SI8310011A8 - Process for obtaining new antibiotics - Google Patents

Description

PROCEDURE FOR OBTAINING NEW ANTIBIOTICS

The application was isolated from our application P-137/77, for which a patent protection decision was issued.

Technical field

The invention relates to the field of antibiotic synthesis and relates to a process for the production of new antibiotic products from the cephalosporin family.

Technical problem

A technical problem solved in the present invention is a process for the preparation of a cephalosporin-type derivative which, at position 7 of the cephalosporin nucleus, has an aminothiazolyl radical starting from the corresponding precursors whose aminothiazolyl radical is protected.

New cefaSporin products that have an aminothiazolyl radical in the 7-position of the cephalosporin core have better antibiotic activity than hitherto known cephalosporin products that have a 7-position other aryl radical.

The state of the art

Cephalosporin-type products that have an aryl radical in 7 positions are already well known. These products have less antibiotic activity than the cephalosporin products obtained by the process of the present invention.

Description of a solution to a technical problem with examples of execution

According to the invention, the present invention provides a process for the preparation of new cephalosporin type antibiotic products having the following formula:

NH-R

in which R represents a hydrogen atom, a group which can be readily eliminated by acid hydrolysis or hydrogenolysis or represents a chloroacetate group, R l represents a hydrogen atom, a group which can be easily eliminated by acid hydrolysis or hydrogenolysis, a chloroacetate group or a saturated or unsaturated alkyl residue with 1 to 4 C atoms, A represents either a hydrogen atom or an equivalent of an alkali or alkaline earth metal, magnesium or an organic amine base, a wavy line indicates that the group OR 'is in the positiony syn, implying that, when R £ represents a group that can be easily eliminated by acid hydrolysis or hydrogenolysis, R _c represents a group that can be easily eliminated by acid hydrolysis or hydrogenolysis, and when R 8 represents a chloroacetyl group, R _c represents a chloroacetyl group, whereas when R 'represents a hydrogen atom, R represents an atom hydrogen.

The object of this invention is, in particular, a process for the production of new oximes derived from 7-amino-thiazolyl-acetamido-cephalosporic acid of general formula I:

NH-R

(I)

- -3 in which R represents a hydrogen atom or a group which can be easily eliminated by acid hydrolysis or hydrogenolysis, R 'represents a hydrogen atom, a group which can be easily eliminated by acid hydrolysis or hydrogenolysis, or represents a saturated or unsaturated alkyl residue having 1 to 4 C atoms, A represents either a hydrogen atom or an equivalent of an alkali or alkaline earth metal, magnesium or an organic amine base, the wavy line indicates that the group OR 'is in one of two possible positions, syn or anti, implying that when R 'represents a group which can be easily eliminated by acid hydrolysis or hydrogenolysis,

R represents a group which can be easily eliminated by acid hydrolysis or hydrogenolysis, and when R 'represents a hydrogen atom,

R represents a hydrogen atom.

The groups readily eliminated by acid hydrolysis or hydrogenolysis and which may represent the groups R, R ', R and R' may include tert-butoxycarbonyl, trityl, benzyl, dibenzyl, trichloroethyl, carbobenzyloxy, formyl, trichloroethoxycarbonyl or 2 -tetrahydropyranyl.

Among the other groups R < 2 > and R ', residues methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, vinyl, propenyl, butenyl, ethynyl and propargyl may be mentioned.

Among grapples marked A, in particular, the equivalent of sodium, potassium, lithium, calcium or magnesium may be mentioned; among the organic bases which may be represented by A may be mentioned trimethylamine, triethylamine, methylamine, propylamine, N, N-dimethylethanolamine, tris (hydroxymethyl) aminometall, arginine or lysine.

The object of the invention is in particular a process for the preparation of products of formula (I ') and formula (I) in which the groups which can be easily eliminated by acid hydrolysis or hydrogenolysis are selected from tert-butoxycarbonyl, trityl, dibenzyl, trichloroethyl and carbobenzyloxy.

Compounds of formula (I?) And (i) defined as syn form can be schematically represented by the following general formula:

CH-OCCH-. 2 ι, 3

Oh

The compounds of formulas (I ⁷ ) and (I) can therefore be schematically defined as the anti-isomeric form represented by the general formula:

NH

The subject of the invention is the method i (I) in which the groups OR ^ for preparing the products of formula (I ') and OR' are in the syn position.

More particularly, the subject of the invention is a process for the production of products of formula (I ') and (I) in which R and R represent a hydrogen atom or a trityl group, R 8 and R' represent a hydrogen atom, a trityl group or an alkyl residue, saturated or unsaturated, with 1 to 4 C atoms and A represents a hydrogen atom, a sodium atom or the equivalent of diethylamine.

The products of the formulas (! ') And (I) may in particular include products which will be described later in the examples, in particular:

- 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid;

- 3-acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid sodium}

- 3-acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -cef-3-em-4-carboxylic acid isomer;

- 3-acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido / -ceph ~ 3-em-4-carboxylic acid syn isomer of sodium isomer

- 3-acetoxymethyl-7-2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -cef-3-em-4-carboxylic acid, as obtained by the procedure described in Example 4;

- 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid sodium salt, as obtained by the procedure described in Example 7;

- Sodium crystallized from 3-acetoxymethyl-7 / 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido / -ceph-3-em-4-carboxylic acid syn isomer;

- 3-acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido / -cef-3-em-4-carboxylic acid isomer and its salts with alkali, alkaline earth metals or with organic amine bases ;

- 3-acetoxymethyl-7- {2- (2-amino-4-thiazolyl) -2- [(2-propenyl-oxy-amino) -acetamido} -ceph-3-em-4-carboxylic acid isomer isomer and its salts with alkali, alkaline earth metals or with organic amine bases;

- 3-acetoxymethyl-7- {2- (2-amino-4-thiazolyl) -2- [{1-methyl-ethoxy) -imino] -acetamido} -ceph-3-em-4-carboxylic acid syn isomer and its salts with alkali and alkaline earth metals or with organic amine bases.

It is understood that the aforementioned products of formula (I) may comply with:

- or in the form of said Formula (I),

- or in the form of a product of formula (I):

£ t

'B' in which R, R 'and A have the meanings given above.

It is also understood that the foregoing products of formula (I ') may exist in the same two forms as those previously mentioned for the products of formula (I).

A process for producing a product of the above formula (I ') wherein 7-amino-cephalosporic acid of the formula:

reacts with an acid of formula Ilc:

(Ilc) or with any functional derivative of that acid, of formula Ilc, in which R1 represents a group which can be easily removed by acid hydrolysis or hydrogenolysis or represents a chloroacetyl group, and R4 represents a group which can be easily eliminated by acid hydrolysis or hydrogenolysis. ^! a chloroacetyl group or a saturated or unsaturated alkyl residue of 1 to 4 C atoms, wherein it is understood that when R1 represents a chloroacetyl group, it also represents ii, to give the product of formula Ic:

in which R ^ and R ^ have the same meaning as previously stated and which corresponds to a product of formula (I ') in which R _c represents a group which Although can be eliminated by acid hydrolysis or hydrogenolysis or represents a chloroacetyl group, and R 8 represents a group which Although it can be eliminated by acid hydrolysis or hydrogenolysis, a chloroacetyl group or some saturated or unsaturated alkyl residue having 1 to 4 C atoms; The product of formula (Ic), or a diethylamine salt thereof, is hydrolyzed, if necessary in an acidic medium, or hydrogenated, or treated with thiourea, depending on what R 'is, to give the product of formula (Ib):

wherein R1 represents a hydrogen atom or a saturated or unsaturated alkyl residue of 1 to 4 C atoms corresponding to a product of formula (I ') in which R and A represent a hydrogen atom and R'

C c represents a hydrogen atom or some saturated or unsaturated alkyl i

a residue having from 1 to 4 C atoms, so that the product of formula (Ic) or (Ib) is optionally converted to salt according to conventional methods.

A process for preparing a product of formula (i) as previously defined and subject to the invention, wherein

7-amino-cephalosporic acid of the formula:

ch ₂ ococh ₃ reacts with an acid of the formula:

(II) or with any functional derivative of that acid, of formula (II), in which it represents an agr group which can be easily separated by acid hydrolysis or hydrogenolysis, and R 'represents a group which can be easily separated by acid hydrolysis or hydrogenolysis or represents saturated or unsaturated alkyl residue having 1 to 4 C atoms, to give the product of formula (Ia):

(Ib) in which R1 ^ and R 'have the same meaning as above, corresponding to a product of formula (I) in which R represents a group which can be easily eliminated by acid hydrolysis or hydrogenolysis, and R' represents a group which can easily be eliminated by acid hydrolysis or hydrogenolysis, or is a saturated or unsaturated alkyl residue of 1 to 4 C atoms, so that the product of formula (Ia) is hydrolyzed optionally in an acidic environment or is hydrogenolized to give the product of formula (Ib):

in which a hydrogen atom or a saturated or unsaturated alkyl moiety having 1 to 4 C atoms corresponding to a product of formula (I) in which both R and A represent hydrogen atoms and R 'represents a hydrogen atom or some saturated or unsaturated alkyl moiety with from 1 to 4 C atoms, so that the product of the formula (Ia) and (Ib) may be converted to the salt according to the usual procedures.

