CS207576B2 - Method of preparation of the oxime derivatives of the 7-a-minothiazolylacetamidocephapsosporane acid - Google Patents

Abstract

7-[(2-Amino-4-thiazolyl)-2-R''1-(oxyimino]cephalosporanic acids (I) with R''1 = H or alkyl, alkenyl or alkynyl having up to 4 carbon atoms are prepared by reaction of 7-aminocephalosporanic acid, the carboxyl group of which is esterified by a group which can be removed by acid hydrolysis or by hydrogenolysis, with an acid of formula: <IMAGE> in which R'1 represents an alkyl, alkenyl or alkynyl group up to 4 C, a group which can be removed by acid hydrolysis or by hydrogenolysis or a chloroacetyl group, or with a functional derivative of this acid, an acid hydrolysis or a hydrogenolysis is then carried out, or the chloroacetyl group is split off by reaction with thiourea. The compounds I and their salts are antibiotics effective, especially, against resistant bacterial strains.

Description

(54) A process for preparing oxime derivatives of 7-aminothiazolylacetamidocephalosporanic acid

The present invention relates to a process for the preparation of novel oxime derivatives of 7-aminothia zolylacetamidocephalosporanic acid of the general formula Ib

in which

R 1 'represents a hydrogen atom or a saturated or unsaturated alkyl group having a total number of carbon atoms of 1 to 4.

In MS. No. 207,575 describes a process for the preparation of novel oxime derivatives of 7-aminothiazolyl-metamido-phosphoosporic acid of the general formula Г

in which

Rc represents a hydrogen atom, a group readily cleavable by acid hydrolysis or hydrogenolysis, or a chloroacetate group,

R c‘ represents a hydrogen atom, a group which is readily cleavable by acid hydrolysis or hydrogenolysis, a chloroacetyl group or a saturated or unsaturated alkyl group having a total carbon number of 1 to 4,

A represents either a hydrogen atom or an equivalent of an alkali metal, an alkaline earth metal, magnesium or an amine organic base, and the wavy line means that the ORc 'group can be in one or the other of the two possible syn or anti positions, 'is a group readily cleavable by acid hydrolysis or hydrogenolysis, then Rc is a group readily cleavable by acid hydrolysis or hydrogenolysis, if Rc' is a chloroacetyl group, then Rc is a chloroacetyl group and if Rc * is a hydrogen atom, then Rc is hydrogen.

The present invention provides a variant of the method described in U.S. Pat. No. 207,575, for the preparation of oxime derivatives of 7-aminothiazolylacetamido-phthalosporainic acid of the general formula Ib

CH 2 O-C-C 6-10

(ib) in which:

R 1 "means an atom: hydrogen or an unsaturated or saturated alkyl group having 1 to 4 carbon atoms, and a wavy line means that the OR 1" group can be in the syn- or anti- position, which is based on being reacted 7-aminocephalosporanic acid derivative of the general formula III

in which

A 1 represents a group readily cleavable by acid hydrolysis or hydrogenolysis, such as benzhydryl, tert-butyl, benzyl, p-methoxybenzyl and trichloroethyl, with an acid of the formula II

NH-R ₁

S ^ N (II)

207S76 or a functional derivative thereof, wherein in Formula II

R 1 represents a group readily cleavable by acid hydrolysis or hydrogenolysis such as tert-butoxycarbonyl, trityl, benzyl, trichloroethyl, carbobenzyloxy, formyl, trichloroethoxycarbonyl or 2-tetrahydropyranyl, or chloroacetyl;

R 1 represents a group readily cleavable by acid hydrolysis or hydrogenolysis such as tert-butoxycarbonyl, trityl, benzyl, trichloroethyl, carbobenzyloxy, formyl, trichloroethoxycarbonyl or 2-tetrahydropyranyl, or unsaturated or chloroacetyl a (C 1 -C 4) alkyl group, and a wavy line means that the OR f group is in the syn- or anti-position to form the product of formula (XI)

wherein R 1, R 1 ', A 1 and the wavy line are as defined above, after which said product of formula (XI) is treated with one or more acid hydrolysis agents such as formic acid, trifluoroacetic acid, acetic acid or zinc / acid system acetic, with one or more hydrogenolizing agents such as hydrogen in the presence of a catalyst, thiourea or one or more of the above to give the product of formula (Ib).

As already described in the description of the invention no. No. 207,575, the groups readily cleavable by acid hydrolysis or hydrogenolysis, which may be R 1 and R f, include, for example: tert-butoxycarbonyl, trityl, benzyl, dibenzyl, trichloroethyl, benzyloxycarbonyl or formyl.

Trichloroethoxycarbonyl or 2-tetrahydropyranyl may also be mentioned.

The meanings of the general substituent A 1 include:

benzhydryl, tert-butyl, benzyl, p-methoxybenzyl and trichloroethyl.

