LU82842A1 - PROCESS FOR THE PREPARATION OF DERIVATIVES OF 1,1-DIOXOPENICILLANIC ACID - Google Patents

Description

The present invention relates to a new process for the production of the compounds of general formula 0 0

5 \ X

rf r 0 = c-N-1 /.

'iB

R2 in which R ^ represents a hydrogen or halogen atom or an alkyl, alkoxy or trifluoromethyl group, and R £ represents a carboxy group or a protected carboxy group, in particular an esterified carboxy group or their salts in the case where is a carboxy group or contains a basic or acid group.

According to the meanings of and R ^, the compounds of formula I are useful as ß-lactamase inhibitors and / or antibiotics and / or as intermediates in the production of antibiotics and / or ß-laptamase inhibitors, R ^ may preferably represent hydrogen, chlorine or bromine.

When R 1 represents an esterified carboxy group, it can represent an ester group which can be easily hydrolyzed either spontaneously or under the influence of esterases or an ester group which can be cleaved by hydrogenolysis. When R 1 represents an α-haloalkyl ester group, compound I is an interesting intermediate. Easily hydrolyzable esters are well known types of esters, for example acyloxyalkyl esters, such as alkanoyloxyalkyl esters, for example acetoxy methyl and pivaloyloxymethyl esters, and the corresponding 1-acetoxyethyl esters and 1-pivaloyloxyethyl, alkoxycarbonyloxyalkyl esters, for example methoxycarbonyloxymethyl and 1-ethoxycarbonyloxyethyl esters, lactonyl esters, for example phthalidyl esters, or lower alkoxymethyl esters and acylaminomethyl. Examples of other interesting esters are lower alkyl esters, benzyl esters, haloalkyl esters, for example chloromethyl esters and cyanomethyl esters. / / {/ * 2

The salts of the compounds of formula I must be "formed by any basic or acid group contained in by reaction with suitable acids or bases, respectively. In the case where the compounds of formula I are to be used as β-lactamase inhibitors or as antibiotics, the salifying acid or base must be pharmaceutically acceptable and non-toxic, while in the case where the compound formula X is an intermediate, any acid or base suitable for the use of the intermediate can be used in salification.

The salts of the compounds of formula I are therefore, in addition to their internal salts (zwitterions), the salts formed with non-toxic acids acceptable in pharmacy, such as hydrochloric acid, phosphoric acid, nitric acid, p-toluenesulfonic acid, acetic acid , propionic acid, citric acid, tartaric acid, maleic acid, etc., but any non-toxic inorganic or organic acids that are acceptable in pharmacy can also be used.

The invention also relates to the salts formed with non-toxic inorganic or organic bases which are acceptable in pharmacy, for example the alkali and alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, as well as the salts formed with ammonia or suitable non-toxic amines, such as lower alkylamines, for example triethylamine, lower hydroxyalkylamines, for example 2-hydroxyethylamine, bis- (2-hydroxyethyl) -amine or tris- (2-hydroxyethyl) ) -amine, cycloalkylamines, for example dicyclohexylamine or benzylamines, for example Ν, Ν'-dibenzylethylenediamine and dibenzylamine, without these examples limiting the invention. Thus, for example, other antibiotics of acidic or basic character can be used as components of these salts of the compounds of formula I.

According to the prior art, some of the compound ^ / of formula I were prepared by oxidation of a compound of (Ù 35 formula / w ’3

Rl <· ._ | ^ s> ^ V, i v \ "or i r> 0" C-N-1 0 = C-N-1 # '* 2' '* 2

5 II III

in which and are as defined above, or a salt thereof as defined above.

According to the patent application of the Federal Republic of Germany made available to the public No. 2.824.535 and • European patent application No. 2927 published on July 11, 1979, this oxidation can be carried out using a number oxidizing agents known in the art for the oxidation of sulfides or sulfoxides to sulfones, but, according to this prior art, the oxidation is advantageously carried out using metal permanganates, such as alkali and alkaline earth metal permanganates, or by using organic peroxycarboxylic acids, such as 3-chloroperbenzoic acid and peraceous acid. However, these methods tend to be problematic, particularly when used on a large scale, giving lower yields and / or technical difficulties, such as filtration problems.