According to a method which is preferable to performing a process for preparing a product of formula (I ') or formula (I), an 7-amino-cephalosporanic acid is acted upon by a functional acid derivative of formula (Ilc) or (II), such as anhydride or acid chloride, wherein the anhydride may be formed in situ by the action of isobutyl or dicyclohexylcarbodiimido chloroformate on the acid. Other halides or other anhydrides created in situ by the action of other alkyl or dialkoylcarbodiimide chloroformate or other dicycloalkylcarbodiimide chloroformate may also be used. Other derivatives of selenium such as -esazide acid, activated acid amide, or activated acid ester obtained from e.g. hydroxy succinimide, p-nitrophenol or 2,4-dinitrophenol. In the case where the reaction

The 7-amino-cephalosporanic acid is carried out with an acid halide of the general formula (Ilc) or (II), or with an anhydride obtained using isobutyl chloroformate, the reaction being preferably carried out in the presence of a base component. It can be used as a base component, e.g. an alkali metal carbonate or some tertiary organic base such as N-methyl morpholine, pyridine or a trialkylamine such as triethylamine.

Formic, trifluoroacetic or acetic acid products may be mentioned as acid hydrolysis agents to which products of formula (Ic) or (Ia) are subjected, when necessary. These acids can be used as anhydrous or in aqueous solution. As a means of hydrogenolysis, the zinc-acetic acid system may be particularly mentioned.

To remove tert-butoxycarbonyl or trityl groups, an acid hydrolysis agent such as anhydrous trifluoroacetic acid or formic or acetic acid containing water is preferred.

To eliminate the trichloroethyl group, a zinc-acetic acid system is preferred, and catalytic hydrogenation is used to remove the benzyl, dibenzyl, and carbobenzyloxy groups.

The action of thiourea on the product of formula (Ic), in which it represents a chloroacetyl group and a R4 chloroacetyl group or saturated alkyl residue of 1 to 4 carbon atoms, is preferably carried out in a neutral or acidic environment. This type of reaction is described by Masaki / J.A.C.S., 90, 4508 (1968) /.

The products of formula (Ic), (1a) or (ib) may be converted to salt by conventional methods. Translating into salt can, e.g. to effect these acids, some inorganic bases, such as e.g. sodium or potassium hydroxide or sodium bicarbonate, or some salts of substituted or unsubstituted aliphatic carboxylic acids such as diethyl acetic or ethylhexanoic acid, or in particular acetic acid.

The most preferred salts of the acids mentioned above are sodium salts. _χ

Conversion to salt can also be achieved by the action of an organic base such as triethylamine.

For the preparation of salts, instead of free acids, keo starting materials and free acid solvates can also be used, e.g. the solvates obtained with water, formic acid or some alcohol may be mentioned.

Solvates with some alcohol, especially ethanol, can also be obtained, e.g. by treating with a mixture of alcohol and water a solvate obtained with the help of formic acid, after which the solution is concentrated.

Said translation into salt is preferably carried out in a single solvent or in a mixture of solvents such as water, ethyl ether, methanol, ethanol or acetone.

The salts are obtained in amorphous form or crystallized, depending on the reaction conditions used.

The crystallized salts are preferably prepared by the reaction of the free acid or its solvates obtained, e.g. from formic acid or ethanol and some of the salts of the aforementioned aliphatic carboxylic acids, preferably with sodium acetate.

In the preparation of the sodium salt, the reaction is carried out in a suitable organic solvent, such as e.g. methanol, a solvent that can hold small amounts of water.

In addition, it is possible to convert amorphous salts to their crystallized forms. Therefore, an amorphous sodium salt, which may be in the form of a solvate, e.g. 0.5, 1 or 1.5 moles of water can be dissolved in a suitable organic solvent, preferably in a low molecular weight alcohol such as methanol? the crystallization can then be carried out directly or by the addition of other solvents, e.g. ethanol, isopropanol, n-butanol, acetone, ethers and, in principle, organic solvents miscible with methanol.

If the starting product, solvent or both components contain water, crystallized salt can be obtained in the form of hydrates. E.g. 3-Acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -cef-3-em-4-carboxylic acid, crystallized sodium, isomer syn, was able to e.g. to be isolated with 0.5, 1 or

1.5 mol of water.

An acid used to hydrolyze salts of products of formula (Ic) or formula (Ia), in which R ^ and R ^ represent a group that Although can be eliminated by acid hydrolysis, and R ^ and R 'represent a group that Although can be eliminated by acid hydrolysis or represent a saturated or unsaturated alkyl residue having 1 to 4 C atoms, preferably formic acid. However, trifluoroacetic acid or acetic acid may be used.

These acids can be applied anhydrous or in aqueous solution.

As a method of hydrogenolysis, to which salts of the products of formula (Ic) or formula (Ia) are subjected, in which R ^ and R ^ represent a group that can be eliminated by hydrogenolysis, and R ^ and R 'represent a group that can be eliminated by hydrogenolysis, or representing a saturated or unsaturated alkyl group of 1 to 4 C atoms, catalytic hydrogenation may be indicated.

The products of the general formula (I ^r ), especially those of the general formula (I), and especially those in the form of syn, exert a very good antibiotic effect, on the one hand, on gram-positive bacteria / such as staphylococci, streptococci, especially staphylococci resistant to penicillin. and on the other hand, to gram-negative bacteria especially to coliforms, Klebsiella, Salmonella and Proteus.

These properties make the aforementioned products pharmaceutically acceptable, applicable as medicaments in the treatment of germ-induced staining, and in particular staphylococci, such as staphylococcal sepsis, malignant staphylococci on the face or skin, pyodermitis, septic or pus sores, anthrax, phlegmons simple acute staphylococci or those after groups, bronchopneumonia, purulent pulmonary abscesses.

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

The products of formula (I) which are pharmaceutically acceptable may be used for the preparation of pharmaceutical preparations containing, as an active principle, at least one of the products mentioned, and in particular one of those with the syn structure described in the examples.

Among these preparations, in particular, pharmaceutical preparations containing, as active ingredient, at least one of the products of general formula (I) in which R represents a hydrogen atom, R 'represents a hydrogen atom or a saturated or unsaturated alkyl residue of 1 to 4 C atoms, and A represents a hydrogen or sodium atom.

Also to be mentioned are pharmaceutical preparations containing as active ingredient:

- ^{with the} Y ⁿ isomer of 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -ceph-3-em-4 "carboxylic acid; that product is particularly described in Examples 4, 6, 20 and 22, or

- 3-acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid sodium isomer salt; this product is particularly described in example 7, or

- a sodium salt crystallized from the syn isomer of 3-acetoxymethyl7- N - (2-amino-4-thiazolyl) -2-methoxyiminoacetamido / -ce-3-em-4 carboxylic acid, or at least one of the following products:

- 3-acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2-ethoxyiminoacetamido / -cef-3-em-4-carboxylic acid syn isomer and its alkali and alkaline earth metal salts - or pharmaceutically acceptable organic amine bases,

- syn isomer of 3-acetoxymethyl-7- {2- (2-amino-4-thiazolyl) -2- ((2-propenyl) -oxyimino) -acetamido} -cephine: 3-em-4-carboxylic acid and its salts with alkali and alkaline earth metals or pharmaceutically acceptable organic amine bases, " ^{having the} Y ⁿ isomer of 3-acetoxymethyl-7- {2- (2-amino-4-thiazolyl) -2- [(1-methylethoxy) -imino] -acetamido} - cef-3-em-4-carboxylic acid and its salts with alkali and alkaline earth metals or pharmaceutically acceptable organic amine bases.

These preparations may be administered orally, rectally, parenterally or topically, by application to the skin or mucous membranes.

The preparations may be solid or liquid and may be in pharmaceutical dispensers commonly used in human medicine, such as e.g. tablets, whether or not in the form of dragees, gelatin capsules, granules, suspensions, grout, pomades, creams, gels, prepared in the usual way. The active ingredient or ingredients may be incorporated into carriers commonly used in such pharmaceutical preparations as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous agents, animal or vegetable fats, paraffin derivatives , glycols, various wetting, dispersing or emulsifying agents, preservatives.