In a preferred embodiment of the process according to the invention the product of the general formula is used

The compound of formula (II) may be prepared by treating the acid with isobutyl chloroformate or dicyclohexylcarbodiimide.

It is also possible to use other halides or other anhydrides formed in situ by the action of other alkyl chloroformates, dialkylcarbodiimides or other dicycloalkylcarbodiimides. It is also possible to use other functional derivatives of the acid of formula (II), such as an acid azide, active acid amide or active acid ester formed, for example, with hydroxysuccinimide, p-nitrophenol or 2,4-dinitrophenol.

When the above reaction is carried out using an acid halide of the general formula II or anhydrides formed with isobutyl chloroformate, the reaction is preferably carried out in the presence of a basic agent.

As the basic agent, for example, an alkali metal carbonate or a tertiary organic base such as N-methylmorpholine, pyridine or a trialkylamine such as triethylamine can be used.

When the products of formula XI are converted to products of formula Ib, the substituents R 1 and A 1 are replaced by hydrogen atoms. The same is the case where R 1 is a group readily cleavable by acid hydrolysis or hydrogenolysis or a chloroacetyl group; then, the transformation is also replaced by hydrogen atoms.

To this end, the product of formula (XI) is reacted with one or more acid hydrolysis reagents when R1 and A 1 are a leaving group hydrolysable by acid hydrolysis and R 1 is a leaving group hydrolysable by acid hydrolysis or an alkyl group.

When R @ 1 and A @ 1 represent a leaving group by hydrogenolysis and R @ 1 is a leaving group by hydrogenolysis or an alkyl group, the product of formula (XI) is treated with one or more hydrogenolyzing agents.

The product of formula (XI) is treated with one or more acid hydrolyzing agents and one or more liydrogenolyzing agents when at least one of R 1, A 1 and R 1 'is a group cleavable by acid hydrolysis and at least one of these groups is a group cleavable by hydrogenolysis .

The product of formula (XI) is finally treated with thiourea and optionally one or more acid hydrolysis or hydrogenolysis reagents when at least one of the general substituents R 1 and R 1 is chloroacetyl.

The acid hydrolysis agent treated with the products of formula XI includes:

formic acid, trifluoroacetic acid or acetic acid. _ ______

Said acids may be used either under anhydrous conditions or in aqueous solutions. It is also possible to use a system consisting of zinc and acetic acid.

For the cleavage of the tert-butoxycarbonyl or trityl group, which may be the general substituents R 1 or R 1 ', and the benzhydryl, tert-butyl or p-methoxybenzyl group, which may be the general substituent A 1, an acid hydrolyzing agent such as e.g. anhydrous trifluoroacetic acid or aqueous solutions of formic acid or acetic acid.

A system consisting of zinc and acetic acid is preferably used to cleave the trichloroethyl group, which may be a general substituent R 1, R 1 and A 1.

Preferably, a hydrogenolyzing agent such as hydrogen in the presence of a catalyst is used to cleave the dibenzyl and benzyloxycarbonyl groups, which may be the general substituents R 1 and R 1, and the bemzyl group, which may be the general substituents R 1, R 1, and A 1.

The reaction of the thiourea with the product of formula XI containing at least one chloroacetyl group is preferably carried out in a neutral or acidic medium. This type of reaction is described by Masaki (JACS, 90, 4508/1968).

The products of formula (II) in which the substituents are as defined above are prepared by first treating the product of formula (IV) with a base and then with an acid.

(IV) wherein

R 'is hydrogen, a group easily cleavable by acid hydrolysis or by hydrogenolysis, or saturated or unsaturated alkyl group having a total carbon number of 1 to 4 and alk represents an alkyl group having a total carbon number of 1-4, к obtain a product of formula XII NH ₂ S ^ N (XII) wherein

R‘ is as defined above, which is treated with a functional derivative of a group readily cleavable by acid hydrolysis or hydrogenolysis or a chloroacetyl group to give the product of formula II

207578

(Vc) in which

R 1 represents a group readily cleavable by acid hydrolysis or hydrogenolysis or a chloroacetyl group; and

R 1 represents a group readily cleavable by acid hydrolysis or hydrogenolysis, a chloroacetyl group or a saturated or unsaturated alkyl group having a total number of carbon atoms of 1 to 4.

The base used to saponify the product of formula (XII) is preferably sodium hydroxide; however, 1 other bases such as potassium carbonate or barite may also be used.

The acid used to isolate the acid of formula XI is preferably dilute hydrochloric acid; however, acetic acid or formic acid may also be used.

The functional derivative of a group readily cleavable by acid hydrolysis or hydrogenolysis is preferably trityl chloride, used in the presence of triethylamine or other tertiary amine bases such as trialkylamines, methylmorpholine or pyridine.

