5-yl radical, the group R10 being in the syn position is 0, 1 or 2, characterized in that the carboxylic acid of the formula II is reacted,

R @ 2 —C — COOH II

N

ORi (II)

According to the invention, the preparation of a compound of formula I, wherein R1 and R2 are as defined above, or a salt thereof, in the presence of from 0.1 to 3.0 moles of a compound of formula IV,

R3

R5

Z II N

STEED,

(U where

A denotes hydrogen, an alkali or alkaline earth metal equivalent or an organic nitrogen base,

R 1 represents hydrogen, C 1 -C 4 alkyl which may be optionally substituted

N — C / \

R 4 O (IV) wherein the radicals R 3, R 1 and R 5 are the same or different and represent alkyl of 1 to 6 carbon atoms, wherein the radicals R 3 and R 4 or R 3 and R 5 may also together form a four to eight membered ring optionally interrupted by oxygen or other a nitrogen atom, and

R 5 can also be a dialkylamino group in which the alkyl groups have 1 to 6 atoms? carbon and may together form a six-membered ring, or a 4- to 8-membered ring, which is interrupted by oxygen or another nitrogen atom, with an acid halide forming agent and the resulting complex is reacted with cephemic acid of formula III,

wherein B and n are as hereinbefore defined, in the form of an amine salt or esters cleavable by acid hydrolysis or hydrogenolysis, or in the form of silyl esters, and, if desired, a cephem compound of the formula I containing a carboxy group is converted another compound as substituent A.

In the eephem compounds of formula I, A may be hydrogen, an alkali metal, particularly sodium, an alkaline earth metal equivalent, especially calcium, an equivalent of an organic nitrogen base, especially diethylamine, diethanolamine or procaine.

R 1 may, for example, be hydrogen, alkyl of up to 4 carbon atoms, such as methyl, ethyl, propyl, butyl, preferably methyl, which may optionally be mono- or polysubstituted by carboxy, C 1 -C 4 alkoxycarbonyl, preferably methyloxycarbonyl or ethoxycarbonyl, phenyl which may optionally be further substituted by C 1 -C 4 alkyl, preferably methyl or halogen, preferably chlorine or bromine, further R 1 may be C 1 -C 6 alkenyl such as allyl or crotonyl, which may optionally be further substituted by halogen, in particular by chlorine or bromine. Further, R 1 may be phenyl optionally substituted with C 1 -C 4 alkyl or halogen.

R @ 2 may be aminothiazolyl in which the amino group is optionally protected by a group containing up to 19 carbon atoms which may be cleaved by acid hydrolysis or hydrogenolysis, such as, for example, chloro- or bromoacetyl, benzoxycarbonyl, tert-butoxycarbonyl or especially trityl.

Substituent B may be acetoxymethyl, carbamoyloxymethyl or -CH2S-Het in which Het represents a five membered ring in which 1-4 carbon atoms are replaced by sulfur and / or nitrogen atoms such as thiadiazolyl, especially 1,3,4-thiadiazolyl radical or a tetrazolyl radical, hereinafter L-methyl-tetrazol-2-yl or ^1, 2-methyl-l, 3,4-thiadiazol-5-yl.

n can be 0, 1 or 2.

The synthesis of carboxylic acids is described in the patent literature, for example in DOS 2 702 501. The carboxylic acids of the formula II in which R1 represents phenyl or * benzyl are novel.

The synthesis of the starting compounds of formula III is known from the literature. In the case where n is 1 or 2, the compounds must be prepared by prior oxidation, as for example described in Ε. H. Flynn, Cephalosporins and Penicillins, Academic Press, New York and London (19721).

The active complexes of the carboxylic compounds of the formula III required for carrying out the process according to the invention are reacted immediately after their formation with the 7-aminocephaline compounds.

The carboxylic acids of the formula II are preferably used as free acids. It is also possible to use salts thereof, such as, for example, alkaline, especially sodium, or also amine salts, such as triethylamine.

As acid chloride-forming agents, thionyl halides such as thionyl chlorides or thionyl bromide can be mentioned, in particular phosphorus pentachloride, phosphorus oxychloride and oxalyl chloride, and preferably phosgene.

When R @ 5, R @ 4 and R @ 8 in the compound of formula (IV) are substituted by C1 -C6 alkyl, for example, methyl, ethyl, propyl, butyl, hexyl, preferably C1 -C4 alkyl radicals, are particularly suitable. methyl. R 5 and R 6 and R 3 and R 5 may also be taken together to form a four to eight membered ring optionally interrupted by an oxygen atom or another nitrogen atom, five to six membered rings being preferred, such as piperidino, morpholine, pyrrolidine, pyrrolidone, azetidinone-2- or piperazine ring.

In particular, N-disubstituted carboxylic acid amides, such as dialkylamides, in which both alkyl groups have 1 to 6 carbon atoms, can also close a six-membered ring or a 4 to 4-membered ring interrupted by oxygen or other compounds as compounds of formula IV. nitrogen atom.

Examples are given

N-methylpyrrolidone,

N-methylaisetidinone,

N, N-diethylbutyramide, dialkylpropionamide and dialkylacetamide;

in which the alkyl groups contain 1 to 3 carbon atoms

Θ carbon atoms such as dimethylacetamide, diethylacetamide,

N-acetylpiperidine,

N-acetylmorpholine,

N-propionyl piperidine,

N-butyrylpyirrolidine,

N-butyrylpiperidine,

N, N-dimethyl-N ‘, N‘ -pentamethyleneurea, tetramethylurea, tetraethylurea.