The dose administered depends on the disease being treated, the case, the route of administration and the product concerned. It can, for example, be chalked from 0.250 to 4 g per day, when administered orally in humans, with the product described in Example 4 or 7, or between 0.500 and 1 g three times daily, administered intramuscularly.

The following is an experimental section, which provides Preparations and Examples that illustrate the invention in detail without limitation. The Preparations describe the preparation of the starting materials required for the synthesis of the desired compound in a suitable Example. It should be noted that in addition to the products described in the examples, the following products are substances that can be obtained by the invention:

- 3-acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2-propyloxyiminoacetamido / -ceph-3-em-4-carboxylic acid isomer and its salts with alkali and alkaline earth metals or organic amine bases,

- 3-acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2-butyloxyiminoacetamido / -ceph-3-em-4-carboxylic acid isomer and its salts with alkali and alkaline earth metals or with organic amine bases , syn isomer of 3-acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2- (2-methylpropyloxyimino) -acetamido / -ceph-3-em-4-carboxylic acid and its alkali and alkaline earth salts metals or with organic amine bases, syn isomer 3-acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2- (1,1-dimethylethoxyimino) -acetamido / -ceph-3-em-4-carboxylic acids and its salts with alkali and alkaline earth metals or with organic amine bases, syn isomer 3-acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2- (2-butenyloxyimino) -acetamido / -cef-3 -em-4-carboxylic acid and its salts with alkali and alkaline earth metals or with organic smine bases, syn isomer 3-acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2- (3-butenyloxyimino) - acetamido / -cef-3-em-4-carboxylic acid and its salts with alkali and alkaline earth metals or with organic amine bases, syn isomer of 3-acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2- (2-butynyloxy-imino) -acetamido / -ceph-3-em-4-carboxylic acid and its salts with alkali or alkaline earth metals or with organic amine bases, syn isomer 3-acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2- (3-butynyloxyimino) -acetamido / -ce-3-em -4-carboxylic acids and their salts with alkali and alkaline earth metals or with organic amine bases, syn isomer 3-acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2- (vinyloxyimino) -acetamido / -ceph -3-em-4-carboxylic acid and its salts with alkali and alkaline earth metals or with organic amine bases, syn isomer 3-acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2- (1- propenyloxyimino) -acetamido / -ceph-3-em-4-carboxylic acid and its salts with alkali and alkaline earth metals or with organic amine bases.

- 3-acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2- (1-propynyloxyimino) -acetamido / -ceph-3-em-4-carboxylic acid isomer and its alkali and alkaline earth salt isomers metals or with organic amine bases,

- 3-acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2- (1-butenyloxyimino) -acetamido / -ceph-3-em-4-carboxylic acid isomer and its alkali and alkaline earth salt isomers metals or with organic amine bases,

- 3-acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2- (1-ethynyl oxyimino) -acetamido / -ceph-3-em-4-carboxylic acid isomer and its salts with alkali and alkaline earth metals or with organic amine bases,

- 3-acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2- (1-propynyloxyimino) -acetamido / -ceph-3-em-4-carboxylic acid isomer and its alkali and alkaline earth salt isomers metals or with organic amine bases,

- 3-acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2- (1-butynyloxyimino) -acetamido / -ceph-3-em-4-carboxylic acid isomer and its alkali and alkaline earth alkali salts metals or with organic amine bases.

PREPARATION 1

Phase A: 2- (2-Amino-4-thiazolyl) -2-hydroxyimino-acetate ethylate / 2- (2-amino-4-thiazolyl) -2-hydroxyiminosulfuric acid /

In 5 ml of ethanol and 0.76 g of thiocarbamide were placed 2 g of γ-chlorooxyiminoacetyl acetate ethylate and stirred for a total of 16 hours at room temperature; as the hydrochloride was crystallized, diluted with 5 ml of ether, dried, washed with ethanol / ether (1: 1) followed by ether to give 1.55 g of hydrochloride.

The resulting 1.55 g of hydrochloride was dissolved at 40-50 ° C in 8 ml of water and neutralized to pH = 5 to 6; by addition of sodium acetate crystallizes the free amine. It was cooled with ice, then it was dried, washed with water, dried and 1.22 g of anti-isomer were obtained, m.p. 154 ° C.

The mother liquors were collected as well as from rinsing from several experiments, concentrated, redissolved in water, washed with ether, acidic sodium carbonate was added, washed, washed with water, 1.9 g of the product was obtained giving two layers in thin layer chromatography. purified by chromatography on silica and eluting with ether. The pure fractions of the syn isomer are combined, filtered and dried, yielding 50 mg of this isomer.

Phase B: 2- (2-Trithylamino-4-thiazolyl) -2-trityl-hydroxyiminoacetate ethyl

To a solution containing 5.4 g of the product obtained in phase A in 54 ml of chloroform and 7.5 ml of triethylamine was added at + 1O ° C. A solution of 15 g of trityl chloride in 30 ml of chloroform was washed after one hour with 40 ml of water, 20 ml of water containing 4 ml of normal hydrochloric acid is decanted, dried and concentrated to dryness.

The dry residue was dissolved in 10 ml of ether, 50 ml of methanol was added, stirred, washed, washed with methanol to give 14.2 g of the expected product twice.

Phase C: 2- (2-Tritylamino-4-thiazolyl) -2-tritylhydroxyiminosulfuric acid

At the reflux point, 10 ml of the phase B ester obtained in 55 ml are suspended in 55 ml of dioxane. 17 ml of a 2N soda solution are slowly added. Continue refluxing, cool and salt. The salt is dissolved in 60 ml of methylene chloride, 20 ml of water and 2 ml of vinegar line. The acid is flushed, washed with water and the first amount of 7 g of acid is obtained.

•

Dioxane was evaporated from the stock solution, 20 ml of mer was added again

of thylene chloride, 10 ml water and 1 ml acetic acid. A new amount of 1.5 g of the product is allocated, a total of 8.5 g.

Analysis:

Calc. for C._H _oo 0 _o N _o S · 0.5 H _o 0 43 33 3 3 2

C 75.85 H 5.03 N, 6.17 S 4.7 Found: 75.8 4.9 5.9 4.6 EXAMPLE 1

3- (2- (2-Trutylamino-4-thiazolyl) -2-tritylhydroxyiminoacetamido) -cef-3-em-4-carboxylic acid 3-acetoxymethyl-7-

Suspend 8.5 g of the acid prepared in phase C of preparation 1 and with 50 ml of methanol. 5 ml of N-methyl morpholine are added to the mixture. It was stirred for 10 minutes at 30 ° C, 30 ml of methylene chloride was added, concentrated, 100 acre of ether was added, stirred, the ether was dried, the first amount of 7.2 g of salt was obtained, evaporated, dissolved in ether and a different quantity of the same product is obtained.

With stirring, in an inert atmosphere, suspend 4.24 g of the above-mentioned morpholine salt in 60 ml of methylene chloride.

It was stirred for 5 minutes, cooled to -5 ° C and 6 ml of molar solution of isobutyl chloroformate in methylene chloride was added. It was stirred for 15 minutes at -5 ° C, cooled to -20 ° C and a solution of 1.36 g of 7-amino-cephalosporanic acid dissolved in 25 ml of methylene chloride and 1.4 ml of trityl amine was added. Leave for one hour at room temperature, wash with 50 ml of water containing 10 ml of IN HCl, dry, wash with water and dry. Mix in ether, filter, wash with ether to give 4.5 g of crude product. The crude product was stirred for 1 hour at + 10 ° C in 10 ml of methylene chloride. The insoluble portion is washed and washed with methylene chloride. 50 ml of ether are added to the filtrate, mixed, the precipitate is dried, washed with ether to give 2.29 g of the expected product.

A second quantity of 0.86 g or a total of 3,136 g of the expected product is obtained.

EXAMPLE 2

3-Acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) 2-hydroxyiminoacetamido / cef-3-em-4-carboxylic acid

2.29 g of the product obtained in Example 1 are suspended in 18.4 ml of 50% aqueous formic acid solution at 55 ° C and stirred vigorously for 15 minutes.

It was cooled, 10 ml of water was added, it was washed, washed with water, evaporated in vacuo, acetone was added, it was drained, 30 ml of ether was added, it was stirred, it was washed, it was washed with ether to give 0.665 g product. In addition, 0.123 g of crystallizing product or a total of 0.788 g are obtained.

0.735 g of product are dissolved in 7.5 ml of methanol and 7.5 ml of acetone. Add 70 mg of activated charcoal, remove the solvent, whisk in ethanol, wash and obtain the first amount of 0.450 g and the second amount of

IR spectrum:

C = c = c-nh ₂ NH 1 0.105 g.