Other functional derivatives of groups readily cleavable by acid hydrolysis or hydrogenolysis may also be used. Examples of such derivatives include tert-butyl chloroformate prepared in situ, or tert-butyl azide formate, trichloroethyl chloroformate or benzyl chloroformate, mixed formic anhydride and acetic acid prepared in situ, benzyl halide, preferably benzyl chloride, or dibenzyl chloride, or dibenzyl chloride, or dibenzyl chloride, or dibenzyl chloride. -ethoxycarbonylphthalimide.

The functional derivative of the chloroacetyl group is preferably chloroacetic anhydride or an acid halide such as monochloroacetyl chloride.

When the reaction is carried out using chloroacetyl halide, it is preferably carried out in the presence of a basic agent which is identical to the above-mentioned basic agents.

The products of general formula Vc in which

R 1 represents a group readily cleavable by acid hydrolysis or hydrogenolysis or a chloroacetyl group,

R _c 'represents a group readily cleavable by acid hydrolysis or hydrogenolysis or a chloroacetyl group other than R 1 and alk represents an alkyl group having a total carbon number of 1 to 4, prepared by preparation of the product of formula X

NH-R ₁ = = CO ₂ dtk

N i

(X) in which R 1 and alk are as defined above, act as a functional derivative of a group readily cleavable by acid hydrolysis or hydogenolysis or a chloroethyl group R _c 'to give a product of formula Vc.

The group readily cleavable by acid hydrolysis or hydrogenolysis, which is R 1, is preferably a trityl group.

The functional derivative of the group readily cleavable by acid hydrolysis or hydrogenolysis to effect the product of formula (X) is preferably dlhydnopyranyl.

However, it is also possible to use the above functional derivatives.

The present invention also relates to a process for the preparation of 7- [2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid in the form of the syn isomer, in which a 7-aminocephalosporanic acid derivative of the general formula PГ is reacted

7 5 7.6

in which

A 1 represents a group readily cleavable by acid hydrolysis or by hydrogenolysis, such as benzhydryl, tert-butyl, benzyl, p-methoxybenzyl and trichloroethyl, with an acid of the formula II ‘in the form of the isomer syn or. with a functional derivative of this acid, wherein in the above general formula ΙΓ,

R 1a and R 1a are each readily cleavable by acid hydrolysis or hydrogenolysis such as tert-butoxycarbonyl, trityl, benzyl, trichloroethyl, benzyloxycarbonyl, formyl, trichloroethoxycarbonyl or 2-tetrahydropyranylo. or a chloroacetyl group, wherein when R 1a represents a chloroacetyl group, then also R 1a represents a chloroacetyl group, to give the product of the general formula XI '

in the form of the syn isomer, wherein, in formula XI *, Ai, Ria and Rt‘a are as defined above, after which the product of formula XI ‘is treated with one or more compounds of formula XI *. several acid hydrolysis agents such as formic acid, trifluoroacetic acid, acetic acid or a zinc / acetic acid system with one or more hydrogenolyzing agents such as hydrogen in the presence of a catalyst, thiourea or one or more of the above reagents to give the desired acid.

In a preferred embodiment of the above process, a functional acid derivative of the formula (I) is a symmetrical anhydride formed in situ by means of dicyclohexylcarbodiimide.

The group which represents R 1a is preferably a trityl group.

R 1a is preferably a trityl or tetrahydropyranyl group, and A 1 is preferably a tert-butyl group.

The present invention also relates to a process for the preparation of the salt of 7- [2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid in the form of the syn isomer, The process according to claim 1, wherein the salt is converted to the salt of 7- [2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid in the form of syn.

Said conversion to a salt of said acid is carried out under conventional conditions, which are also described in the description of the invention to U.S. Pat. No. 207,575.

In particular, the present invention provides a process for preparing a sodium salt of 7- [2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamido] -3-acetoxymethyl-3-cephem-4- carboxylic acid isomer syn.

Also described is a process for the preparation of 2- (2-tritylamino-4-thiazolyl) -2-tritylhydroxyiminoacetic acid in the form of the syn isomer, which comprises treating with a base of a formula IV in which R is treated with a base. is hydrogen, and the product of formula (XII) obtained is treated with trityl chloride.

In a preferred embodiment of the process, the product of formula IV is first treated with sodium hydroxide and then with acetic acid.

Also described is a process for the preparation of ethyl [2- (2-tritylamino-4-thiazolyl) -2-tetrahydropyranyloxyiminoroacetate in the form of the syn isomer, which process comprises treating a product of formula X wherein R 1 is trityl and alk is ethyl, dihydropyran.

The products prepared by the process according to the invention have very good antibiotic activity both on Gram positive bacteria such as staphylococci and streptococci, especially penicillin resistant staphylococci and on Gram negative bacteria such as coliform bacteria, Klebsielly, Salmonella and Proteus.

In view of the above characteristics, the products may be used as medicaments in the treatment of diseases caused by germs, in particular in the treatment of diseases caused by staphylococcal infestations such as staphylococcal blood poisoning, pyodermitis, septic and septic wounds, anthrax, phlegmones, eresipelia, influenza, bronchopneumonia and pneumonia.