The oxidation of simple organic sulfides to corresponding sulfones has also been described using hydrogen peroxide in the presence of a suitable catalyst (J. Org. Chem.

25 Vol. 28 (1963), pages 1140-1142). However, when applied to penam derivatives, this method previously only yielded sulfoxides. Thus, U.S. Patent 3,993,646 describes a process for converting compounds of formula II into compounds of formula III by subjecting the former to an oxidation process using peracid3, peracid salts or hydrogen peroxide as oxidizing agents, in the presence of a compound / containing a metal from group Vb or VIb of the Classification Periodical - ^ / dic. / J / t. 4.

l · The Applicant has surprisingly discovered that it is possible to oxidize certain penicillanic acid derivatives or their sulfoxides to the corresponding sulfones without destroying the -. lactam cycle using hydrogen peroxide, a mild oxidizing agent, provided that it operates in the presence of tungsten or molybdenum i ’as catalyst. This process eliminates side reactions from | oxidative degradation and simplifies the isolation and purification of the 1 product, thus giving high yields, and it is therefore particularly suitable for production on a large scale.

According to the invention, the oxidation is generally carried out by dissolving the starting material of formula II or III or its salt in water, or alternatively, if it is insoluble in water, in a suitable organic solvent . The catalyst is dissolved in water

Or in a suitable organic solvent, the two solutions are mixed, and hydrogen peroxide is added to the mixture, either in one portion or gradually, with effective stirring, preferably by maintaining the reaction temperature at about or below room temperature.

Even in the case where the starting material of formula II or III has a limited solubility in water, it is possible, "r. stirring well, to implement the process of the invention i * aqueous medium with a satisfactory result. In the case of an extremely insoluble starting product, solvents can be added. water, such as an alkanol or dioxane. Water-miscible solvents can also be used, provided that a phase transfer catalyst, for example, quaternary ammonium, such as Tetrabutyl bromide ** ** "Examples of organic reaction media which are preferred include, but are not limited to, the following:

ΐ 30 for example methanol, ethanol, propanol, Isopropanol, t V gJ | dioxane, dialkyl ethers, lower alkyl esters * ^ SAME * ‘lower fats, aliphatic and aromatic hydrocarbons! ^^ H ^ ·" ues' or unsubstituted, tetrahydrofuran, dimethylformamid "> hylphosphorotriamide. u <ÆÊsBm I 35 Examples of reaction media orff ,,,, | ^ HHH | j preferred are ethanol, isopropanol, chloride d? tetrahydrofuran. // ’5

The need for efficient cooling may be particularly appropriate during the conversion of sulfide to sulfoxide because the reaction rate is high, and the reaction is exothermic, while the conversion of sulfoxide to sulfone requires heating or a longer time. reaction time at ambient temperatures.

The process of the invention is also particularly advantageous for the preparation of certain esters of formula I, in particular the imparting intermediates of formula la \ 10 ο o R ^ Y-re ^ 0-C-N-1,

* 1COOCH-X

15 · "3 in which R ^ is as defined above, R ^ is a hydrogen atom or a lower alkyl, aryl or arylalkyl group, preferably hydrogen or a methyl, phenyl or benzyl group, and X represents a halogen atom, preferably chlorine. The compounds of formula la are important intermediates in the production of diesters of formula 0 0 R. 5 \ /

Vt8Y

t '0 0 IV

0-C-N-1, „25 '' C-O-CH-O-C-R.

. 4 * 3 in which R ^ and R ^ are as defined above, and R ^ CO-represents the acyl radical of a penicillin or an amidino-penicillanoyl radical.

The compounds of formula la can be prepared according to the following reaction scheme; / 'J.

