HU184827B - Process for preparing 6-fluoro-1,8-na phthy ridyl-derivatives - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R1 is H or protecting group; R2 is alkenyl, alkyl, etc.), and a salt thereof. EXAMPLE:1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-( 1-piperazinyl )-1,8-naphthyridine- 3-carboxylic acid. USE:An antimicrobial agent and a synthetic intermediate therefor having improved effects on urinary tract infection, ascending renal infection and systemic infection even in a small dose with very low toxicity. PROCESS:A compound of formula II (R3 is H or alkyl) is oxidized with a hypohalogenate or silver oxide, or reacted with an iodine-pyridine mixture and then treated with an alkali to give the compound of formula I.

Description

The present invention relates to a process for preparing the 6-fluoro-8-naphthyridine derivative of formula ί and its salts. and its salts are useful as antibacterial agents.

These compounds are prepared according to the invention by using a 1,8-naphthyridine compound of formula II. Kepler

R 1 is hydrogen or a protecting group, preferably C 2 -C 5 acryl. and

R _{2 is} hydrogen or C 1-4 alkyl, and optionally, when R 1 is protecting, the resulting product is hydrolyzed.

In the compounds of Formula II, the protecting group R 1 may be, for example, an acyl group such as ethoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, acetyl or trifluoro, or an arylsulfonyl group such as p-toluenesulfonyl. These groups can be cleaved by hydrolysis.

The compound of formula I and salts thereof are effective against both Gram-positive bacteria, such as Staphylococcus aureus speciess, and Gram-negative bacteria, such as Escherichia coli or Pseudomonas aerugincsa speciess.

In particular, the compound of formula I and its hydrochloride or methanesulfonate salt have excellent therapeutic properties, for example, in the treatment of low-dose infections of the urinary tract (including infections that penetrate the kidneys) and systemic infections, but are extremely low. The antibacterial activity and toxicity of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (3-piperidinyl) -3-carboxy-1,8-naphthyridine prepared by the process of the present invention , and blood plasma and urine levels are presented in the following experimental section

Experiment 1 - In vitro antibacterial activity

Tribe kill 3 'aa Staphylococcus aureus 209P JC-1 0.78 Gram Staphylococcus aureus No. 50774 0.78 -positive Streptococcus faecalis P-2473 12.5 bacterial Streptococcus pyogenes 65-A 12.5 laboratories Coryncbaclcrium pyogenes C-21 1.56 Escherichia coli NIHJ JC-2 0.2 Escherichia coli P-5101 0.1 Escherichia coli P-140-a 0.2 Salmonella typhimurium S-9 0.1 Gram Salmonella enteritidis No. 1891 0.1 -negative Shigclla flexneri 2a 0.2 bacterial Shigeíla flexneri 4a P-330 0.39 laboratories Kiebsiella pneunnniae No. 13 0.2 Enterobacter doacae P-2540 0.2 Pseudomonas aeruginosa Tsuchijima 0.39 Pseudomonas aeruginosa No. 12 0.78 Serratia marqescens 1FO 3736 0:39 Proteus morganil Kono 0.2 Proteus mirabilis P-2381 0.39 Above Table 3 shows the MIC header column; in

gave minimum inhibition values in Chemotherapy, 22 (6). 1126 (1974).

Experiment 2 - Therapeutic effect against infections

Infection Strain ED _S0 (togkg)

(+1) Staphylococcus aureus No. 50774 10 systemic Escherichia coli P-5101 1.8 infection Pseudomonas aerigompsa No. 12 9.0

Kidney (+2) Pseudomonas aeruginosa No. 12 2.4 invading infection

The experiment (4-1) is carried out under the following experimental conditions:

Experimental animal: Male mice with ddY-S strain Bacterial count data:

(1) Staphylococcus aureus No. 50774; 5 · 10 ⁸ germinating cells [mouse;

(2) Escherichia coli P-5101: 9-10 ⁶ germ cells / mouse; and (3) Pseudomonas aeruginosa No. 12: 5 · 10 ³ germinated cells / mouse.

Type of infection:

For Staphylococcus aureus No. 50774: intravenous injection;

Escherichia coli P-5101 and Pseudomonas aeruginosa

For No. 12: intraperitoneal injection.

Medication:

Oral administration of the compound of Formula I immediately and six hours after infection.

Evaluation of results:

The ED _£ values were confirmed 14 days after infection for Staphylococcus aureus No. 50774, 7 days after infection for Escherichia coli P-5101 and 7 days after infection for Pseudomonas aeruginosa No. 12, also by Baehrens-Kaerber method. survival rates.