Said pharmaceutically acceptable products may also be used as medicaments in the treatment of collibacillos and associated infections. in the treatment of infections caused by Proteus, Klebsiella and Salmonella and in the treatment of other diseases caused by gram-negative bacteria.

The products can thus be used for preparation. pharmaceutical preparations containing as active ingredient one of the aforementioned products prepared by the process according to the invention.

Examples of such preparations are, in particular, pharmaceutical preparations containing 7- [2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid as an isomer as active substance. and its physiologically acceptable salts with alkali metals, alkaline earth metals, magnesium and organic amine bases.

In particular, pharmaceutical preparations containing as active substance:

7- [2- (2-amino-4-thiazolyl) -2-hydroxy-ylamino] acetainido] -3-acetoxymethyl-3-cephem-4-carboxylic acid in the form of the syn isomer and 7- [2- (2-Amino-4-

-thiazolyl) -2-hydroxyiminoacetamido] -3-acetyl (4-methylthio-4-carboxylic acid) in the form of isome.ru syn .

These preparations may be in solid or liquid form, as commonly used in medicine, such as in the form of normal tablets or dragees, granules, suppositories, injectables, ointments, creams or gels; these preparations may be prepared by methods known per se.

The active ingredient (s) may be incorporated in the pharmaceutical preparations into the customary auxiliaries such as talc, acacia, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, vegetable or animal fats, paraffin derivatives, glycols, -different surfactants, - dispersing or emulsifying agents and preservatives.

The dosage of the active ingredient is dependent on the type of disease being treated, the age and condition of the subject being treated, the mode of administration of the active ingredient, and the active ingredient itself. For example, this dose is 0.5 to 1 gram three times a day for intramuscular administration for the product of Example 1 or 2 in man.

In the following, several examples of embodiments of the process according to the invention are given.

Example 1

7- (2- (2-Amino-4-hiazolyl) -2-hydroxyiminoacetamido) -3-acetoxymethyl-3-cephem-4-carboxylic acid, isomer syn

Stage A:

Ethyl [2- (2-amino-4-thiazolyl) -2-hydroxyimino] acetate, isomer syn

0.8 g of thiourea is dissolved in 2.4 ml of ethanol and -4.8 ml of water. A solution of 2 g of ethyl 4- (4-chloro-2-hydroxyiminoacetyl) acetate is then added to the solution thus obtained over a period of -5 minutes and the mixture is stirred for 1 hour at ambient temperature. The residue is neutralized to pH 6 and solid sodium bicarbonate is then added to the neutralized portion, the mixture is cooled with ice, centrifuged, washed with water and dried in vacuo at 40 ° C.

1.32 g of the expected product are obtained. Teplota- point of the product is ^{232, or} C.

For C5H9O3N3S:

calculated:

% C, 39.06;% H, 4.21;% N, 19.52; found:

38.9% C, 4.4% H, 19.7% N, 14.6% S.

NMR Spectrum:

(DMSO, 60MHz)

(a) triptet centered at 1.25 ppm;

J = 7Hz;

(b) a quadruplet centered at 4.27 ppm;

J = 7Hz;

(c) singlet at 6.83 ppm;

(d) singlet at 7.11 ppm;

(ej singlet at 11.4 ppm.

Stage B:

2- (2-Amino-4-thiazolyl) -2-hydroxyiminoacetic acid, syn isomer

21.5 g of the product of Step A are added to 200 ml of absolute ethanol and 55 ml of 2N sodium hydroxide. The resulting mixture was then stirred in a water bath at 45 ° C. After 30 minutes, the reaction mixture was placed in an ice water bath, and the pH of the reaction mixture was adjusted to 6 by addition of acetic acid. Precipitation will occur.

The precipitate is centrifuged, washed with ethanol containing 50% water and then ether. After drying, 16.9 g of the desired product are obtained.

R 1 = 0.05 (eluent: ethyl acetate-ethanol-water: 70/20/10).

Stage C:

2- (2-Tritylamino-4-thiazolyl-) -2-tritylhydroxyiminoacetic acid sodium salt, isomer syn

16.9 g of the acid prepared in step B, 50 ml of dimethylformamide and 42 ml of triethylamine are combined.

The reaction mixture is then cooled to -20 ° C whereby the triethylamine salt partially crystallizes. 54 g of trityl chloride in 100 ml of chloroform are then introduced at -20 DEG C. over 15 minutes. The mixture is then added. Allow to warm to 1 hour with stirring. ambient temperature. The mixture was poured into 200 ml of water containing 40 ml of 2 N hydrochloric acid.

The mixture is decanted, the organic phase is washed twice with 200 ml of water, dried, centrifuged, the solvent is stripped off under reduced pressure and the residue is taken up in ethyl acetate.