Preferred compounds of formula IV are diethyl acetamide,

Ν, Ν-dimethylpropionamide,

N, N-diethylpropanamide,

N-acetylpiperidine and tetramethylurea, particularly preferred is dimethylacetamide.

The stability of the corresponding reaction products formed with the halide forming agent is of particular importance for the use of the compounds of formula IV in the process of the invention. On the other hand, it is known about the reaction product of thionyl chloride and dimethylformamide that it can decompose explosively already with the Fe ³⁺ traces, as already mentioned.

The preparation of the active complexes with the carboxylic compounds of the formula II is successful in a dry, inert solvent which does not prevent further reactions. Solvents which may be mentioned are halogenated hydrocarbons such as methylene chloride or chloroform, esters such as ethyl acetate, or aromatic hydrocarbons such as toluene or xylene, but also an ether such as diethyl ether or diisopropyl ether.

The carboxylic acids of the formula (II) are used in an at least stoichiometric amount, based on the 7-amino-cephem compound to be added, to ensure an optimal process.

If the isolation of the active complexes is unsuccessful, it may be more advantageous to use a compound of formula IV in an amount of about 0.1 to about 3 equivalents, preferably 0.1 to 1.5 equivalents, adding an appropriate amount of a halogenating agent and then a carboxylic acid. an acid of formula

II. The order of addition is not critical.

According to the invention, the activation of the carboxylic acid of the formula II by the described complexes can be carried out over a wide temperature range, for example between -70 ° C to +30 ° C, with a range between -20 degrees Celsius and +10 degrees Celsius.

The second step of the process of the invention - acylation - follows directly after the formation of the active complexes. For this purpose, the carboxylic acids of the formula III can be used, for example, in the form of their amine salts, in particular trialkylamine salts such as triethylamine, trimethylbenzylamine or ethyldicyclohexylamine salt, but also dialkylarylamine salt such as například, Ν-dimethylaniline. They can also be used in the form of their esters, especially when a later conversion to the free carboxyl group is desired. Suitable esters are those which are cleaved by acid hydrolysis or hydrogenolysis. Suitable silyl esters are in particular trialkyl, preferably trimethylsilyl esters, which can be obtained by methods known from the literature.

Free hydrogen halide produced by acylac. If necessary, the addition of a base is neutralized by the addition of a trialkylamine, such as triethylamine, trimethylbenzylamine, ethyldicyclohexylamine, but also dialkylarylamine such as N, N-dimethylaniline.

The acylation reaction can be successfully performed at temperatures between, for example, -80 ° C to +30 ° C, especially between -20 ° C to +30 ° C. At this temperature, the reaction is generally complete after about 30 to 60 minutes.

The acylation products thus obtained can be well isolated in a known manner, optionally after cleavage of the optionally present protecting group. The cleavage of the amino protecting group can be carried out, for example, as described in DOS 2 702 501 or in Houben-Weyl, Vol. XV / 1, pp. 272f.

The esters of the invention may be isolated and used as such or may also be converted into the free acids by known methods such as acid hydrolysis or hydrogenolysis. If the compounds of the formula I according to the invention are obtained in the form of their amine salts, they can be converted into the free acids or alkali salts by known methods.

The following examples illustrate the process of the invention without limiting it.

Example 1

3-Acetoxymethyl-7- [2- (2-tritylamino-4-thiazolyl) -2- (syn) -methoxyiminoaceamido] -3-cephemic acid diethylamine salt g (0.1 mol% 82% 2- (2-tritylamino-4) -thiazolyl-2- (syn) -methoxyimino-acetic acid is suspended in 800 ml of toluene in a four-necked flask, 400 ml of toluene are distilled off under vacuum at a bath temperature of about 50 ° C, and then cooled to -5 ° C. addition of 9.3 ml (0.1 mol) of N, N-dimethylacetamide at -5 ° C was added dropwise

12.2 g (0.12 mol) of phosgene in 60 ml of toluene. It was then stirred at -5 ° C for 16 hours. A solution of 28.6 g of 7-aminocephalosporanic acid (95% = 0.1 mol), filtered with the addition of activated carbon, and 55.3 ml (0.4 mol) is added dropwise to the suspension thus obtained at -5 to 7 ° C. of triethylamine in 500 ml of methylene chloride. Stir for 30 minutes at -5 ° C and then for 60 minutes until the temperature rises to 10-15 ° C. The pH is adjusted to 2 by addition of 2N hydrochloric acid, the contents are poured into a mixture of 500 ml of methylene chloride and 500 ml of water and the phases are separated. The organic phase is washed once with 500 ml of water, dried over sodium sulphate and evaporated in vacuo (at the end with an oil pump). The residue was dissolved in 270 ml of acetone and heated to reflux for 30 minutes after addition of 10.3 ml of diethylamine. After a short time, crystallization begins. After standing at room temperature for several hours, it is cooled in an ice bath, filtered off with suction, washed with cold acetone and dried. In this way, the diethylamine salt in the syn configuration is obtained in very good yield.

NMR (DMSO, 60 MHz):

6.68 ppm = thiazole ring protons

Example 2

3-Acetoxymethyl-7- [2- (2-tritylamino-4-thiazolyl) -2- (syn) -methoxyiminoacetamido] -3-cephem-4-carboxylic acid diethylamine salt g (0.1 mol) 82% 2- (2-Tritylamino-4-thiazolyl) -2- (syn) -methoxyiminoacetic acid was suspended in a 4-neck flask in 600 mL of toluene and the toluene was distilled off under vacuum at a bath temperature of about 50-60 ° C. The residue is suspended in 400 ml of toluene, cooled to -10 ° C and, after addition of 9.3 ml (0.1 mol) of Ν, dim-dimethylacetamide, dropwise over 20 minutes at -10 ^to C 10.2 ml (0). (12 mol) of oxalyl chloride diluted with 40 ml of toluene. Stir for 2.5 hours at -15 ° C and 2.5 hours at -15 to -5 ° C.