1774 cm 1740 cm 1676 cm 1630 cm

L

1520 cm (beta-lactam)

PREPARATION 3

Phase A: 2- (2-Amino-4-thiazolyl) -2-methoxyimino-acetate ethyl

Into 1 ml of absorbent ethanol 1 g of gamma-chloro-alpha-methoxyiminoacetyl acetate ethyl was added and 0.42 g of crushed thiourea was added. The mixture was stirred at room temperature for about 2 hours. It was diluted with 60 ml of ether, the resulting hydrochloride crystallized, stirred, dried, washed, dried to give 685 mg of hydrochloride. This was dissolved in 4 ml of water at 50 ° C, potassium acetate added to pH = 6 and the separated amine crystallized. Cool, dry, wash with water and dry; 270 ml of expected product is obtained; m.p. 161 ° C. The product obtained has a syn configuration, NMR (CDCl3, 60 MHz) ppm: 4 (N-OCH2); 6.7 (proton from thiazole ring).

Phase B: 2- (2-Trithylamino-4-thiazolyl) -2-methoxyiminoacetate ethyl

In 92 ml of methylene chloride at 30 ° C dissolve 4.6 g of the product obtained according to the procedure of the previous step. Cool to -1O ° C, add 2.9 ml of tritylamine, cool to -35 ° C for 15 minutes, add 6.1 g of trityl chloride, allow to rise to room temperature for a total of 2 hours and 30 minutes . Wash with water, for 0.5 N with HG1, then with sodium acetate solution in water. Dry, concentrate, re-dissolve in ether, concentrate again, dissolve in methanol, add water and ether, allow to crystallize, dry, wash with ether to give 6.15 g of the expected product; m.p. 120 ° C.

The resulting product has a syn configuration.

Phase C; 2- (2-Trithylamino-4-thiazolyl) -2-methoxyiminosulfuric acid

7.01 g of phase B ester were dissolved in 35 ml of dioxane.

Heat the oil bath to 110 ° C for 5 minutes, add 9 ml of 2N baking soda and allow to reflux for 30 minutes with stirring. They are crystals of sodium. It is cooled, filtered, washed with dioxane and ether to give the first salt of 5.767 g. The mother liquor was concentrated to give another amount of 1,017 g, ie a total of 6,784 g of salt.

Into 65 ml of methylene chloride and 6.5 ml of 2N HCl was added 3.06 g of salt, washed with water, dried and evaporated to dryness to give the free acid quantitatively.

The resulting product has a syn configuration.

NMR (DMSO, 60 MHz) ppm: 3.68 (N-OCH 2); 6.6 (proton from thiazole ring).

EXAMPLE 3

3-Acetoxymethyl-7- / 2- (2-trimethylamino-4-thiazolyl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid

The dry acid obtained in phase C of the previous Preparation was dissolved in 30 ml of dry methylene chloride. 0.78 g of dicyclohexylcarbodiimide was added and stirred at room temperature for 1 hour. The dicyclohexylcarbamide formed was cooled to -1Q ° C, and then a solution containing 1.01 g of 7-amino-cephalosporic acid in 13 ml of methylene chloride and 0.9 ml of triethylamine was added. Allow the temperature to rise to room temperature, add 1 ml of acetic acid, settle, wash with water to which hydrochloric acid has been added, then with water, dry, evaporate to dryness, redissolve in 10 ml of dioxane, add 1 ml of water and 3 ml of saturated acidic sodium carbonate solution. Stir, process, wash and evaporate to dryness. It is dissolved in methylene chloride, washed with 10 ml of water and 5 ml of normal hydrochloric acid, decanted, washed with water, dried, stirred in ether to give 1.747 g of crude product which is purified by dissolving in ethyl acetate from which ether precipitation is carried out . 1.255 g of pure product are obtained.

The resulting product has a syn configuration.

The gamma-chloro-alpha-methoxyimino-acetylacetate ethyl (ester) used at the beginning of Preparation 3 was obtained as follows:

22.5 g of gamma-chloro-alpha-oxyimino · acetylacetate ethyl were added to 100 ml of methylene chloride. It was placed in ice and 275 ml of a fresh solution of diazomethane (21.6 g / l) was added slowly with stirring. It is left to stand for five minutes and the excess diazomethane is destroyed with a little aluminum, concentrated and then purified by elution with methylene chloride on silica. 11.93 g of the expected product is obtained. 2- (2-Amino-4-thiazolyl) -2-methoxyiminoacetate ethyl used in Example 3 was prepared as follows:

Phase a: 2-Acetyl-2-methoxyimino-acetate ethyl

Into 900 ml of pure acetone was added 180 g of crude 2-acetyl-2-hydroxy iminoacetate ethyl. At 1 ° C under nitrogen, 234 g of potassium carbonate is added, then 10 ml of dimethyl sulfate is added. It was stirred for 3 hours at room temperature, ice was added, poured into 4 l of water, extracted with methylene chloride, washed with water, dried and the solvents were evaporated. 185 g of the expected product are obtained.

Step 8: 4-Bromo-2-methoxyimino-acetylacetate ethyl

197 g of the product obtained in step a are added to 1 liter of methylene chloride and 200 mg of p-toluenesulfonic acid are added. At 20 [deg.] C., 1/10 portion of the solution containing 191 g of pure bromine in 200 ml of methylene chloride was added. When the reaction begins, the remainder of the bromine solution is added at 20 ° C for 1 hour. The temperature was then allowed to rise to 25 ° C to complete the reaction. Wash with ice water, extract again with methylene chloride, dry and evaporate the solvent. 268 g of the expected product is obtained.

Phase γ; 2- (2-Amino-4-thiazolyl) -2-methoxyiminoacetate ethyl

270 g of thiourea are added to 270 ml of ethanol and 540 ml of water. 268 g of the product obtained in step 0 in 270 ml of ethanol was introduced under nitrogen for half an hour. It was stirred for 1 hour at 20 ° C, cooled to 15 ° C, and acidic potassium carbonate was added in small portions until pH = 5. It was washed, washed with water, dried and 133.8 g of the expected product was obtained. The product obtained is identical to that obtained in phase A.

EXAMPLE 4

3-Acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido / cef-3-em-4-carboxylic acid

In 4 ml of 50% aqueous formic acid solution at 55 ° C, 0.975 g of the product obtained in Example 3 was stirred for 10 minutes. Add 4 ml of water, evaporate, evaporate to dryness in vacuo. Mix in 2 ml of ethanol, wash, wash with ethanol and ether to give 0.428 g of pure product.

Analysis: calculated for C,, H. _O_N, .S _n i 16 17 7 5 2

C 42.19 42.3

H 3.76 4.1

N, 15.37. 15.2

Found:

The resulting product has a syn configuration.

S 14.08 13.8

NMR (DMSO, 60 MHz) ppm: 2.03 (-CCH _q ); doublet 9.58. J = 8Hz (CONH) K »j

6.76 (proton of tiazolskog _{finger °).}

EXAMPLE 5

Sodium is 3-acetoxymethyl-7- / 2- (2-quino-4-thiazolyl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid

To 45.55 g of pure 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid obtained according to the procedures of Example 4 or 6, 100 were added. ml of distilled water. Gradually add 8 g of acidic sodium carbonate with the addition of about 20 ml of ethanol.

80 ml of ethanol was added again, 5.5 g of activated charcoal / stirred for 5 min23 nuts, treated, washed with ethanol, and evaporated to dryness in vacuo. It was redissolved in 100 ml of ethanol, evaporated to dryness and the residue was dissolved in 100 ml of ethanol. 2 1 acetone was added, stirred vigorously, filtered, washed with acetone followed by ether. After drying under vacuum, 43.7 g of a white product are obtained which

are re-hydrated in the air , whereby it reaches the final one weight from 45.2 g. / a / = +55 ± 2 ° ( with 0.8 % water). Analysis: calculated C 40.24 H 3.38 N, 14.67 S 13.43 At 4.81 found: 40.3 3.8 14.4 13.3 4.84

The resulting product has a syn configuration.

NMR (D2O, 60 MHz) ppm: 2.01 (COCH2) doublet at 9.53.

J = 8Hz (NHCO), 6.75 (thiazole proton).

PREPARATION 6

Phase A: 2- (2Hamino-4-thiazolyl) -2 - / (2-propenyl) oxyimino / ethyl acetate

a) 9.7 g of 2-hydroxyimino-4-chloro-acetylacetate ethyl, 30 ml of acetone and 9.15 ml of 3-iodopropene were cooled in ice, 27.5 ml of 2N soda solution was added and left at room temperature for 1.5 hours.

b) 3.8 g of thiocarbamide were introduced into the reaction medium, heated to 60 ° C for 15 minutes, then kept at room temperature for 45 minutes, acetone was removed, methylene chloride was added, water, sodium carbonate, stirred, dried. re-extracted with methylene chloride, dried, evaporated to dryness to give 9.75 g of the residue which was chromatographically separated on silica eluting with ether to give 2.7 g of product which was redissolved in isopropyl ether, the crystals were dried, washed and dried. 783 mg of the expected product is obtained, m.p. 100 ° C. The resulting product has a syn configuration.