Add 100 ml of saturated sodium bicarbonate solution, stir and decant. The sodium salt crystallizes. The mixture was cooled with ice, centrifuged and the solid washed with ethyl acetate. 27 g of the desired sodium salt are obtained.

R t = 0.33 (ether).

Stage D:

Tert-Butyl 1- {7- [2- (2-tritylamino-4-thiazolyl) -2-trityrhydroxyiminoacetamido] -3-acetoxymethyl-3-celem-4; carboxylate, isomer syn

17.2 g of sodium 2- (2-tritylamino-4-thiazolyl) -2-tritylhydroxyiminoacetic acid (isomer syn) obtained in step C are mixed in 170 ml of chloroform and 170 ml of 1N hydrochloric acid. The mixture was decanted and washed five times with water. After drying and centrifugation, the solvent is stripped off.

The residue is taken up in 170 ml of methylene chloride. 2.8 g of dicyclohexylcarbodiimide are added. The mixture is then stirred for one hour and then 1.9 g of dicyclohexylurea is centrifuged.

To the filtrate is then added 3.66 g of tert-butyl (7-amino-3-acetoxymethylcell-3-em-4) carboxylate.

The mixture was stirred for two hours at ambient temperature, washed with normal hydrochloric acid, then with water, 5% aqueous sodium bicarbonate solution and finally with water again.

The organic phase is dried, centrifuged, the solvent is stripped off, the residue is taken up in methylene chloride and eluted on a column of silica gel, eluting with methylene chloride containing 5% ether.

The important fractions (R 1 = 0.78 in ether) were combined. The solvent was removed under reduced pressure and the residue was taken up in isopropyl ether.

After separation of the layers and centrifugation, the solid is washed with isopropyl ether.

5.8 g of the expected product are obtained.

For C57H51O7N5S2:

calculated:

69.7 o / ₀ c, 5.2 o / o H, 7.1% N, 6.5% S; found:

% C, 70.4;% H, 5.6;% N, 5.9%;

NMR Spectrum: (-CDCl3, 60 MHz)

(a) singlet at 1.55 ppm;

(bj single at 2.06 ppm;

(c) singlet at 6.45 ppm;

(d) singlet at 7.31 ppm.

Stage E:

7- [2- (2-Amino-4-thiiazolyl) -2-hydroxyiminoacetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid isomer syn g of the product obtained in Step D above is added to 3 ml of trifluoroacetic acid. . The resulting mixture was stirred for 30 minutes at ambient temperature and then 30 ml of isopropyl ether was added. The salt crystallizes. The crystallized salt is centrifuged and washed with isopropyl ether.

0.652 g of the salt of 7t [2- [2-amino-4-thiazolyl) -1-trityl-hydroxy-yinoacetic acid amide] -acetoxymethyl-Stetaphthylcarbothexylic acid is obtained.

This product is dissolved in 6 ml of tetrahydrofuran and 3 ml of formic acid (50% aqueous solution) are added to the obtained solution. The mixture is stirred for 15 minutes at 50 ° C, the solvents are stripped off and the residue is taken up. of ether, centrifuged and washed with ether to give 0.441 g m-tartrate of the desired product.

The salt is triturated with 2 ml of water containing 3 drops of pyridine (pH is about 6). After centrifugation, washing with water and drying, 0.136 mg of the desired product is obtained.

The resulting filtrate was dried and the residue was taken up in ethanol. After centrifugation, washing in ethanol yields -0.04 g of an additional portion of the desired product.

NMR Spectrum:

[DMSO, -60 MHz]

[bj singlet at 6.67 ppm;

(c) -singlet at 7.08 ppm; (d) -singlet at 11.3 ppm.

Ethyl '[2s (2-tritylammx-4-Shiazolyl) s2thyds • roxximinn] acetate, isomer son

Example 2

7 ´ [2 ´ (2-Amino-thiazoles 1) -2-Фуxy roxyim ^^ T ^ oacetamido] · 3'-acetoxyme.thyls t3-cefemt4-carbxxylic, isomer syn

43.2 g of ethyl '[2' (2'-mtt-4-thiazolyl) -2'-hydroxy-2'-hydroxy] acetate in the form of isome.ru syn, prepared in Step A of Example 1, is added to 120-ml of anhydrous dimethylformamide.

The mixture was cooled to -35 ° C and 32 ml of triethylamine was added thereto, followed by 60 g of trityl chloride over 30 minutes. The temperature of the reaction mixture was allowed to rise to ambient temperature and complete dissolution was observed. The mixture was then heated to 30 ° C. After one hour, the reaction mixture was poured into 1.2 L of ice water containing 40 ml of hydrochloric acid (424.4 g / l).

The resulting mixture was then stirred in an ice water bath and centrifuged. The solid was washed with normal hydrochloric acid and triturated with ether.

69.3 g of the corresponding chlorohydrate are obtained.

The free base is obtained by dissolving the product in 5 volumes of methanol to which 120% triethylamine has been added and precipitating by the slow addition of 5 volumes of water.