To this suspension was added dropwise a solution of 28.6 g (0.1 mol) of 95% aminocephalosporanic acid and 55.3 (0.4 mol) of triethylamine in 500 ml of methylene chloride at -8 to -5 ° C over 20 minutes. Stir for 30 min at -5 ° C and 60 min at -5 to -30 ° C, adjust the pH to 2 with 2 N hydrochloric acid and pour into a mixture of 500 mL methylene chloride and 500 mL water, shake and separate up stage. The organic phase is washed with 500 ml of water and concentrated in vacuo (finally with an oil pump).

The pale yellow residue is dissolved in 270 ml of acetone and stirred at reflux for 30 minutes after addition of 10.3 ml of diethylamine. After standing at room temperature for 2 hours, it is cooled in an ice bath for 1 hour, filtered off with suction, washed with acetone and dried. The diethylamine salt having a syn configuration is obtained in very good yield.

NMR (DMSO, 60 MHz):

6.68 ppm - thiazole ring protons

Example 3

3-Acetoxymethyl-7- [2- (2-tritylamino-4-thiazolyl) -2- (syn) -methoxyimino-acetainido] -3-cephem-4-carboxylic acid diethylamine salt

5.4 g (10 mmol) of 82% (2-tritylamino-410)

-thiazolyl) -2- (syn) -methoxyiminoacetic acid was suspended in 80 ml of toluene. At 50-60 ° C half of the solvent is distilled off in vacuo and the suspension is cooled to -25 ° C. After addition of 1.02 ml (11 mmol) of Ν, Ν-dimethylacetamide, 2.2 g (11 mmol) of phosphoropentachloride are added. Stir 30 minutes at -20 ° C and 3 hours at -5 ° C. After addition of 100 ml of absolute diisopropyl ether, the solid product is sucked off with the exclusion of moisture and stored in a vacuum desiccator.

The complex compound thus obtained was added at -25 ° C to a solution of 2.8 g (10 mmol) of 95% 7-aminocephalosporanic acid and 5.4 ml (40 mmol) of triethylamine in 50 ml of methyl chloride. After warming to room temperature, it was stirred at room temperature for 1 hour. Working up and conversion to the diethylamine salt by a conventional route are described in Examples 1 and 2. The product obtained also has a syn configuration.

Example 4

3-Acetoxymethyl-7- [2- (2-tritylamino-4-thiazolyl) -2- (syn) -methoxyimino-acetamido] -3-cephem-4-carboxylic acid diethylamine salt

4.8 g (24 mmol) of phosphoropentachloride are suspended in 100 ml of toluene, while stirring at room temperature a solution of 2.2 ml (24 mmol) of Ν, dim-dimethylacetamide in 10 ml of toluene is added and stirred for 1 hour at room temperature. The complex crystallizes and settles After pouring off the aspirated solution and repeating the procedure with 100 ml of fresh toluene, the residue is again treated with 100 ml of toluene and the suspension is cooled to -5 DEG C. 8.8 g (20 mmol) of 2- ( 2-tritylamino-4-thiazolyl) -2- (syn) -methoxyiminoacetic acid and stirred for 20 hours at -5 ° C.

At the same time, a solution of 5.4 g (20 mmol) of 7-aminocephalosporanic acid in 100 ml of methylene chloride was added dropwise to the obtained suspension at -5 ° C and stirred for 1 hour at room temperature. Work-up and conversion to the diethylamine salt was carried out as described in Examples 1 to 3. The product obtained was syn-configured.

Example 5

3-Acetoxymethyl-7- [2- (2-tritylamino-4-thiazolyl) -2- (syn) -methoxyiminoacetamido] -3-cephem-4-carboxylic acid diethylamine salt

46.5 g (0.1 mol) of 2- (2-tritylamino-4-thiazolyl) -2- (syn) -methoxyiminoacetic acid sodium salt are suspended in 600 ml of toluene and the toluene is distilled off under vacuum at a bath temperature of 60 ° C . The residue was suspended in 400 ml of toluene, 9.3 ml (0.1 mol) of Ν, Ν-dimethylacetamide was added and cooled to -10 ° C. A solution of 12 g (0.12 mol) of phosgene in 150 ml of toluene is then added dropwise with stirring at -10 to -5 ° C with stirring. After stirring for 17 hours at -10 ° C, the suspension thus obtained was added over 10 minutes to a stirred and -10 ° C cold mixture of 25.8 g of 7-aminocephalosporanic acid, 55.3 ml of triethylamine and 500 ml of methylene dichloride. The temperature is raised to +15 ° C over 90 minutes, the pH is adjusted to 2 with 2N hydrochloric acid, the contents are poured into a mixture of 500 ml of methylene dichloride and 500 ml of water and the phases are separated. The organic phase is washed once with 500 ml of water and concentrated in vacuo. The pale yellow residue is dissolved in 270 ml of acetone and, after addition of 10.3 ml of diethylamine, is heated to boiling under stirring for 30 minutes. After standing at room temperature for 1 hour, it is filtered off with suction, washed with acetone and dried. The diethylamine salt having the syn configuration is obtained in very good yield.

NMR (DMSO- d 6)

6.68 ppm = thiazole ring protons

If benzene is used instead of toluene in the formation of the benzene complex, the diethylamine salt is also obtained in good yield, the yield being slightly lower in the ether solvent.