Phase B: 2- (2 < / RTI > tritylamino-4-thiazolyl) -2 - [(2-propenyl) -oxyimino) acetate ethyl

Mix 511 mg of the product prepared in phase A, 0.92 ml of dime24 tilformamide, 1.8 ml of methylene chloride and 0.29 ml of triethylamine. Cool to -15 ° C, add 615 mg of trityl chloride. For 1.5 hours at room temperature, add 2 ml of IN HCl, then 5 ml of water, dry, dry, evaporate to dryness to give 1.28 g of crude product.

The resulting product has a syn configuration.

Faca C: 2- (2-Trithylamino-4-thiazolyl) -2 - / (2-propenyl) -oxyimino / acetic acid

1.28 g of the product obtained in phase B, 6.2 ml of dioxane and 3 ml of 2N soda solution are heated at 12 ° C. It was refluxed for one hour, the crystalline sodium salt, dried, washed with dioxane / ether, dried and 805 mg of product was isolated.

It was again transferred to 10 ml of methylene chloride and 3 ml of IN HCl, stirred until dissolved, decanted, dried, evaporated to dryness, dissolved in ether, filtered to give 715 mg of product, m.p. 16 ° C. The resulting product has a syn configuration.

EXAMPLE 6

3-Acetoxymethyl-7- {2- (2-trimethylamino-4-thiazolyl) -2 - [(2-propenyl) oxyimino] -acetamido} -ceph-3-em-4-carboxylic acid

Mix 470 mg of the product prepared in phase C of the previous Preparation, 5 ml of methylene chloride and 130 ml of dicyclohexylcarbodiimide, wash with a little of methylene chloride and leave to stand for 1.5 hours at room temperature. The dicyclohexylcarbamide formed was filtered off, the filtrate was cooled and 136 mg of 7-aminocephalosporanic acid dissolved in 2.4 ml of methylene chloride and 0.14 ml of triethylamine were added under an inert gas atmosphere. For 1.5 hours at room temperature, 2 ml of IN HCl and water are added, stirred, decanted, washed with water, dried, evaporated to give 610 mg of crude product. The resulting product has a syn configuration.

EXAMPLE 7}

3-Acetoxymethyl-7- {2- (2-amino-4-thiazolyl) -2 - [(2-propenyl) -oxyimino] -acetamido} -ceph-3-em-4-carboxylic acid

610 mg of the product obtained in Example 1 were added for 15 minutes at 60 ° C, taken in 3 ml of 50% aqueous formic acid solution, 4 ml of water was added, stirred, triphenyl carbinol was washed, washed with water, evaporated to dry under vacuum, re-enter in water> 'stir, wash, rinse to give 120 mg of expected product (acid); m.p. ~ 16 ° C.

Violet_sgectar:

In ethanol: max 236 nm ^E l ⁼ 375 ε = 18000 inflection 252 nm ^E r 316 inflection 295 nm ^E r 138 ε = 6600 Ethanol-N / 10 HCl mixture max 263 nm 380 ε = 18300 inflection 280 nm ^Ε ί = 317 •

NMR (DMSO, 90 MHz) ppm: 2.02 (OAc), 6.68 (thiazole proton) Prtbizvod has a syn configuration.

PREPARATION 8

Phase A: 2- (2-Amino-4-thiazolyl) -2-acetoxyiminoacetate ethyl

a) In 60 ml of acetyl and 14.3 ml of diethyl sulfate, 19.4 g of ethyl gamma-chloro-alpha-oxyiminoacetoacetate are added. Cool on ice for 1θ'minutes and then add 55 ml of 2N soda solution for 30 minutes and stir for 40 minutes.

b) 7.6 g of thiocarbamide are added to the reaction mixture, heated to 55 ° C for 20 minutes, acetone removed, transferred to ethyl acetate, added

6.9 g of potassium carbonate, stirred, decanted, re-extracted with ethyl acetate, dried and evaporated to dryness. 17.4 g of the residue were separated and chromatographed on silica eluting with ether. The expected product was collected, transferred to isopropyl ether, dried, washed, dried and 2.8 g of the expected product were obtained, m.p. 129 ° C. The resulting product has a syn configuration.

Phase B: 2- (2-tr ^; Itylamino-4-thiazolyl) -2-ethoxyiminoacetate ethyl

3.16 g of the product obtained in phase A, 6 ml of dry dimethylformamide? Are placed in an inert gas atmosphere. 12 ml of methylene chloride and 1.89 ml of triethylamine. It was cooled to -15 ° C and 3.98 g of trityl chloride was slowly added. Allow to stand for half an hour, raise the temperature to + 1 ° C, and keep for 3.5 hours at room temperature. 13 ml of IN HCl was added, stirred, decanted and washed with IN HCI and water. Extracted with methylene chloride, dried, evaporated to dryness to give 7.89 g of crude residue. The resulting product has a syn configuration.

Phase N: 2- (2-Trithylamino-4-thiazolyl) -2-ethoxyiminosulfuric acid

At 11 ° C, 7.89 g of the product obtained in phase B, 40 ml of dioxane and 19.5 ml of 2N soda solution are kept for 2 hours. It was washed, washed with ether / dioxane, then with ether alone and dried. 6.25 g of sodium salt was obtained, which was transferred to 60 ml of methylene chloride and 20 ml of IN HCl, the two phases were stirred, 20 ml of methanol was added, decanted, washed again with water, extracted again with methylene chloride / methanol, dried, evaporated , 5.85 g of pure 2- (2-tritylamino-4-thiazolyl) -2-ethoxyiminosuric acid is isolated.

The resulting product has a syn configuration.

EXAMPLE 8

3-Acetoxymethyl-7- / 2- (2-trimethylamino-4-thiazolyl) -2-ethoxyiminoacetamido] -ceph-3-em-4-carboxylic acid

3.43 g of 2- (2-Trithylamino-4-thiazolyl) -2-ethoxyiminosulfuric acid coated in phase C of the previous Preparation are added to 34 ml of methylene chloride, the suspension is cooled and 970 mg of dicyclohexylcarbodiimide is added, washed with methylene chloride and washed for one hour. stir at room temperature. Dicyclohexylcarbamide is saved.

The filtrate was cooled to -20 ° C and a solution cooled to -20 ° C containing 1.02 g of 7-amino-cephalosporic acid in 18 ml of methylene chloride and 1.06 ml of triethylamine was added at once.

Allow 1.5 hours to raise the temperature, add 1.8 ml of acetic acid, 9 ml of IN HCl, stir, decant, wash with water, extract with methylene chloride, dry, concentrate to give 4.56 g of the expected product.

The resulting product has a syn configuration.

EXAMPLE 9

3-Acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2-ethoxyiminoacetamido / cef-3-em-4-carboxylic acid

In 23 ml of 50% aqueous formic acid solution was added 4.56 g of the product obtained in Example 8, heated to 55 ° C for 5 minutes, diluted with water (30 ml) and triphenyl carbinol. The filtrate was evaporated to dryness, transferred to water, stirred, washed, washed, dried. 116 mg of the impure product was obtained. A new amount of 674 mg of crystallized product was obtained by concentrating the filtrate, a total of 790 mg was obtained.

The purification was carried out as follows:

1.063 g of crude product was mixed in 5 ml of water, heated to 70 ° C for 5 minutes, cooled, stirred for half an hour, drained, washed, dried and 815 mg of purified product was obtained.

These 8 mg mg was transferred to 2 ml water and 3 ml acetone, per Although it was heated, the insoluble portion was drained, 3 ml water was added, heated to 60 ° C, acetone was bubbled, the created grains were drained, washed with water. then ether, so 438 mg of the expected product was isolated.

Analysis: calculated for C, _H, _O _n N _c S _n :

19/52

C 43.39 H 4.08 N 14.92 S 13.66 Found: 44.5 4.4 14.8 13.3

The product has syn configurations.

NMR (DMSO, 60 MHz) ppm: 2.05 (OAc)} 6.75 (proton from thiazole ring).

PREPARAT 10

Phase A; 2-Acetyl ~ 2- (1-methylethoxyimino) -acetate of ethyl

39.8 g of 2-acetyl-2-hydroxyiminoacetate ethyl were added to 200 ml of pure acetone. Cool on ice, add 52 g of potassium carbonate, then 25 ml of 2-iodopropane for half an hour. It is then stirred for 2 hours, 800 ml of water and 500 ml of methylene chloride are added, stirred, decanted, extracted again with methylene chloride, dried, filtered, concentrated and 42.5 g of the expected product isolated.