T

6 ï! j R1 S g y \ ë g y r Y + v-ch-x-> "τ-r 'i · * 0-C-N-i ,, * 0 * C-N-

'COOM * t COOCHX

5 * 3

i V VI VII

'v) oxidation according to the invention in which R ^, R ^ and X BOnt te ^ s as defined above, M represents „a cation such as Na +, K +, an ammonium ion, a trialkylammonium ion 10 or a tetraalkylammonium ion , for example a tetrabutylammonium ion, and Y represents a bromine or iodine atom or an alkylsulfonyloxy, halosulfonyloxy, α-halogenoalkoxysulfonyloxy or arylsulfonyloxy radical.

The esterification process V -> VII is carried out in a suitable solvent, for example dimethylformamide, acetone or hexamethylphosphorotriamide, for a sufficient time and at a suitable temperature to carry out the desired conversion, usually at a temperature of 0 to 60 ° C. .

Compounds of formula la can also be produced by first subjecting a compound of formula V to the oxidation process of the invention and then esterifying the eulfone obtained to obtain the desired compound of formula la. However, when preparing the compounds of formula la, it is preferred to first carry out the esterification and then the oxidation according to the invention. The two methods for preparing the compounds of formula la form part of the invention.

Some of the compounds of formula VII are new and as such are part of the invention. A particular example of interesting intermediate is the compound of formula VII, hitherto unknown, in which and represent hydrogen and X is the chlorine.

The catalyst used in the oxidation according to the invention is advantageously in the form of a salt. If the reaction medium is aqueous, an alkali metal salt may be the formdV

IJ

7 preferred, while in an organic reaction medium it may be suitable to use the catalyst in the form of a salt with an organic cation, for example a quaternary ammonium salt, such as a salt of tetrabutylammonium.

The following examples illustrate the invention without, however, limiting its scope.

EXAMPLE 1 1.1-Chloromethyl dioxopenicillanate A - Tetrabutylammonium penicillanate 10 To a cooled solution (+ 5 ° C.) of 35.7 g (0.105 mol) of tetrabutylammonium hydrogen sulphate in 80 ml of water, 100 ml of dichloromethane, then 30% sodium hydroxide to bring the pH to about 3. 24 g (0.1 mole) of potassium penicillanate are added and the pH ô 7 is adjusted with 30% sodium hydroxide .

The organic layer is separated and the aqueous phase is extracted three times with 25 ml portions of dichloromethane. The combined extracts are dried and the solvent is removed in vacuo to obtain 45 g of the desired compound in the form of a brown-yellow oil.

B - Chloromethyl penicillanate 20 45 g of tetrabutylammonium penicillanate are dissolved in 100 ml of chloroiodomethane and allowed to stand for 20 h at room temperature. Excess chloroiodomethane is removed under reduced pressure, first under 10 mm Hg, finally under 0.1 mm Hg.

The semi-crystalline residue is treated with 200 ml of ethyl acetate and the separated tetrabutylammonium iodide is filtered off and washed with ethyl acetate. The filtrate is evaporated in vacuo and the brown residue is chromatographed on silica gel (hexane-ethyl acetate 4: 1) to obtain the desired compound in the form of a · yellow pole oil, The IR spectrum (chloroform) presents a -1 30 strong band at 1765-1785 cm.

The NMR spectrum (CDCl 4) shows peaks at i * 1.55 (s); 1.87 (s); 3.10 (dd, J-16, J-2); 3.62 (dd, J-16, J-4); 4.50 (s); / 5.30 (dd, J-2, J-4) J 5.65 (d, J-6.5); 5.88 (d, J-6.5). Γ

II

8 C - 1.1-Chloromethyl dioxopenicillanate * To a stirred solution of 12.5 g (0.05 mole) of chloromethyl penicillanate in 50 ml of 96% ethanol, 100 mg of sodium tungstate dissolved in 0.5 ml of water. 11 ml of 30% hydrogen peroxide are added in one portion. There is no immediate heat release but, after a few minutes, an exothermic reaction begins. The temperature is maintained below 30 ° C while cooling in ice water and the mixture is left to stand at room temperature for 20 h. The crystalline mass is cooled to 0 ° C. and the crystals are separated by filtration, washed and dried and recrystallized from ethyl acetate-hexane to obtain the desired compound, mp 95-96 ° C. The IR spectrum (chloroform) shows strong bands at 1805, 1780, 1330 and 1120 cm "1.