For C26H23O3S. 1/4 H2O:

calculated:

67.6% C, 5.1% H, 9.1 a / _o N, 6.9% S; found:

67.5% C, 5.1 O / o H, 8.8 O / o N, 6.8% S.

NMR Spectrum:

(CDCl3, 60 MHz)

(a) triplet centered at 1.31 ppm, I = 7 Hz;

(b) quadruplet centered at 4.37 ppm,

J = 7Hz;

(c) singlet at 6.37 ppm;

(d) singlet at 7.28 ppm.

Stage B:

Ethyl [2- (2-tritylamino-4-thlazolyl) -2-tetrahydropyranyloxyimino] acetate, syn isomer

5.6 g of the product of Step A are added to 56 ml of redistilled dihydropyran. The reaction mixture was placed on an ice-water bath and 2.4 g of p-toluenesulfonic acid was added thereto.

The reaction mixture is stirred for one and a half hours while allowing the temperature of the mixture to rise to ambient temperature. The heated mixture is then poured into a mixture of 100 ml of benzene, 100 ml of water and 2 ml of triethylamine.

After decanting, washing with water, drying, centrifuging and washing with benzene, the solvent is stripped off. The residue is taken up in isopropyl ether and the solution is seeded for crystallization and left in the refrigerator overnight. The crystals are then centrifuged and washed in isopropyl ether.

4.42 g of product, melting at 184 DEG C., are obtained.

For the p-toluenesulfonic acid salt of C38H39O7N3S2 calculated:

63.9% C, 5.5% H, 5.9 a / ₀ N, 9.0% S; found *

63.7 o / o C 5.5 0/0 H 5.8 _0/0 N, 8.9 »/ o S.

NMR Spectrum: (CDCl 3, 60 MHz) (e)

(b) (a) with ₂ and ₂ with ₃

(a) a triplet centered at 1.36 ppm;

(b) a quadruplet centered at 4.39 ppm;

(c) singlet at 6.60 ppm; (id) singlet at 6.91 ppm;

(e) singlet at 7.28 ppm.

Stage C:

2- (2-Tritylamino-4-thiazolyl) -2-tetrahydropyranyloxyiminoacetic acid, syn isomer

4.56 g of the product prepared in Step B are added to 45 ml of dioxane and 8.4 ml of 2 N sodium hydroxide. The reaction mixture was then heated to reflux for one hour and thirty minutes. The mixture was then cooled in an ice-water bath to precipitate salt. This was centrifuged and washed with aqueous dioxane and then ether to give 4.66 g of the sodium salt.

The corresponding acid is obtained by dissolving the product in 50 ml of dioxane, acidifying with formic acid (pH = 5) and precipitating by adding 90 ml of water.

The product melts at 180 ^° C.

NMR Spectrum: (CDCl3, 60 MHz)

6.69 ppm (thiazole cycle proton);

7.31 ppm (aromatic residue).

Stage D:

Tert-Butyl 7- [2- (2-triethylamino-4-thiazolyl) -2-itetropyranyloxyininoacetamido] -3-acetoxymethyl-3 -cephem-4-carboxylate, isomer syn (0.362 g of the product prepared in Step C) is added to 0.244 g of tert-butyl 7-amino-o-3-acetoxyinethyl-3-cephem-4) carboxylate and

0.280 g of dicyclohexylcarbodiimide in 4 ml of anhydrous chloroform. The reaction mixture is then stirred for two hours at ambient temperature. The dicyclohexylurea formed is centrifuged and washed with chloroform.

The resulting liquid fraction after centrifugation is removed by solvent distillation under reduced pressure; the residue is dissolved in 1 ml of ether and chromatographed on a silica gel column using ether as the eluent.

The fractions with Rf = 0.38 were combined and the solvent was removed under reduced pressure. The residue is taken up in isopropyl ether, centrifuged and washed with isopropyl ether. 0.184 g of the expected product is obtained.

For C43H45O8N5S2 calculated:

C, 62.7; H, 5.5; N, 8.5; S, 7.8; found:

% C, 62.8;% H, 3.9;% N, 8.1%;

N'MR-spek.trum:

(CDCl3, 60 MHz)

(a) 1.53 ppm;

(b) 2.07 -ppm;

(c) 5.46 ppm;

(d) 6.76 ppm;

(e) 7.28 ppm.

Stage E:

7- [2- (2-Amino-4-hiazolyl) -2-hydroxyiminoacetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid isomer syn

The 638 mg of the product obtained in Step D above is stirred for 15 minutes at room temperature in 1.8 ml of trifluoroacetic acid. 18 ml of isopropyl ether are then added to the unpurified mixture. After centrifugation of the precipitate, 404 mg of product are obtained.