Phase B: 4-Bromo-2- (1-methylethoxyimino) -ethyl acetate ethyl

In 190 ml of methylene chloride containing traces of p-toluenesulfonic acid, 41.5 g of the product obtained in the previous step is added. It is stirred and a solution containing 11.9 ml of bromine in 50 ml of methylene chloride is introduced at room temperature for 1 hour. It is mixed, ice water is added, it is filtered off, re-extracted with methylene chloride, washed again with ice water, dried, concentrated and 55 g of the expected product are obtained.

Phase C: 2- (2-Amino-4-thiazolyl) -2- (1-methylethoxyimino) acetate ethyl

Into 55 ml of ethanol and 105 ml of water add 14.9 g of thioacrbamide and add for 40 minutes a solution containing 55 g of the product prepared in phase B dissolved in 55 ml of ethanol. It was stirred for 2.5 hours at room temperature, 220 ml of 10% aqueous sodium carbonate solution was added, stirred, washed, washed, dried and 42.15 g of crude product chromatographed on silica eluting with ether was isolated; the fractions rich in the expected product were collected, evaporated, the crystals were transferred to isopropyl ether, filtered, washed, and 10.75 g of the expected product was obtained.

The resulting product has a syn configuration.

Phase D: 2- (2-Tritylamino-4-thiazolyl) -2- (1-methylethoxyimino) and ethyl acetate

In 20 ml of dry dimethylformamide, 40 ml of methylene chloride and 6.2 ml of triethylamine, 11 g of the product obtained in phase C are added, the mixture is cooled, 13.2 g of trityl chloride is added slowly, 2.5 hours are added, 43 ml of IN HCI are added. , stirred, filtered, washed again with 40 ml, water, extracted with methylene chloride, dried, filtered, evaporated to dryness to give 27.7 g of the expected product.

The resulting product has a syn configuration.

Phase E: 2- (2-Tritylamino-4-thiazolyl) -2- (1-methylethoxyimino) -acetic acid

A mixture of 27.7 g of the product obtained in phase D, 150 ml of dioxane and 65 ml of 2N soda solution was refluxed for 2 hours. The sodium salt was crystallized, cooled, quenched, washed with ether / dioxane (1: 1), dried to give 16.85 g of crude sodium salt. In 15.9 g of dimethylformamide, 100 ml of water and about 500 ml of methanol dissolve 15.9 g of the mentioned sodium salt. 30 ml of 2N HCl was added, methanol was removed, diluted with water, washed, washed, dried and then 9.8 g of the obtained viscous product was transferred to 220 ml of a mixture of methylene chloride and methanol (50:50). It was evaporated to dryness, ether was added, it was stirred, the crystals were drained, washed, dried to give 4.9 g of the desired acid, mp. -170 ° C.

The sample for analysis was prepared by dissolving 300 mg of the crude product in 2 ml of methylene chloride and 1 ml of methanol, diluting with water, and methylene chloride, stirring, draining crystals, washing with motilene chloride and water, drying. 230 mg of pure product were obtained for analysis.

Analysis: Calculated: C 68.77 H 5.34 N 8.91 S 6.8 Found: 68.6 5.5 8.8 6.8

The resulting product has a syn configuration.

EXAMPLE 10

3-Acetoxymethyl-7- / 2- (2-trimethylamino-4-thiazolyl) -2- (1-methylethoxyimino) -acetamido] -ceph-3-em-4-carboxylic acid

4.89 g of acid are taken under argon. obtained in the preceding Preparation of st & iZi in 13.5 ml of dimethyl ilformamide. After dissolution, it was cooled in ice and 1.62 g of dicyclohexylcarbodiimide dissolved in 16 ml of methylene chloride was added, Crystallizing dicyclohexylcarbamide. Me30 is in ice, washed, washed with methylene chloride, dried; 1,424 g of dicyclohexylcarbamide were isolated. Cool in a methanol / ice bath and add a solution of 1.41 g of 7-amino-cephalosporic acid in 30 ml of methylene chloride and 1.45 ml of triethylamine. It was stirred for 3 hours at room temperature, 20 ml of normal hydrochloric acid was added, stirred, decanted, extracted again with methylene chloride, dried, filtered to give 9.05 g of the expected and starting product mixture. Transfer to methylene chloride, initiate crystallization, allow to crystallize with stirring, crystals are drained, washed, dried; 1.6 g of pure starting product are obtained. Evaporate to dryness, the residue is taken up in isopropyl ether with vigorous stirring. 4.91 g of insoluble viscous product was isolated which represents the expected product.

The resulting product has a syn configuration.

EXAMPLE 11

3-Acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2- (1-methylethoxyimino) acetamido / -ceph-3-em-4-carboxylic acid

4.91 g of the crude product obtained in Example 10 was added to 30 ml of 50% aqueous formic acid, stirred in a water bath at 60 ° C, diluted with water, washed with triphenylcarbinol, washed with water, dried and obtained 1.39 g of triphenylcarbinol. Evaporate to dryness, transfer to water again, whisk, wash, rinse with water, dry. 800 mg of expected product was obtained.

The sample to be analyzed is obtained by dissolving 972 mg of crude product in 4 ml of methanol, diluting with 20 ml of ether, isolating the insoluble portion, washing, drying and yielding 404 mg of pure expected acid, m.p. = 200 ° C.

Analysis: Calculated: C 44.71 H 4.38 N 14.48 S 13.26 Found: 44.5 4.5 14.1 13.2

The product has a syn configuration. ₃

NMR (DMSO, 60 MHz) ppm: 2.01 (CH ₃ CO); doublet at 9.46 J = 8 Hz (CONH), 6.7 (proton from thiazole ring).

PREPARATION 12

Phase Ar 2- (2-chloroacetamido -4-thiazolyl) -2-methoxyiminoacetate ethyl, syn isomer

In 20.0 ml of methylene chloride 45.8 g of 2- (2-amino-4-thiazolyl) 2-methoxyiminoacetate ethyl, isomer syn, prepared according to phase A of Preparation 3 are added. 20 ml is distilled off, cooled to 10 ° C and added of 50 ml of pyridine. 41 g of monochloroacetic acid anhydride were added and warmed gently until dissolved. At 20 ° C it was left under nitrogen for 6 hours, added 5 ml of water, stirred, poured into 300 ml of ice-cold 2NHC1. It is filtered off, extracted with methylene chloride, washed with water, acidic sodium carbonate, dried, passed over charcoal, evaporated, 300 ml of isopropyl ether added. The product crystallizes. It is evaporated until a thick dough is obtained, ice is cooled, it is washed, washed, dried and 45.4 g of product are obtained, m.p. 113 ° C.

The pure sample is obtained by recrystallization from a mixture of methylene chloride and isopropyl ether; m.p. 118 ° C.

NMR (CDCl ₃ , 60 MHz):

¹ 0 (d)

a) centered triplet at 1.38 ppm J = 7 Hz;

b) singlet at 4.05 ppm;

c) quadruplet quadruplet at 4.44 ppm J = 7 Hz;

d) singlet at 4.33 ppm; ³

e) singlet at 7.27 ppm;

f) singlet at 9.95 ppm.

Phase B; 2- (2-Chloroacetamido-4-thiazolyl) -2-methoxyiminosulfuric acid, syn isomer

In 230 ml abs. of ethanol was added 46 g of the product obtained in phase A. Under nitrogen, 30 ml of pure soda was added under nitrogen. The product dissolves and the sodium salt begins to crystallize throughout the mass. After 16 hours, it is washed and washed. The resulting salt was dissolved in water, cooled with ice, 100 ml of 2N HCl was added, saturated with sodium chloride, extracted with ethyl acetate containing 10% ethanol. Dry, pass over activated charcoal, pre-distill under vacuum, remove water with benzene, transfer to methylene chloride, evaporate to dryness, transfer to methylene chloride, ice, strain, wash, dry, yield 34.5 g of expected product -

excerpts; from the mixture m.p. about 200 ° C. The product is acetone / isopropyl alcohol. purify by recrystallization Analysis: calculated for CgHgO ^ N ^ ClS = 277.68 C 34.60 H 2.90 N 15.13 Cl 12.77 S 11.55 Found: 34.81 2.8 14.8 12.6 11.5

NMR (DMSO, 60 MHz):

a) singlet at 3.92 ppm;

b) singlet at 4.38 ppm;

c) singlet, about 5 ppm;

d) singlet at 7.58 ppm;

e) singlet at 12.6 ppm.