15 EXAMPLE 2

1.1-dioxopeniclllanic acid To a cooled stirred solution (10 ° G) of 12 g (0.05 mole) of potassium penicillanate and 100 mg of sodium tungstate in 50 ml of water, 11 ml of peroxide are added in portions 20 30% hydrogen. During the addition of the first 5 ml, heat is given off and the temperature is kept below 30 ° C. by cooling in ice water. The mixture is left to stand at room temperature for 20 h and the excess hydrogen peroxide is destroyed by sodium bisulfite. The mixture is saturated with sodium chloride and the pH is adjusted to 1.5 with concentrated hydrochloric acid under 50 ml of ethyl acetate, the layers are separated and the aqueous phase is extracted twice with 25 ml ethyl acetate. The combined extracts are dried and the solvent is removed in vacuo. The crystalline residue is washed with hexane to obtain the desired compound as crystals! colorless, F, 154 ° C (decomposition), / //

EXAMPLE 3 / U

Chloromethyl 1,1-dioxopenicillanate Ly 9 To a stirred solution of 2.5 g (0.01 mole) of chloromethyl penicillanate in 25 ml of ether, 2.5 ml of hydrogen peroxide is added to 30% and 40 mg of sodium tungstate in 0.25 ml of water. The mixture is stirred for 2 days at room temperature, then the ether is removed in vacuo and the crystals are separated by filtration, washed with water and then with cold 2-propanol to obtain the desired compound in the form of colorless crystals, mp 96-97 ° C.

EXAMPLE 4 10 Chloromethyl 1,1-dioxopenicillanate To a stirred solution of 2.5 g (0.01 mole) of chloromethyl penicillanate and 0.5 g of tetrabutylamraonium bromide in 25 ml of dichloromethane, 2 is added, 5 ml of 30% hydrogen peroxide and 40 mg of sodium tungstate in 0.25 ml of water. The temperature is kept below 30 ° C by cooling with water. After stirring for 2 days at room temperature, the dichloromethane is removed in vacuo, and the residue is extracted with ether. The ethereal phase is evaporated in vacuo and the residue is chromatographed on silica gel (hexane-ethyl acetate 3.‘2) to obtain the. 20 sought compound in the form of colorless crystals, mp, 96-97 ° C., EXAMPLE 5 1.1-chloromethyl dioxopenicillanate To a stirred solution of 2.5 g (0.01 mole) of chloromethyl peni-cillanate in 25 ml of propanol-2, 2.5 ml of 30% hydrogen peroxide and 40 mg of sodium tungstate in 0.25 ml of water are added. The temperature is kept below 30 ° C and then allowed to stand at room temperature for 24 h.

After cooling to 0 ° C., the crystals are separated by filtration and washed with cold 2-propanol to obtain the desired compound / in the form of colorless crystals, mp 96-97eC. /) / î 10 EXAMPLE 6. 1.1-1-Chloroethyl Dioxopenicillanate A - 1-Chloroethyl Peniclllanate

Following the procedure of Example IB, but replacing chloroiodomethane with 1-chloro-1-iodoethane, the desired compound is obtained in the form of an oily substance which is used in the next step without other purification.

B - 1-1-chloroethyl Djoxopenicillanate "

Following the procedure of Example IC, but replacing the chloromethyl penicillanate with the 1-chloroethyl penicillanate prepared according to A above, the desired compound is obtained in the form of a crietalline mixture of the two diastereoisomers .