Experiment (+2) was carried out using Dainippon Pharmaceutical Co., Dd. Female mice anesthetized with the sodium salt of 5-ethyl-5- (1-methylbutyl) -barbituric acid, manufactured by the Japanese company, and then infected with Pseudomonas aeruginosa No. 12 by the Japanese company Eiken Kagaku Co., Ltd. trypto-soy, in a 1.5: 10,000 dilution, in 0.1 ml injection. Mice were not given drinking water for two days on the day before and on the day of infection. Compound I was administered orally after the infection. At 3, 8, 24, 30, 48, and 54. On the fifth day after administration, the mice were sacrificed, the kidneys harvested, transversely dissected and plated on King A. The resulting system was maintained at 37 ° C. incubate overnight The ED _S0 values according to the Probit method are taken as the curative effect when no infectious bacteria are detected in the kidney calculate

184,827

Experiment 3 - Toxicity

Acute toxicity

The compound of formula I is orally administered to male mice of strain ddY-S. LD _SO was calculated 7 days after administration using the Baehrens-Kaerber survival rates. This value, expressed in mg / kg, is more than 4000.

Subacute toxicity

Six female mice of an average weight of 20 g, of the JCL-ICR strain, are dosed orally at a dose of 2 g / kg / day in a 0.2% aqueous solution of carboxymethylcellulose for 14 days. The body weight of each mouse was measured during the experimental period. After the hematological examination on day 15, the mice were sacrificed, the organs were weighed and the organs examined histopathologically. No abnormalities in body weight, organ weight, hematology values and histopathological observations in dandruff in animals treated with the compound of formula I were found.

Experiment 4 - Blood Plasma and Urine Sample Blood Plasma Urine Time (Hours) 0.5 1 2 3 6 8 10 0-24 Concentration 0.6 2.4 5.5 5.9 4.2 3.7 2.4 606

[.ug / nrl] [40.7%]

The value in square brackets in the table refers to the percent recoveries of the compound of Formula I.

The experimental method is as follows: Two male hunting pouches weighing 12 kg each are dosed orally with 200 ml milk in a capsule containing 25 mg / kg of the compound of formula I. After administration, blood samples are taken at regular intervals by venipuncture and the samples are centrifuged separately to separate the plasma. However, 24 hours after administration, the selected urine is collected. The concentration of the compound of formula I in blood plasma and urine is determined using the so-called thin-layer coupling method using Escherichia coli Kp strain as an indicator organism.

Thus, the process of the present invention provides the compound of formula I in excellent yield by oxidizing a compound of formula II, dissolved or suspended in a solvent, and optionally subjecting the resulting product to hydrolysis to deprotect. View to implementing the oxidation, can be used in any oxidation method or agent, which aldehydes (R-CHO aldehydes of the formula - R is an organic group in the formula) or ketones (R C0CH Formula ₃ ketone) organic carboxylic acids (R-COOII general kcpletű carboxylic acids) is commonly used for the oxidation of. For example, the oxidation of a starting compound of formula II may be carried out with a hypohalogen such as potassium hypocollite or sodium hypojodite; a manganese or chromium compound such as potassium permanganate, sodium dichromate or chromium (VI) oxide; nitric acid; in the presence of potassium tert-butylate with air (oxygen); silver oxide; iodopyridine and base; or with carbon tetrachloride in the presence of a base in an aqueous solvent such as a mixture of tert-butanol and water. The oxidation of a compound of Formula II with bromine or iodine in an alkaline medium is equivalent to the oxidation with the above-mentioned hypohalites. The reaction temperature and solvent are selected according to the oxidation method used. Thus, the reaction temperature is usually -5 ° C to +80 ° C. The solvent used may be any solvent which does not participate in the oxidation reaction or remains stable under the conditions of oxidation. Examples of useful solvents include dioxane, acetone, pyridine, chloroform, tert-butanol, ethanol, hexamethylphosphoric triamide, acetic acid, water, and mixtures of water and the listed organic solvents.

If the starting compound is a compound of formula II wherein R1 is a protecting group, the deprotection may be carried out simultaneously with the oxidation process of the present invention, provided that the oxidation reaction conditions permit. If the protecting group is not cleaved by the end of the oxidation reaction, it can be cleaved by hydrolysis.

The hydrolysis is carried out by contacting the product with water. Generally, the reaction is carried out in the presence of a catalyst such as sr or a base to accelerate the hydrolysis. Examples of suitable acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, and organic acids such as acetic acid, trifluoroacetic acid, formic acid or toluenesulfonic acid.

Suitable bases include alkali metal hydroxides such as sodium or barium hydroxide; alkali metal carbonates, such as sodium or potassium carbonate; and sodium acetate.

The reaction may also be carried out by heating the product directly with one of the acids mentioned and then adding water. The reaction solvent is usually water, but depending on the nature of the product formed, an organic solvent such as ethanol, dioxane, ethylene glycol dimethyl ether, benzene or acetic acid may be used. The reaction temperature is usually 0 ° C to 150 ° C, preferably 30 ° C to 100 ° C.

The compound of formula 1 obtained by the process of the invention can be isolated and purified in a conventional manner. Thus it can be isolated in free form and V2gy in the form of a salt depending on the nature of the starting material and the reaction conditions. The compound of formula I can be converted into a pharmaceutically acceptable salt by treatment with a suitable acid or base. Suitable acids for this purpose are various organic or inorganic acids, such as hydrochloric acid, acetic acid, lactic acid, succinic acid, lactobionic acid or methanesulfonic acid.

As the experiments reported above clearly demonstrate, the compound of formula I is an excellent antibacterial agent.