EXAMPLE 12

3-Acetoxymethyl-7- (2- (2-chlorodethoamidor-4-t-ylquinol).-2-methoxyimino acetamido / -cef-3-em-4-carboxylic acid, syn Isomer

In 80 ml of methylene chloride was added 15.3 g of the product obtained in phase B of the previous Preparation. 8 ml of triethylamine are added at 5 ° C. 3.8 ml of thionyl chloride and 26 ml of methylene chloride are introduced at 0 ° C under nitrogen. Leave it at 0 ° C for 15 minutes, then add 7 ml of triethylamine. Under nitrogen, at 0 ° C, 13.6 g of 7-amino-cephalosporanic acid dissolved in 100 ml of methylene chloride and 14 ml of tyrtilamine are introduced. Allow the temperature to rise to 20 ° C and stir for 1 hour. Evaporate the solution in vacuo to dryness at 30-35 ° C. The residue was dissolved in 250 ml of water, passed over activated carbon, 50 ml of 2N HCl was added. The precipitate was drained, washed with water. The crude product obtained is suspended in 80 ml of ethanol. At + 5 ° C, 7 ml of triethylamine is added. Suddenly, with stirring, at + 5 ° C, 15 ml of 4N 4 H 2 SO 4 was added. The product crystallizes after 15 minutes. It was washed, washed with ethanol with humidity, then with ether and dried in vacuo. 18.6 g of the expected product is obtained.

/ alpha / _D = + 26 ° (+ 1 °) with 1% in dimethylformamide.

c) a singlet at 4.38 ppm;

d) singlet at 7.45 ppm;

EXAMPLE 13

3-Acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -cef-3-em-4-carboxylic acid, syn isomer

5.32 g of the acid obtained in Example 12 are suspended in 10.6 ml of water and 912 mg of thiocarbamide. At 20 ° C, 1 g of acidic sodium carbonate is added. After dissolution, it was stirred for 6 hours at about 20 ° C under nitrogen. After about 1.5 hours, the rubber product begins to settle. Then 30 ml of water and 3 ml of formic acid are added. Cool to 5 ° C. Wash off, wash with 10% formic acid water. The residue was dissolved at about 5 ° C in 30 ml of water containing triethylamine. At 5 ° C, 3 ml of formic acid is added, the precipitate is dried, washed with wetting with water containing formic acid. The dark brown tire is removed. The aqueous phases are collected and treated with activated charcoal. A light yellow solution is obtained which is saturated with ammonium sulfate. The precipitate was filtered off, boiled with water, filtered off, washed with water and a precipitate formed.

The mother liquors were sewn with ammonium sulfate, which formed a precipitate which was drained, washed three times, and precipitate formed B. Sediments A and B were combined. Transfer to methanol, stir for 1 hour at 20 ° C and leave for 16 hours at 0 ° C. It was washed, washed with ethanol, ether, dried under vacuum to give 3.47 g of the expected product, syn isomer.

c) doublet at 5.19 ppm; j

d) singlet at 6.8 ppm.

This product is identical to the age used in Example 4..

EXAMPLE 14

3-Acetoxymethyl-7- (2-X2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid isomer is a sodium isomer

19.8 g of 3-acetoxymethyl-7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid, syn isomer, are dissolved in 65 ml of molar sodium acetate solution in methanol. , obtained according to Example 4. It is allowed to crystallize for 35 minutes at room temperature. Add 40 ml of ethanol over 1 hour, stir for 2.5 hours with stirring in ice water, wash, wash twice with 10 ml of methanol / ethanol (1: 1), twice with 10 ml of ethanol and then twice with 20 ml of ether. After drying for 2 hours at 45 ° C under vacuum and 48 hours under vacuum with sulfuric acid, 16.191 g of crystalline product were obtained.

By avoiding any contact with atmospheric humidity during operation, a product having the following physical parameters is obtained:

E ^ O (by Karl Fischer) = 0.2%

Methanol - 0 Ethanol = 0 .1% 1 .45% J

Determined by gas chromatography

Analyze: calculated for C., O _n N _r S „At 16 16 7 5 2

477.5

C 40.24 H 3.38 N 14.67 S 13.43 At 4.81

Found: 39.9 3.5 14.5 13.1 4.8

The product rehydrates on air.

An X-ray (Debye Scherrer) made it possible to confirm the crystalline nature of the product obtained.

Isopropanol may be used instead of ethanol to crystallize the expected product.

EXAMPLE 15 '

3-Acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid syn isomer of sodium

Phase A; Solvate of 3-acetoxymethyl-7- / 2- (2-amino-4-thiaz, olyl) -2-methoxyiminoacetamido / -ceph-3-em-4-carboxylic acid, syn isomer, and formic acid

In small quantities, 87.2 g of 3-acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid diethylamine salt were added with stirring. mix 220 ml of pure formic acid and 220 ml of water. It was stirred for 30 minutes at 50 ° C, cooled, and 30.1 g of triphenyl carbinol were removed by strain. 450 ml of water was poured into the filtrate, a weak precipitate was removed using activated charcoal and evaporated to 40 ° C under vacuum until a precipitate formed. Add 200 ml of anhydrous ethanol, cool with ice, process, wash with ethanol and ether and dry under vacuum.

31.1 g of the expected product is obtained.

Analysis: calculated for C 16 ^H 17 ^N 5 ° 7 ^N 2 • hco ₂ hh ₂ o = 541.5 C 39.3 H 4.08 N, 13.48 S 12.34 H ₂ O 3.46 Found: 39.2 4.1 13.2 12.8 4.15

Phase B: Crystallized sodium salt

In 75 ml of methanol, 15 g of freshly prepared solvate obtained according to phase A are dissolved and 4.5 g of potassium acetate and 3 g of activated carbon are affected. After straining, 5 ml of isopropanol is added with stirring. After 16 hours at 0 ° C crystals were separated, washed with ethanol and ether and dried for 2 hours at 50 ° C under strong vacuum.

7.95 g of the expected product is obtained, which is then held for a short time in air.

Analysis: calculated for C. -.H. _r N _c NaO ^ S _n · 1Η _Ο Θ = 495.5 16 16 5/2 2

C 38.78 H 3.66 N 14.14 At 4.64 S 12.94

Found: 38.6 3.7 13.8 4.6 13.2

EXAMPLE 16

3-Acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid syn isomer of sodium

Phase A: Solvate of 3-acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) 2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid, syn isomer, and ethanol

In a mixture of 1 1 96% ethanol and 350 ml water dissolve 52 g of formic acid solvate obtained in phase A of the preceding Example. Evaporate in vacuo until a volume of approximately 300 ml is obtained. During concentration, the solvate begins to crystallize. It was cooled on ice for 1 hour, washed, washed with a little ethanol and dried in vacuo at room temperature in the presence of conc. sulfuric acids. 44 g of the expected product are obtained.

Analysis: calculated for C, ..H, _, N _c O _n S_ · 0.8 CH..OH = 492.3 16 17 5 7 2 25

C 42.94 H 4.46 N 14.23 S 13.02

Found: 43.0 4.4 14.1 12.9

Phase B: Amorphous sodium salts

In 60 ml of water at 0 ° C was added 3 g of a solvate of ethanol obtained in phase Ij and with stirring was added 0.504 g of acidic sodium carbonate dissolved in 6 ml of water. The neutral solution is treated and directly lyophilized. The product is then briefly exposed to free air.

Analysis: calculated for C ,, H., N _c NaO_S _n · 1.5 H ~ O = 504.47 16 16 5 7 2 Z

C 38.09 H 3.8 N 13.88 Found: 38.2 3.9 13.6

EXAMPLE 17

3-Acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid syn isomer of sodium

To 4.95 g of 3-acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido / -ceph ~ 3-em-4-carboxylic acid, the syn isomer obtained according to Examples 4 or 13, was added 5 ml of ethanol and, with stirring in an ice-water bath, 10 ml of molar (IM) aqueous solution of acidic sodium carbonate. After dissolution, 15 ml of ethanol are added, evaporated in vacuo at 30 ° C, transferred to ethanol and dried to constant weight. Powder is obtained which is transferred to 15 ml of methanol. Crystallization is caused and left in the refrigerator overnight. 3,407 g of crystalline product were isolated.

EXAMPLE 18

3-Acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid syn isomer of sodium

In 2 ml of methanol was dissolved 0.5 g of the amorphous sodium salt obtained according to Example 16, and 0.25 ml of n-butanol was slowly added with stirring and kept in the refrigerator at about 6 ° C for 48 hours. The crystals were washed with a little cold methanol and dried under vacuum at 40 ° C for 3 hours in the presence of conc. sulfuric acids.

0.2 g of crystalline product are obtained, which is then held in air for a short time.

Analysis: calculated for C., H ,, N _r NaO_S ~ · 1.5 H „O = 504.47 16 16 5 72 2

C 38.09 H 3.8 N 13.88 O 26.96

Found: 38.4 3.8 13.8 27.1

Working under analogous conditions, crystals are slightly different, e.g. contain 0.5 mol of water or 1 mol of water and 1 mol of ethanol.