EXAMPLE 7 6a-bromo-1,1-dioxopenicillanic acid To a solution of 4.3 g (0.015 mole) of 6ct-bromo-penicillanic acid in 15 ml of ethanol, 1.5 ml of sodium tungstate are added 0.5 M aqueous then 4 ml of 30% hydrogen peroxide. After about 5 min, the temperature gradually rises to 50 ° C and the mixture is kept at this temperature for 2 h. After cooling with ice, the excess hydrogen peroxide is destroyed by sodium bisulfite and the mixture is brought to dryness under vacuum. The residue is extracted with 50 ml of ether and the extract is evaporated in vacuo. The residue is recrystallized from an ether-diisopropyl ether mixture to obtain the desired compound as colorless crystals, mp 124-126 ° C.

The NMR spectrum (CD ^ OD) has peaks at * 1.48 (s); 1.59 (s); 4.48 (s); 5.10 (d, J "2 Hz); 5.35 (d, J-2 Hz).

EXAMPLE 8 1,1-Dioxopenicillanoyloxymethyl phenoxymethylpenicillanate

To a solution of 1.41 g (5 millimoles) of chloromethyl 1,1-dioxo- / penicillanate in 25 ml of dimethylformamide, on / - J

y y.

11 adds 1.94 g (5 millimoles) of potassium phenoxymethylpenicillanate * and the mixture is stirred at room temperature for 18 h, After dilution with 100 ml of ethyl acetate, the mixture is washed with four times 25 ml of water, dried and evaporated in vacuo. The residual oil is purified by chromatography on a dry column of silica gel (ethyl acetate-petroleum ether 8: 2) to obtain the desired compound in the form of a slightly yellowish foam, EXAMPLE 9 10- ( 1,1-dioxopenicillanoyloxymethyl da-amino, a-phenylacetamido) -penicillanate

Following the procedure of Example 8, but replacing the potassium phenoxymethylpenicillanate with potassium 6- (D-a-amino, a-phenylacetamido) -penicillanate, the desired compound is obtained in the form of a colorless foam.

The NMR spectrum (D ^ O) presents signals at 6 * * 1.38 (s, 6H; 2-CH3); 1.46 (s, 3H; 2-CH3); 1.58 (s, 3H; 2-CH.j); 3.56 (m, 2H; 6a-H and 6β-H); 4.60 (s, 1H; 3-H); 4.63 (s, 1H; 3-H); 5.03 (m, 1H; 5-H); 5.27 (s, 1H; CH-NH2); 5.53 (s, 2H; 5-H and 6-H); 5.97 (bs, 20 1H; OCH ^ O) and 7.53 (s, 5H; aromatic CH) ppm.

Tetramethylsilane is used as an external standard, EXAMPLE 10

1.1-dioxopenicillanic acid, A stirred solution of 288 g (1 mole) of morpholine penicillanate in 1 liter of water is acidified to pH 3.4 with hydrochloric acid, after which 12.5 g of tungstate are added. sodium, 330 ml (3.3 moles) of hydrogen peroxide are added in portions at 307. in about 4 hours, keeping the temperature below 25 ° C. After standing overnight at 5 ° C, excess hydrogen peroxide is destroyed by sodium bisulfite. 300 g of sodium chloride are added and 1 pH is adjusted to 1.1 with hydrochloric acid, after which the mixture is extracted three / times with 1 liter of ethyl acetate. After drying, the λ is concentrated! organic phase under vacuum at about 1 liter, after which we add J /

U

Γ! t '1' 12 to 3 liters of heptane. After standing overnight at 5 ° C., the crystals are collected and washed with heptane to obtain the desired compound in the form of pale yellow crystals, F, 148-150 ° C.