When oxalyl chloride is used as the halogenating agent in place of phosgene and proceeding as indicated, the title compound is obtained in about one-third lower yield.

Example 6

3-Acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2- (syn) -methoxyiminoacetamido] -3-cephem-4-carboxylic acid g (0.02 mol) 2- (2-amino- 4-thiazolyl) -2 (syn) -methoxyiminoacetic acid is suspended in 200 ml of toluene and the toluene is distilled off under vacuum at a bath temperature of 60 DEG C. The residue is suspended in 100 ml of methylene chloride, 1.86 ml (0.02 mol) is added. Of N, N-dimethylacetamide and cooled to -10 DEG C. A solution of 3 g of phosgene in 10 ml of toluene is then added with stirring over 10 minutes and stirred at -5 DEG C. for 5 hours. -5 to -8 ° C over 10 minutes with a charcoal-filtered solution

5.4 g (0.02 mol) of 7-aminocephalosporanic acid and 11 ml of triethylamine in 100 ml of methylene dichloride. Stir for half an hour at -5 ° C and for 1 hour at 15 ° C. The mixture was then freed of solvent under vacuum (finally with an oil pump). The brown-yellow amorphous residue was dissolved in 45 ml of 80% formic acid and added dropwise to 300 ml of stirred ammonium sulfate solution over 1.5 hours. The precipitate formed is filtered off with suction, washed with 150 ml portions of water and dried under vacuum over sodium hydroxide pellets. The crude product was then suspended in 10 mL of 98% ethanol and stirred at 50 ° C for 30 minutes. After cooling, it is filtered off with suction, washed with alcohol and dried. The compound thus obtained is in the syn configuration.

NMR (DMSO, 60 MHz):

6.68 ppm = thiazole ring protons

Example 7

3-Acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2- (syn) -methoxyiminoacetamido] -3-cephem-4-carboxylic acid g (0.02 mol) 2- (2-amino- 4-Thiazolyl) -2- (syn) -methoxyiminoacetic acid is suspended in 200 ml of toluene and the toluene is distilled off under vacuum at a bath temperature of 60 ° C. The residue is suspended in 100 ml of methylene chloride, 2.8 ml (0.03 mol) of N, N-dimethylacetamide is added, and after cooling to -10 DEG C., a solution of 2.55 ml (0.15 ml) is added dropwise with stirring over 10 minutes. 03 mol) of oxalyl chloride in 10 ml of methylene chloride. The resulting light yellow solution was stirred at -10 ° C for 5 hours and then the mixture was added

5.2 g of 7-aminocephalosporanic acid, 11 ml of triethylamine and 100 ml of methylene chloride. Stir for 1.5 hours at + 15 ° C and then remove the solvent in vacuo, finally on an oil pump. The residue was dissolved in 50 ml of 80% formic acid was added dropwise over 1.5 hours to 350 ml of an aqueous 35% ¹ ammonium sulphate solution. The precipitate is filtered off with suction, washed with water and dried, then suspended in 15 ml of 98% ethanol and stirred at 50 DEG C. for 30 minutes. After cooling, it is filtered off with suction, washed with ethanol and dried. The light gray product has a syn-configuration.

NMR (DMSO, 60 MHz):

6.68 ppm - thiazole ring protons

Example 8

3-Acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2- (syn) -methoxyiminoacetamido] -3-cephem-4-carboxylic acid

As in Example 7, 4.5 g of 2- (2-amino-4-thiazolyl) -2- (syn) methoxyiminoacetic acid sodium salt with 1.86 ml of N, N-dimethylacetamide and 3 g of phosgene are used. After acylation and purification over the formate, a pale yellow colored product is obtained which is syn-configuration.

Example 9

7- [2- (2-Amino-thiazol-4-yl) -2-syn-benzyloxyiminoacetamido] cephalosporanic acid

A solution of 18.2 g of 2- (2-tritylamino-thiazol-4-yl) -2-syn-benzyloxyiminoacetic acid in 160 ml of absolute toluene is combined with 3.05 g of Ν, Ν-dimethylacetamide, cooled to -8 degrees Celsius. and 13.5 ml of a 38% phosgene solution are added dropwise, initially precipitating the product which after a short time becomes an almost colorless crystalline product.

After five hours, the suspension is added at -5 ° C to a solution of 9.6 g of 7-aminocephalosporanic acid and 19.6 ml of triethylamine in 160 ml of absolute methylene chloride, stirred at -1 ° C for 45 minutes, and left at 5 ° overnight. C and finally treated with an additional 125 ml of methylene chloride with 150 ml of ice water.

The pH of the reaction mixture was adjusted to pH 1 with 2N hydrochloric acid, the organic phase was separated, washed three times with ice water and dried over sodium sulfate, then concentrated to dryness. 7- [2- (2-Tritylamino-thiazol-4-yl) -2-syn-benzyloximino-acetamidoycephalosporanic acid remains as a pale beige solid 20 g of the tritylated compound obtained are added to 110 ml of 50% formic acid and heated to 50 [deg.] C. The substance is shortly dissolved and the triphenylcarbinol precipitates as colorless crystals.

After one hour, it is filtered off, the filtrate is concentrated in vacuo and the residue is stirred with 250 ml of water to give a white crystalline product. This was filtered off with suction, washed with isopropanol and finally with ether. 7- (2- (2-Aminothiazol-4-yl) -2-syn-benzyloxyiminoaceamide orcephalosporanic acid is isolated as colorless crystals.