The 404 mg of the product is then stirred for 15 minutes at 50 ° C with 2 ml of an aqueous 50% formic acid solution. The mixture is concentrated to dryness under vacuum and the residue is taken up in 1 ml of ethanol. Concentration to dryness is carried out at 30 ° C. A drop of pyridine is then added to the ethanol mixture and the desired product is centrifuged.

This product is identical to the product obtained in Example 1.

Example - 3

7- [2- (2-Tritylamino-4-thiazolyl) -2-tritylhydroxyiminoacetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid isomer syn

Stage A:

Ethyl [2- [2-tritylamino-4-azazolyl] -2-tritylhydroxyimmojacetate, isomer syn

1.08 g of ethyl [2- (2-amino-14-thiazolyl) -2-hydroxyiminoleacetate as the isomer syn, prepared in Step A of Example 1, is dissolved in 8 ml of chloroform. ml of triethylamine and then at -5 [deg.] C. for 25 minutes a solution of 3 g of trityl chloride in 6 ml of chloroform, and the mixture was stirred for 1 hour at ambient temperature.

The mixture is then washed with 18 ml of water, 8 ml of normal hydrochloric acid and three times with 20 ml of water. After drying, the solid is centrifuged and the liquid concentrated to dryness. The residue is taken up in isopropanol, from which it is crystallized.

2.3 g of the expected product are obtained, melting at 140 ° C.

Stage B:

2- (2-Tritylamino-4-thiazolyl) -2-tritylhydroxyiminoootic acid,

Isomer syn

0.7 g of the product obtained in Step A are dissolved in 3.5 ml of warm dioxane. The solution thus obtained is heated to 110 DEG C. and 1 ml of 2N sodium hydroxide is added dropwise to this solution with stirring. Stirring is continued for one hour and 50 minutes at a temperature close to the boiling point of the reaction mixture, after which the reaction mixture is cooled and the sodium salt which has precipitated is centrifuged.

The product obtained is identical to the product obtained in Step C of Example 1.

Stage C:

7- [2- (2-tritylamino-4-thiazolyl-2-thitylhydroxyiminoaicetamido) -3-acetoxymethyl-3-cephem-4-carboxylic acid, isomer syn

5.12 g of the sodium salt obtained in step B above are suspended in 50 ml of chloroform. 50 ml of normal hydrochloric acid are then added to the suspension. The mixture was then stirred, decanted and washed three times with 50 ml of water. After drying, centrifuging and concentrating to dryness, 2- (2-tritylamino-4-thiazolyl) -2-tritylhydroxyiminoacetic acid is obtained as the syn isomer.

The acid thus obtained is dissolved in 50 ml of methylene chloride. 1.6 g of dicyclohexylcarbodiimide are then added to the obtained solution and the mixture is stirred at ambient temperature for one hour; the dicyclohexylurea is centrifuged and the solution is cooled to -10 ° C; 7-aminocephalosporanic acid as a solution in 10 ml of methylene chloride and 1.2 ml of triethylamine was added to the cooled solution. The reaction mixture is stirred for two hours at room temperature and 50 ml of normal hydrochloric acid are added to the reaction mixture. The mixture is then stirred, decanted, washed three times with 50 ml of water, dried, centrifuged and concentrated to dryness.

The residue was taken up in ethanol and centrifuged to give 2.36 g of crude condensate. This product is converted to the diethylamine salt of 7- [2- (2-tritylamino-4-thiazolyl) -2-tritylhydroxyiminoacetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid isomer syn by the action of diethylamine in ether .

Normal hydrochloric acid is added to the obtained salt in the presence of methylene chloride to reach an acidic pH range. The solution was washed with water, dried and evaporated to dryness.

0.75 g of purified desired product is obtained.

Example 4

7- [2- (2-Amino-4-thiazolyl) -2-hydroxyiminoacetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid isomer syn

The ditrityl product obtained in the preceding Example 3 is dissolved in 5 ml of a 50% aqueous formic acid solution. The solution thus obtained is stirred for 15 minutes at 50 DEG C., the solvents are then stripped off, the residue is taken up in ether, centrifuged and washed with ether.

In this way the product is obtained in the form of formate.

The formate thus obtained is triturated with 3 ml of water containing a few drops of pyridine (pH about 6). After centrifugation, washing with water and drying, the desired product is obtained, which is identical to the products obtained in Examples 1 and 2.

Example 5

7- [2- (z-Amino-4-thiazolyl) -2-hydroxyiminoacetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid, isomer syn

0.613 g of the acid obtained in Examples 1, 2 or 4 are dissolved in a mixture of 2 ml of distilled water and 2 ml of a molar solution of sodium acetate in methanol. 60 mg of activated carbon are added to the solution thus obtained, the solution is centrifuged, washed with 2 ml of methanol and concentrated to dryness under vacuum at 30 ^DEG C.; The residue is taken up in ethanol to give 0.432 g of the desired sodium salt after centrifugation and drying.