EXAMPLE 11 5 potassium potassium dioxopenicillanate I A solution of 23.3 g (0.1 mol) of acid is heated | 1,1-dioxopenicillan in 100 ml of 997 ethanol at 45 ° C in a bath | | »Of steam. A solution of 10 g of potassium acetate] in 60 ml of warm 99% ethanol is added, and crystallization is initiated | 10 by scraping. After standing for approximately 10 min, the 1 crystals are separated by filtration and washed with ethanol and ether I to obtain the desired compound in the form of colorless crystals.

} EXAMPLE 12 il Acid 6a-chloro-l, 1-dioxopénicillanique il S 15 By replacing in the procedure of example 7 | 6ot-bromopenicillanic acid with 6a-chloropenicillanic acid, Îot 6ot-chloro-1} dioxopenicillanic acid is obtained in the form of crystals, mp, 134-137 ° C, in diisopropyl ether, * The spectrum of NMR (CDCl ^) presents signals to! "1.50 (s, 3H; 2-¾)} 1.64 (s, 3H; 2-CH3); 4.46 (s, 1H; 3-H); 1 4.70 (d, J-1.5 Hz, 1H; 6-H) and 5.18 (d, J-1.5 Hz, 1H; 5-H) ppm. Tetramethylsilane is used as an internal standard.

A crystallized potassium salt of the compound] is obtained above, by adding an equimolar amount of 2-ethylhexanoate \ | 25 of 0.8 M potassium in acetone to a stirred acid solution | o-chloro-1,1-dioxopenicillanic in acetone, I EXAMPLE 13 I * 1.1-Pivaloyloxymethyl diopenicillanate j A - Pivaloyloxymethyl peniclllanate 1 30 A stirred suspension of 12 g (0.05 mole) of penile! potassium cillanate in 50 ml of DMF, 7.5 ml of pivom / l: {late chloromethyl is added, After stirring for 24 h, 100 mVy of ether are added and the mixture is washed with 100 ml and with 50 ml of water. The organic layer is dried and brought to dryness under vacuum to obtain the desired compound in the form of a pale yellow oil.

The IR spectrum (CHC1.) Has a strong broad band * ~ 1 ^ * “centered at 1765 cm.

5 B - 1.1-pivaloyloxymethyl dioxopenicillanate To a stirred solution of 3.14 g (0.01 mole) of the compound obtained under A in 25 ml of 96% ethanol, 2.2 ml of hydrogen peroxide is added to 307., then 1 ml of 0.5 M aqueous sodium tungstate. The temperature rises to approximately 35 ° C. in 10 min. After stirring for 20 h, 50 ml of water are added and the ethanol is removed in vacuo. The separated oil is extracted with ethyl acetate, dried and evaporated to dryness under vacuum. The residue is recrystallized from ether to obtain the desired compound in the form of colorless crystals, F. 103-104eC.

The NMR spectrum (CDCl 4) shows peaks at & m 1.27 (s); 1.47 (s); 1.62 (s); 3.52 (m); 4.47 (s); 4.70 (m); 5.73 (d, J16 Hz); 5.98 (d, J-6 Hz).

EXAMPLE 14 Acetoxymethyl 6-methoxy-l.1-dioxopenicillanate 20 A - 6a ~ Acetoxymethyl methoxypenicillanate A stirred suspension of 4.61 g (0.01 mole) of 6-aminopenicillanate acetoxymethyl 4-toluenesulfonate a cold mixture (0-3 ° C) of 400 ml of dichloromethane and 400 ml of water, 3.45 g (0.05 mole) of sodium nitrite and 1.90 g (0.01 mole) are added 4-toluenesulfonic acid, the latter being added in three equal portions at 5 min intervals. After stirring at 0-3 ° C for a further 20 min, the organic layer is separated, dried and concentrated in vacuo to about 40 ml. 2 ml of methanol and 0.2 ml of boron trifluoride etherate are added with stirring, which immediately gives off nitrogen. After stirring for 5 min, 10 ml of aqueous potassium hydrogen carbonate are added. 0.2 M. The organic layer is separated, washed with 2 times 5 ml of saturated aqueous sodium chloride, dried and evaporated in vacuo. The residual oil is purified by chromatography / \,

U

!