Thin layer chromatogram:

R _f 0.35 (n-Bu-OH: H 2 O: EtOH: AcOH == 20: 4: 3: 3)

Example 10

7- (2- (2-aminothiazol-4-yl) -2-syn-benzyloxyiminoacetamido) -3- (1-methyltetrazol-2-yl) thiomethyde- ^3- cephem-4-carboxylic acid

A solution of 11.4 g of 2- (2-tritylaminothiazol-4-yl) -2-syn-benzyloxyiminoacetic acid in 120 ml of absolute toluene was added to 2.0 g of Ν, Ν-dimethylacetamide and added dropwise at -8 ° C. 8.5 ml of a 38% phosgene solution in toluene. After five hours, a solution of 7.35 g of 3- (1-methyltetrazol-2-yl-thiomethyl- ^{3 3} -cephem-4-carboxylic acid in a mixture of 9.6 g of triethylamine and 160 ml) was added dropwise over 10 minutes at -5 ° C. The reaction mixture is then stirred at -5 ° C for 1 hour, then left at +2 ° C for 16 hours, then 70 ml of water is added and the pH is adjusted to 1 with 1N hydrochloric acid.

After brief stirring, it is filtered off, the organic phase is washed twice with water and concentrated to dryness. 7- [2- (2-Tritylamino-thiazol-4-yl) -2-syn-benzyloxyiminoacetamido] -3- (1-methyl-tetrazol-2-yl-thiomethyl ⁾ -3,3 -cephem-4-carboxylic acid is obtained. acid as a cream colored solid.

g of the solid obtained is added to 65 ml of 50% formic acid and heated to 50 ° C. After 1.5 hours, the triphenylcarbinol formed is filtered off with suction.

2 g of activated carbon are added to the filtrate, filtered and concentrated to dryness. The residue is stirred with 250 ml of water, the resulting cream powder is filtered off with suction, washed with water and dried. The crystals obtained are stirred with 100 ml of ether, stirred for 2 hours and finally dried.

There was thus obtained 7- [2- (2-aminothiazol-4-yl) -2-syn-benzyloxyiminoacetamido] -3- (1-methyltetrazol-2-ylthiomethyl) -N- ³ -cephene-4-carboxylic acid as a beige colorless substance. .

Thin layer chromatogram:

R _f 0.35 (n-BuOH: H2O: EtOH: AcOH = 20: 4: 3: 3)

Example 11

7- (2- (2-aminothiazol-4-yl) -2-syn-benzyloximinoacetamido) -3- (2-methyl-1,3,4-thiadiazol-5-yl-thiomethyl-A ³ -cephem-4- carboxylic acid

In an analogous manner, 7-amino-3- (2-methyl-1,3,4-thiadiazol-5-yl-thiomethyl) -? ³ -cephem-4-carboxylic acid and 2- (triphenylmethylamino-thiazole-4) are obtained. 7- [2- (2-tritylaminothiazol-4-yl) -2-syn-benzyloxyiminoacetamido] -3- (2-methyl-1,3,4-thiadiazole-5-yl) -2-syn-benzyloxyiminoacetic acid yl-thiomethyl j -A ³ -ce ° 4on em-7-carboxylic acid, which was converted with 50% formic acid at 60 degrees centigrade to 7- [2- (2-amino-thiazol-4-yl) syn- benzyloxyiminoacetamido] -3- (2-methyl-1,3,4-thiadiazol-5-ylthiomethyl ⁾ -3,3-cephem-4-carboxylic acid (cream-colored solid).

Thin layer chromatogram:

R _f 0.38 (n-BuOH: H 2 O: EtOH: AcOH = 20: 4: 3: 3).

Example 12

7- (2- (2-Aminothiazol-4-yl) -2-syn-phenoxyiminoacetamido) cephalosporanic acid

In an analogous manner, the corresponding complex is obtained from 2- (triphenylmethylaminothiazol-4-yl) -2-syn-phenoxyiminoacetic acid in toluene after addition of Ν, Ν-dimethylacetamide with phosgene, which reacts with a solution of 7-aminocephalosporanic acid to 7- (2- (2-triphenylmethylaminothiazol-4-yl) -2-syn-phenoxyiminocephalosporanoic acid.

The resulting tritylated product was stirred for 1 hour with 50% formic acid at 60 ° C, the cleaved triphenylcarbinol was separated, the filtrate was concentrated to dryness and triturated with ether. Remains 7- (2- (2-aminothiazol-4-yl) -2-syn-fenolxyiminojcefalosporanová acid as a solid, which on the thin layer chromatogram appears as a single substance with R _f 0.54 (Bu-OH: H 2 O: EtOH: AcOH = 10: 4: 3: 3j.

Example 13

3-Acetoxymethyl-7- [2- (2-tritylamino-4-thiazolyl) -2- (syn) -methoxyiminoacetamido] -3-cephem-4-carboxylic acid diethylamine salt g (0.1 mol) 82% 2- (2-Tritylamino-4-thiazole) -2- (syn) -methoxyiminoacetic acid was suspended in a 4-neck flask in 800 mL of toluene. 300 ml of toluene were distilled off under vacuum at a bath temperature of about 50 degrees Celsius. After cooling the suspension to -5 ° C, 9.3 ml (0.1 mol) of N, N-dimethylformamide and 70 ml of a 2M solution of phosgene in toluene (4.14 mol) were added over 15 minutes and then stirred for 5 hours.