Example 6

Crystalline 7- [2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid, isomer syn

1.78 g of the acid obtained in Examples 1, 2 or 4 are suspended in 8 ml of methanol. 8 ml of a molar solution of sodium acetate in methanol are added to the suspension thus obtained, and the desired sodium salt crystallizes immediately. The mixture was stirred for a further 15 minutes to complete the conversion, centrifuged, washed with ethanol and then with ether.

1.53 g of white crystalline product are obtained.

For C 15 H 14 O 7 N 5 S 2 Na calculated:

38.88 a / _o C, 3.04% H, 15.11% N, 13.84% S,

4.96% Na;

found:

38.8% С, 13.1% H, 15.1% Ν, 13.8 ο / _ο S,

4.85% Na. .

Infrared spectrum:

(nujol) \

= 0 1753, 1724, 1683 cm -1 ^!

OF

NH, OH 3597 cmNMR spectrum:

[DMSO, 60MHz]

Singlet at 2.01

-C — CH3;

II

0 singlet at 6.65 (thiazole-cyclone proton);

singlet at 7.16 [amine NHz group].

Example 7

An injection preparation having the following composition is prepared:

- 7- [2- (2-amino-) -

-4-1 halo-o-oyl) -2-hydroxyiminoacetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid isomer, 500 mg, - aqueous sterile excipient up to 5 m, l.

Example8

Gelatin capsules are prepared as follows:

- 7- (2- (2-amino-4'-thiazolyl) -2-hydroxyiminoacetamido) -3-acetoxymethyl-3-methyl-4-carboxylic acid, isomer syn 250 mg, - excipient to make up the weight of one capsule to 400 mg.

Claims (3)

Object of the invention A process for the preparation of oxime derivatives of 7-aminothiazole / lylacetamido-cephalic / sporanoic acid of the general formula Ib wherein: R 1 "represents a hydrogen atom or a saturated or unsaturated alkyl group having 1 to 4 carbon atoms, and a wavy line means that the" OR 1 "group may be in the syn or autosity position, characterized by reacting an acid derivative of 7- aminocephalosporan compounds of formula III O * in which A 1 represents a group readily cleavable by acidic acid hydrolysis or by hydroigenolysis, such as benzhydryl, tert-butyl, benzyl, p-methoxybenzyl and trichloro-6-oxyl, with an acid of formula II 20757 « V or with a functional derivative of the acid, wherein in formula II R 1 is a group readily cleavable by acid hydrolysis or hydrogenolysis such as tert-butoxycarbonyl, trityl, benzyl, trichloroethyl, benzyloxycarbonyl, formyl, trichloroithoxycarbonyl or 24-tetrahydropyranyl, or chloroacetyl; readily cleavable acid hydrolysis or hydrogenolysis such as tert-butoxycarbonyl, trltyl, benzyl, trichloroethyl, benzyloxycarbonyl, formyl, trichloroethoxycarbonyl or, 2-tetrahydropyranyl, or an unsaturated alkyl or unsaturated alkyl group And the wavy line is as defined above to form a product of formula XI wherein -R 1, R 1 ', A 1 and the wavy line are as defined above, whereupon said product of formula XI is treated with one or more , several acid hydrolyzing agents such as formic acid, trifluoroacetic acid, acetic acid or zinc / acetic acid system with one or more hydrogenolyzing agents such as hydrogen in the presence of a catalyst, thiourea or one or more of the above to form of the product of formula Ib. 2. A process according to item 1 for the preparation of 7- [2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid in the form of the syn isomer, characterized in that is reacted with a 7-aminocephalosporanic acid derivative of the formula III * (iii'j) wherein: Ai is a group which is readily cleavable by acid hydrolysis or hydrogenolysis, such as benzhydryl, tert-butyl, benzyl, p-methoxybenzyl and trichloroethyl, with an acid of the general formula ΙΓ in the form of the syn isomer or a functional derivative. R @ 1 and R @ 1a are a group readily cleavable by acidic hydrolysis or hydrogenolysis, such as tert-butoxycarbonyl, trityl, benzyl, triacyl (orethynyl, benzyloxycarbonyl, formyl, group, tricnlore'thoxyka ^ι rtιonylová or group. 2-teiiralhydropyranylová group, or chloroacetyl group, and when Ri'a means chlolraicetylovou group,. Ria also means a chloroacetyl group, to give a product of formula in the form ΧΓ syn isomer wherein, in formula XI ', A 1, R 1a and' R 1 'are as defined above, after which the product of formula XI * is treated with one or more acid hydrolysis agents such as formic acid, trifluoroacetic acid, acetic acid or acetic acid; Zinc / acetic acid system with one or more hydrogenolyzing agents such as hydrogen in the feed % of a catalyst, thiourea or one or more of the above agents to obtain the desired acid. 3. A process according to claim 2, wherein R @ 1 is trityl or tetrahydropyranyl, and R @ 1 in which A @ 1 is tert-butyl, and other general symbols. are as defined above.