IH

ί ”j graphed on silica gel (ethyl acetate-hexane 3: 7) to obtain • the desired pure compound in the form of a yellow oil pays.

The NMR spectrum (CDCl 4) shows peaks) ^ - 1.46 (s); 1.55 (s); 2.11 (s); 3.51 (s); 4.50 (s); 4.57 (d, J-1.5 Hz); 5.29 5 (d, J-1.5 Hz) and 5.78 (s).

B - 6a-Methoxy-11-acetoxymethyl dioxopenicillanate To a stirred solution of 0.72 g (0.0024 mole) of the compound obtained under A in 6 ml of tetrahydrofuran, 0.52 ml of hydrogen peroxide is added at 30% then 0.24 ml of 0.5 M aqueous sodium tungstate. The temperature rises to 36 ° C. in 5 min. After stirring for 20 h, 20 ml of water are added and the tetrahydrofuran is removed in vacuo. The residue is treated with ethyl acetate to obtain a yellowish oil which is purified by chromatography on silica gel (ether) to give an oil which crystallizes in ether giving the desired compound as crystals colorless, F. 88-90eC.

! The NMR spectrum shows signals at 0 '- 1.41 (s); 1.56 (a); 2.14 (s); 3.57 (s); 4.41 (s); 4.62 (d, J-1.5 Hz); 5.02 (d, J-1.5 Hz) and 5.72-5.91 (ABq, J-5.8 Hz).

It is understood that the invention is not limited to the preferred embodiments described above by way of illustration and that a person skilled in the art can make modifications to it / without departing from the scope of the invention , 1

J

Claims (11)

1. Process for the production of compounds of general formula 0 0 5 N. — JIX, / rn Ύ * o “c-N-v. R2 in which Rj represents a hydrogen or halogen atom or an alkyl, alkoxy or trifluoromethyl group, and R2 represents a carboxy group or a protected carboxy group, in particular an esterified carboxy group; or their salts in the case where R ^ is a carboxy group or contains a basic or acidic group, characterized in that a compound of formula is subjected 15. H 0 Vh «„ \ -ΐΎ 0-C-N - ”/. 0-C-N-> 4. Λ '** 20. ii III in which R ^ and R ^ are as defined above, or one of their. salts as defined above, to an oxidation by hydrogen peroxide in the presence of a tungsten or molybdenum catalyst, 2. Method according to claim 1, characterized in that the oxidation is carried out in a suitable solvent at a temperature between the boiling point of the solvent used and a temperature approximately equal to or lower than room temperature, preferably between 20 and 30 ° C, 3. Method according to claim 1 or 2, characterized in that the catalyst is used in the form of a salt, r j! t i j: '16 i 4. Method according to claim 1, characterized in that R ^ represents hydrogen and R ^ is a carboxy group. 5. Method according to claim 1, characterized in that R ^ represents bromine and is a carboxy group. 5 6, A method according to claim 4 or 5, characterized in that a salt of a compound of formula 1 is formed. J: 7. A method according to claim 1. characterized in that R ^ represents hydrogen and R ^ is a group -COOCH ^ Cl. 8. Method according to claim 1, characterized in! 10 that R ^ represents bromine and is a group -COOCH ^ Cl, 9. New compounds useful as intermediates in the process according to claim 1, characterized in that they | meet the formula | i î 1 R 3 J 15 l '<* _ X) ra si r Γ V' * Ia i N ## iC00CHX V! VII i x) i 20 oxidation according to the invention wherein R ^ is as defined above, is a hydrogen atom i or a lower alkyl, aryl or arylalkyl group and j X represents a halogen atom. j * Soothsayers: -S— boards - t DD ....... pages of which ..... to .......- loss page I JH description pages ........ <L; ._ pages de rever; c: c ^ :. j "'% ..... A _______ abbreviated desc-iptif - LuxeTibcorg, ^ le p, ί j