A solution of 27.2 g (0.1 mol) of 7-aminocephalosporanic acid and 48.7 g (0.2 mol) of N, O-bis-trimethylsilylacetamide in 300 ml of methylene chloride was added dropwise at -5 ° C. Stir 30 minutes at -5 degrees Celsius and 60 minutes at room temperature. After dilution with 500 ml of methylene chloride, it is shaken three times with 500 ml of water, the organic phase is dried over sodium sulphate and evaporated in vacuo. The residue was dissolved in 250 ml of acetone and heated to reflux for 30 minutes after addition of 10.3 ml of diethylamine. After cooling, it is filtered off with suction, washed with acetone and dried. In very good yield, the title compound is obtained having the syn configuration:

NMR (DMSO, 60 MHz):

6.68 ppm = thiazole ring protons

Example 14

3-Acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2- (syn) -methoxyiminoacetamido] -3-cephem-4-carboxylic acid

20.1 g (0.1 mol) of 2- (2-amino-4-thiazolyl) -2- (syn) -methoxyiminoacetic acid are suspended in 350 ml of methylene chloride, cooled to -10 ° C, and 9.3 ml are added. (0.1 mol) of Ν, Ν-dimethylacetamide and then with stirring, during 5 minutes, 75 ml of a solution of phosgene in toluene (2 molar solution = 0.15 mol). After 25 minutes, the solution was added dropwise to the pale yellow solution over 30 minutes

21.4 g (0.08 mol) of 7-aminocephalosporanic acid and 39 ml (0.16 mol) of bis-trimethylsilylacetamide in 500 ml of methylene chloride, such that the temperature does not exceed -3 ° C. During this time, the deposition of the resinous product begins. To eliminate it completely, add 3 ml of water after 30 minutes. The organic solution is decanted and discarded, the residue is digested with 200 ml of methylene chloride, the solvent is removed and the residue is freed from the solvent in vacuo at room temperature. The pale yellow amorphous residue contains the title compound. It is dissolved in 150 ml of 80% formic acid and the solution is added dropwise to 700 ml of a 40% aqueous ammonium sulphate solution. The resulting gummy precipitate was collected and triturated three times with 60 ml of ice water. It is suctioned and dried. The product is a formate of the title compound having a syn-configuration.

NMR (DMiSO; 60 MHz):

6.68 ppm (thiazole ring protons),

8.13 ppm (formyl)

To deformylate, it is suspended in 50 ml of absolute ethanol, stirred for 30 minutes at 50 ° C, filtered off with suction and washed with ethanol. The light gray title compound thus obtained has the sym configuration.

NMR (DMSO, 60 MHz):

6.68 ppm of thiazole ring protons

P 1 'k 1 a d 15

3-acetyl-xymetbyl-7- [2- ^{(2-Amiina-4-Th-imidazolyl)} -2- (syn) -methoxyimino-acetamido] -3-ceíein-4-carboxylic acid

10.0 g (0.05 mol) of 2- (2-amino-4-thiazolyl) 2- (3-yne) -methoxyimino-acetic acid are suspended in 200 ml of absolute methylene chloride. After cooling to -10 DEG C., 4.65 ml (0.05 mol) of dimethylacetamide and 5.75 ml (0.62 mol) of phosphorus oxychloride are added dropwise and the mixture is stirred for 2.5 hours. To this suspension was added dropwise a solution of 10.8 g (0.04 mol) of 7-aminocephalosporanoic acid and 19.5 ml (0.08 mol) of bis-trimethylsilylacetamide in 250 ml of methylene chloride at -10 ° C. It is stirred for 2 hours at 0 ° C and worked up as in Example 13. The title compound thus obtained has a syn configuration.

NMR (DMSO, 60 MHz):

6.6-8 ppm of thiazole ring protons

Example 1-6

3- Aceoxymethyl-7- [2- (2-amino-4-thiazolyl) -2- (syn) -methoxyimino-acetamido] -3-cephem-4-carboxylic acid

As in Example 14, 5 g (0.025 mol) of 2- (2-amino-4-thiazolyl) -2- (syn) -m-ethoxyiminoacetic acid are treated with 3.17 g of N-acetylpiperidine and 3.8 g of phosgene. The product has a syn-configuration.

Example 17

3-Acetoxymethyl-7- [2- (2-amino-thiazolyl) -2- (syn) methoxyimino-acetamido] -3-cephem-4-carboxylic acid

As in Example 14, 2.5 g of N-methylpyrrolidone and 3.8 g of phosgene are treated with 5 g (0.035 mol) of 2- (2-amino-4-thiazolyl) 2- (syn) methoxyiminoacetic acid. The product has a syn-configuration.

Example 18

3-Acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2- (syn) -methoxyiminoacetamido] -3-cephem-4-carboxylic acid

As in Example 14, 5 g (0.025 mol) of 2- (2-amino-4-thiazolyl) -2- (syn) -methoxyiminoacetic acid was treated with 2.5 g of N, N-dimethylphenylpropionamide and 3. 8 g phosgene. The product has a syn configuration.

Example 19

3-Ac-ethoxymethyl 1-7- [2- (2-amino-4-thiazolyl) -2- (syn) -methoxyiminoacetamido] -3-cephem-4-carboxylic acid

As in the example. 14 is treated with 5 ml of 2- (2'-amino-4-thiazolyl) -2- (syn) -methoxyiminoacetic acid 315 ml of Ν, Ν-diethyl acetamide and 3.8 g of phosgene. The product has a syn-configuration.

Preparation of the starting compounds for Example 9

a) 2-syn-Benzyloxyiminoacetacetic acid (ethyl ester)

To a solution of 23.5 g of 2-syn-oxyiminoacetoacetic acid ester in 120 ml of acetone, 30.5 g of potassium carbonate is added under stirring at 15 ° C, then 25.6 g of benzyl bromide are added dropwise to the reaction mixture. Stir for 4 hours at room temperature and then leave for 16 hours without stirring.