X-ray (Debye Scherrer) products obtained above confirm the crystal nature of the products obtained.

- 39 EXAMPLE 19

Diethylamine is 3-acetoxymethyl-7- / 2- (2-trimethylamino-4-thiazolyl) 2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid

The crude .3-acetoxymethyl-7- [2- (2-triethylamino-4-thiazolyl) -2-methoxyiminoacetamido] -ceph-3-em-4-carboxylic acid was dissolved in 350 m dioxane. 350 ml of diethyl ether is slowly added with stirring followed by 33 ml of diethylamine. The mixture was stirred for 20 minutes and the crystallized 2- (2-tritylamino-4-thiazolyl) -2-methoxyiminosulfuric acid crystalline diethylamine was saved. This salt was washed twice with 30 ml of dioxane-ether mixture each time to give 62.6 g. The filtrate was evaporated to a syrupy consistency and about 2.5 liters of diethyl ether was added. She stirred and froze. 110.3 g of the expected diethylamine salt are obtained. The resulting product has. syn configuration. ·

EXAMPLE 20

3- Acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido / cef-3-em-4.-carboxylic acid> ---- 1

- 40 To 180 ml of 50% aqueous formic acid solution held at 50 ° C was added 36 g of the product obtained in Example 19. It was stirred for 20 minutes at 50 ° C and the resulting triphenyl carbinol was saved. 180 ml of ethanol were added and evaporated to dryness under reduced pressure. The residue was dissolved in a mixture of 100 ml of water and 20 ml of ethanol and evaporated again. It is redissolved in 100 ml of water, stirred for 15 minutes at 15 ° C, dried, washed with water and ether to give 15.6 g of the expected product.

EXAMPLE 21

Diethylamine isomer of 3-acetoxymethyl-7- / 2- (2-tritylamino-4-tazolyl) -2-methoxyiminoacetamido / -ceph-3-em-4-carboxylic acid isomer

200 g of 2- (tritylamino-4-thiazolyl) -2-methoxyiminosuric acid and 1200 ml of methylene chloride were added to the balloon. The suspension was warmed to reflux with stirring under argon, and 600 ml of methylene chloride were distilled off at atmospheric pressure. It is brought to 18-2O ° C and 54 g of dicyclohexylcarbodiimide dissolved in 54 ml of methylene chloride are added while maintaining this temperature. It was stirred for 1 hour under argon at 18-20 [deg.] C. and a previously prepared solution of 61.4 g of 7-amino-cephalosporic acid in 900 ml of methylene chloride and 63 ml of triethylamine was added at this temperature for 15 minutes. It was stirred for 1.5 hours at 20 ° C (pH = 6.5-7). Then 50 ml of acetic acid was added, stirred for 15 minutes at 20 ° C, and then removed to remove 7-amino-cephalosporanic acid initially. Wash 4 times with 200 ml of methylene chloride each. The organic solution was washed 3 times with 400 ml of demineralised water each and then dried over magnesium sulfate. Wash off, wash twice with 200 ml of methylene each. of chloride, under argon evaporated to dryness. The dry ul clear extract was dissolved under argon, stirring at 20-25 ° C in 700 ml of dioxane. Under vacuum and under argon, at a temperature of less than 30 ° C, 300 ml of dioxane-methylene chloride are distilled off. Bring to 20 ± 2 ° C and add 500 ml of diethyl ether. Add 52 ml of diethylamine. After about 10 minutes, 2- (2-tritylamino-4-thiazolyl) -2-methoxyiminosulfuric acid diethylamine was crystallized. Leave for 1 hour under argon at 20 ° C. It is then washed 3 times with 100 ml of dioxane-diethyl ether solution each. The separated diethylamine salt was dried to give 113.6 g.

- 41 For 30 minutes, the organic solution is poured, stirring, into.

3.25 liters of isopropyl ether. Allow to stand for 15 minutes with stirring, then allow to vacuum. It was washed twice with 400 ml of isopropyl ether each time, dried under vacuum to give 182 g of the product identical to that obtained in Example 19.

EXAMPLE 22

3-Acetoxymethyl-7- / 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -cef-3-em-4-carboxylic acid, syn isomer

Into 347 ml of formic acid and 87 ml of demineralized water, 182 g of the product obtained in the preceding Example are introduced, stirring, under argon, at 2 8-30 ° C. There is a complete dissolution and crystallization of triphenyl carbinol. The mixture was stirred under argon at 28-30 ° C for 2.5 hours and then stirred for 15 minutes in 1740 ml of demineralised water and 847 g of amino sulfate. Allow to stir for 30 minutes. It was washed, washed 2 times with 174 ml of demineralized water each time, dried under vacuum at 25-30 ° C to give 147 g of the expected product and triphenyl carbinol mixture. The crude product is kept for 1 hour at 18-2O ° C moistened with 753 ml of ethyl ether. It is washed, washed twice with 174 ml of diethyl ether each time, dried at 25-30 ° C. 89 g of the expected product is obtained.

This product is mixed with 445 ml of ethanol under stirring and under nitrogen. The suspension was brought to 45-50 ° C with stirring and held for 1 hour under these conditions. It is then stirred for 1 hour at 18-20 ° C. It was washed, washed twice with 45 ml ethanol each, dried under vacuum at 20 ° C. 76.85 g of the expected product is obtained.

This product was placed in 230 ml of acetic acid. It was stirred for 15 minutes under nitrogen and 77 ml of demineralized water was added, then about 700 ml of water was added to this solution. The mixture was stirred at 18-2O C for one hour, and about 269 g of ammonium sulfate was added gently over 10 minutes. Allow 15 minutes and add 3.85 g of activated charcoal. The mixture is stirred for 15 minutes, washed, washed with 77 ml of demineralized water with 25% acetic acid. With stirring at 18-20 ° C, 154 ml of formic acid are added, the final product is added to the pellet, and crystallization is caused by rubbing with a glass rod. Allow to stand for 2 hours with stirring at 18-20 ° C and then 2 hours at 0-5 ° C

- 42 washes 4 times with 77 ml of demineralized water each with 5% formic acid. The vacuum is dried at 20-25 ° C. 49.45 g of formate product are obtained.

The resulting formate was stirred in 250 ml of ethanol for 1 hour with stirring at 45-50 ° C and left for 1-20-20 ° C for 1 hour. Wash off, wash twice with 50 ml ethanol each. It is dried at 20 ° C under vacuum, then 10 to 15 hours at 35-40 ° C. 45.45 g of the expected product is obtained.

/ alpha / ^ = + 64.5 (0.5% solution in water with 0.5% formic acid).

The starting material used in this Example was made as described in Example 21.

The best way to use invention in an economy that is known

Applicant

The invention can best be applied in industry when the following procedure is used:

0.975 g of 3-acetoxymethyl-7- / 2- (2-trithylamino-4-thiazolyl) 2-methoxyimino-acetamido / -ceph-3-e- are stirred in 4 ml of 50% aqueous formic acid at 55 ° C for 10 minutes. 4-carboxylic acids. Add 4 ml of water, drain, evaporate to dryness in vacuo. Mix in 2 ml of ethanol, dry, wash with ethanol and then with ether to give 0.428 g of pure 3-acetoxymethyl-7- (2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido) - cef-3-em-4 ~ carboxylic acids.

ROUSSEL-UCLAF, France represents:

Miodrag P. Popovich

30.V 88.

Dos: 2072/40 - DIV IV

P-Ϊ1 / 83.

Claims (1)

The procedure for obtaining new antibiotics of the formula: (! ') CH - O-C-CH2 n 3 in which R 'represents hydrogen or a saturated or unsaturated carbon O hydrogen group of a straight or branched chain with 1-3 carbon atoms; A represents hydrogen or an alkali metal equivalent, such as sodium; and the wavy line indicates that the group -OR 2 is in the syn position, wherein the syo isomer of the compound of the formula: (Ic) wherein R1 represents a group which can be easily eliminated by acid hydrolysis, such as trityl or a chloroacetyl group; and R ^ represents a group which can be easily eliminated by acid hydrolysis, such as trityl ,. , or a saturated or unsaturated hydrocarbon group of a straight or branched chain having 1-3 carbon atoms; or its diethylamine salt, is reacted with an acid hydrolysis agent such as formic acid in an aqueous solution and at a temperature of 50-60 C; or, in the case of a chloroacetyl group, with thiocarbamide, in aqueous solution, at room temperature and> in the presence of an acid, such as formic acid, to give a compound of the formula: (Ib) O-C-CH II O in which R 'is as defined above; and what, if necessary, is the resulting C product converted to its alkali metal salt.