The solids were filtered off and the solution was concentrated to dryness. The residual oil was freed of excess benzyl bromide under vacuum (6.6 Pa) at 80 ° C, then, after cooling, a 5% sodium bicarbonate solution was added to the residue and extracted with ether. The ether phase is washed twice with water, dried over sodium sulphate and then concentrated. A pale yellow oil of 2-syn-benzyloxyiminoacetoacetic acid ester remains. (Thin-layer chromatogram system chloro-Ofori / ethyl acetate 2: 1, R _f 0.74).

bj 2-Syn-benzyloxyimino-4-bromoacetic acid ethyl ester

A solution of the ester (12.5 g) of 2-N-benzyloxyiminoacetacetic acid in 80 ml of absolute methylene chloride was added to 150 ml of toluenesulfonic acid, and then 2 grams of bromine from the required 8 grams of bromine was added at room temperature. Upon stirring, the initially dark brown solution was discolored. The remaining bromine is then added dropwise. After the addition was complete, it was stirred at room temperature for 1.5 hours, the reaction mixture was cooled to 0 ° C and washed with 10% sodium bicarbonate solution.

The organic phase was separated, dried over sulfate, concentrated and the residual oil crystallized from cyclohexane. There was obtained 2-syn-benzyloxyimino-4-bromo-acetic acid ethyl ester as colorless crystals, m.p. 66-68 ° C.

c) 2- (2-Amino-thiazol-4-yl) -2-syn-benzyloxyiminoacetic acid ethyl ester

To a solution of 2.66 g of thiourea in 50 ml of 40% ethanol was added dropwise over 20 minutes at room temperature a solution of 11.8 g of 2-syn-benzyloxyimino-4-bromoacetic acid ethyl ester in 60 ml of 98% ethanol and 40 ml of acetone. . The reaction mixture is then stirred at 25 ° C for 2 hours, then concentrated until crystallization of the final product begins and the crystals obtained are isolated. The product is dissolved in 50% ethanol while warm, then the pH of the solution is adjusted to 7 with aqueous ammonia. The precipitated cream colored crystals are isolated, washed with 40 ¹ % ethanol and diisopropyl ether and dried. There was thus obtained 2- (2-aminothiazol-4-yl) -2-n-benzyloxyiminoacetic acid as an ethyl ester, m.p. 135 DEG-138 DEG C., as almost colorless crystals.

d) 2- (2-Triphenylmethylaminothiazol-4-yl) -2-syn-benzyloxyaminoacetic acid ethyl ester

A solution of 18.3 g 2- (2-aminothiazol-4-yl j -2-syn-benzyloxyiminooctové acid in 125 ml of a dichloromethane absolutního--ane and 25 ml of dimethylformamide at -15 ^Q C 6.7 g of triethylamine, then cooled to -35 ° C, 17.5 grams of triphenylchloromethane is added in portions and stirred at -30 ° C for 1 hour and then at room temperature for 3 hours.

The reaction solution is then cooled to 0 ° C, washed several times with 2N hydrochloric acid and finally with water, the organic phase is isolated, dried over sodium sulfate and the solvent is removed. 2- (2-Triphenylmethylaminothiazol-4-yl) -2-syn-benzyloxyiminoacetic acid is obtained as an ethyl ester as a cream colored solid (thin layer chromatogram: acetic acid ester / chloroform 1: 1, Rf) _. 0.98, compare with the starting material - i.e. R _f 0.63 which was used without further purification.

e) 2- (2-Triphenylmethylaminothiazol-4-yl) -2-syn-benzyloxyiminoacetic acid sodium salt

The obtained 2- (2-triphenylmethylamino-thiazol-4-yl) -2-syn-benzyloxyimino-thiazol-4-yl) -2-syn-benzylioxyiminoacetic acid ethyl ester was dissolved in a mixture of 230 ml of ethanol and 40 ml of dioxane at 60 ml. The reaction mixture is treated with a solution of 3 g of sodium hydroxide in 45 ml of water and heated at reflux for 2 hours. The reaction mixture is then strongly concentrated, the residue is treated with 350 ml of water and 2- (2-triiphenylmethylamino-thiazol-4-yl) -2-syn-benzyloxy-amino-octo216507 acid sodium salt is isolated as a colorless solid, m.p. 257-258 ° C. (with decomposition).

f j 2- (2-Trifluoromethylamino-1H-thiazol-4-yl) -2-sym-benzyloxyiminoacetic acid

The obtained 2- (2-triphenylmethylaminothlazol-4-yl) -2-syn-benzyloxyiminoacetic acid sodium salt was suspended in 250 ml of methylene chloride and stirred at 5 ° C with 50 ml of 2N hydrochloric acid. An acid is formed which is soluble in dichloromethane.

The organic phase is isolated, dried with sodium sulfate and the solvent is removed. The residue was dissolved in cyclohexane to give an almost colorless solid which was isolated and washed with diisopropyl ether. It is obtained

2- (2-trifluoromethyl enylmetbylaminothi azole-4-yl) -2-syn-benzytoxyiminooctová acid as an amorphous solid which has a thin layer of chloroform / methanol 6: 1 R _f value of 0.21.

Preparation of the starting compounds of Example 12 as well as bromoacetylglyoxylic acid ethyl ester

120 g of acetylglyoxylic acid ethyl ester are dissolved in 700 ml of methylene chloride and a solution of 146 g of bromine in 200 ml of methylene chloride is added at 5 DEG C. over 1 hour.

After handling the solution, the solvent was stripped off and the residual oil was used without further purification.

bj 2-Amino-thiazol-4-yl-glyoxylic acid ethyl ester

A solution of 60 g of urea in 450 ml of water and 450 ml of ethanol was added dropwise to 195 g of bromoacetglyoxylic acid ethyl ester (at 5 ° C.) After the addition was stirred for 30 minutes at room temperature and 30 minutes at 30 ° C. Charcoal was added and the reaction mixture was filtered, and the pH of the filtrate was adjusted to 7 by the addition of sodium bicarbonate, whereby 2-amino-thiazol-4-yl-glyoxylic acid crystallized as the ethyl ester, m.p. 147 ° C.

c j 2,2-Triphenylmethylaminothiazol-4-yl-glyoxylic acid in the form of ethyl ester

A solution of 90 g of 2-aminothiazole-4-glyoxylic acid ethyl ester in 225 ml of dimethylformamide and 375 ml of dichloromethane is added to 27 g of triethylamine at -15 DEG C. and then to 75 g of triphenylchloromethane. After stirring for 15 minutes at -30 ° C and then for 3 hours without cooling bath. The reaction mixture obtained is added to 500 ml of dichloromethane, washed with 300 ml of 1N HCl and then twice with 200 ml of water. The phases are dried over sodium sulphate, the solvent is evaporated. An oil remains which is used without further purification.

d) 2-Trifemylmethylaminothiazol-4-yl-glycylic acid

A solution of 156 g of crude 2-triphenylmethylammothiazol-a-yl-glyoxylic acid ethyl ester in 150 ml of methanol is added to a solution of 14.8 g of sodium hydroxide, refluxed for 5 minutes, crystallizing the sodium salt of 2-triphenylmethylaminothiazole-4. -yl-glyoxylic acids.

The sodium salt obtained is suspended in 380 ml of water and 76 ml of 2N hydrochloric acid are added with vigorous stirring. After 15 minutes, the precipitate was filtered off with suction, washed with water and dried. 2-Triphenylmethylaminothiazol-4-yl-glyoxylic acid is obtained as yellow crystals, m.p. 163 DEG-165 DEG C. (dec.).

e j 2- (2-Triphenylmethylaminothiazol-4-yl) -2-syn-phenoxyiminoacetic acid

To a solution of 450 ml of glacial acetic acid and 90 ml of water was added 30 g of triphenylmethylaminothiazol-4-yl-glyoxylic acid and 8 g of O-phenylhydroxylamime were added at 15 ° C. The reaction mixture is first clear, then crystallization of the oxime begins. After 15 minutes, 200 ml of water is added with stirring at 10-15 ° C. The separated crystals are aspirated, stirred with acetone and filtered again. 2- (2-Triphenylmethylamino-thiazol-4-yl) -2-syn-phenoxyimineacetic acid is isolated, m.p. 141 DEG-143 DEG C. (dec.) As a colorless solid.

Claims (3)

A process for the preparation of 7- [2- (2-aminothiazol-4-yl) -2-oximiinoaeetamido] -ceph-3-em-4-carboxylic acid derivatives of the general formula I, wherein A is hydrogen, alkali metal or alkali metal equivalent soil or organic nitrogen bases, R 1 is hydrogen, C 1 -C 4 alkyl which may be optionally substituted with carboxy, C 1 -C 4 alkoxycarbonyl, phenyl, C 1 -C 4 alkylphenyl or halo-phenyl, C 2 -C 6 alkenyl which may still be substituted by halogen, phenyl, alkylphenyl having 1 to 4 carbon atoms in the alkyl moiety and halophenyl, R @ 2 denotes aminothiazolyl in which the amino group is optionally present. protected by up to 19 carbon atoms, cleavable by acid hydrolysis or hydrogenolysis, and B denotes acetoxymethyl, carbamoylmethyl or the group -CHaS-Het, wherein Het represents a five-membered ring in which 1-4 carbon atoms are replaced by sulfur and / or nitrogen atoms, or 1-methyl-tetrazol-2-yl or 2-methyl a 1,3,4-thiadiazol-5-yl radical, the group R10 being in the syn position and is 0, 1 or 2, characterized in that the carboxylic acid of the formula II is reacted, Rz = C = COOH II N \ (Ii wherein R 1 and R 2 are as defined above, or a salt thereof, in the presence of from 0.1 to 3.0 mol of a compound of formula (IV) of the invention R3 Rs \ / N — O R 4 O (IV) wherein the radicals R 3, R 4 and R 5 are the same or different and represent alkyl of 1 to 6 carbon atoms, wherein the radicals R 5 and R 4 or R 3 and R 5 may also together form a four to eight membered ring optionally interrupted by oxygen or other nitrogen atom and R 5 may also represent a dialkylamino group in which the alkyl groups have 1 to 6 carbon atoms and may together form a six-membered ring, or a 4 to 8-membered ring which is interrupted by oxygen or another nitrogen atom with an acid halide forming agent and reacted with cephemic acid of the formula III, in which B and n are as defined above, in the form of an amine salt or in the form of optionally acid hydrolysis or hydrogeinolysis of the cleavable ester or silyl ester, and optionally converting the carboxyl group obtained the group represented by the substituent A. 2. A process according to claim 1 wherein the tertiary amide is dimethylacetamide, diethylacetamide, dimethylpropionamide, diethylpropionamide, N-acetylmorpholine, N-acetylpiperidine, N-methylpyrrolidone or tetramethylurea. 3. The process according to claim 1, wherein the acid halide forming agent is phosphoropentachloride, phosphorus oxychloride, oxalyl chloride or phosgene.