184,827 have a high degree of toxicity and low toxicity, thus providing excellent results in the preparation of a pharmaceutical composition for the prevention and / or treatment of warm-blooded, including human, bacterial infections.

The dosage of a compound of Formula I or salt thereof for use in a human subject will vary depending on the age, weight and condition of the subject being treated, as well as the route and frequency of administration. Typically, for adults, this dose will be 0.1 to 7 g, preferably 0.2 to 5 g per day.

The compounds of the present invention may be formulated into conventional pharmaceutical excipients and / or excipients, for example, for oral or topical administration.

The term "pharmaceutical carrier and / or excipient" refers to substances which do not react with the compounds of the present invention. For example, water, gelatin, lactose, starch, cellulose (preferably microcrystalline cellulose), carboxymethylcellulose, methylcellulose, sorbitol, magnesium stearate, talc, vegetable oils, benzyl alcohol, resins, propylene glycol, propylene glycol, Methyl 4-hydroxybenzoic acid may be mentioned. The pharmaceutical compositions may be prepared, for example, in the form of powders, granules, tablets, ointments, suppositories, creams or capsules, and may be sterilized and / or may contain excipients such as preservative, stabilizing or wetting agents. They may optionally contain other therapeutic agents.

The starting compounds of formula II are novel compounds and may be prepared, for example, by the procedure outlined in the following Reference Example.

The invention is further illustrated by the following Reference Example and Embodiments.

PREPARATION

To a mixture of 1350 ml of fuming nitric acid and 2250 ml of concentrated sulfuric acid is added 450 g of 2,6-dichloropyridine, and the resulting mixture is kept under stirring on a water bath at 90-100 ° C for 4 hours. After cooling, it is poured into 5000 ml of ice-water with stirring. The precipitate was collected and washed with water. The procedure described above is repeated, and the batch of product is dissolved simultaneously in 5000 ml of chloroform. The resulting solution was neutralized with saturated sodium bicarbonate solution and the chloroform layer was separated. From the latter, 880 g of 2,6-dichloro-3-nitropyridine is distilled off from chloroform. This compound was used directly without further purification.

Anhydrous piperazine (785 g), chloroform (4000 ml), ethanol (1000 ml) and triethylamine (635 ml) were cooled to -20 ° C, and 880 g of 2,6-dichloro-3-nitropyridyl chloroform were added thereto. Cooled to -13 ° C to -20 ° C. A solution of 1293 ml of acetic anhydride in 1300 ml of chloroform was then added over 30 minutes. After the addition was complete, stirring was continued for 20 minutes and water (1000 mL) was added. The chloroform layer was separated and the solvent was evaporated. The residue is a mixture of water and ethanol! crystallized in 1.2 kg of 2- (4-3-acetyl-1-piperazinyl) 4

Yield: -6-chloro-3-nitropyridine, m.p. 137-138 ° C after recrystallization from ethyl acetate.

An autoclave was charged with 0 kg of 2- (4-acetyl-1-piperazinyl) -6-chloro-3-nitropyridine, 3000 ml of 25% aqueous ammonium hydroxide solution and 3000 ml of ethanol, followed by stirring. the resulting mixture was kept at 90-91 ° C for 4 hours. The resulting precipitate was collected, washed with water and. dried to give 610 g of 2- (4-acetyl-1-piperazinyl) -6-amiflo-3-n-t-phidine, m.p. 202-203 ° C after recrystallization from ethanol / chloroform.

A mixture of 1744 g of 2- (4-acetyl-1-piperazinyl) -6-arrino-3-nitro-pyridine, 6000 ml of acetic acid and 1000 ml of acetic anhydride is refluxed for 1.5 hours and then evaporated to dryness under reduced pressure. The residue was mixed with nearly 4000 ml of acetone and the precipitated crystals were collected. 1869 g of 6-acetylamino-2- (4-acetyl-1-piperazinyl) -3-nitropyridine, m.p. 189-193 DEG C., m.p. 221-223 DEG C. after recrystallization from acetonitrile. .

At 50-55 ° C with stirring, 1.0 kg of a suspension of 6-acetylamino-2- (4-3-acetyl-1-piperazinyl) -3-nitropyridine in 4000 ml of acetic acid and 8000 ml of ethanol in small portions over an hour 1464 g of zinc powder are added. The reaction mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in a mixture of 2400 m 'ethanol. The resulting solution was cooled to below -5 ° C and a solution of 269.4 g of sodium nitrite in 400 ml of water was added with stirring over 25 minutes. After stirring for an additional 20 minutes, the precipitate was collected and washed with ethanol (1000 mL) to give 1158 g of 6-acetylamino-2- (4-acetan-1-piperazinyl) -pindine-3-diazonium tetrafluoroborate, m.p. 121-124 ° C. .

While stirring, a suspension of the above diazonium tetrafluoroborate in 1322 g of 13 L cyclohexane was refluxed for 5 hours, cooled, the reddish-brown precipitate was collected and then, with vigorous stirring, suspended in 4000 ml of water and 3000 ml of chloroform. The organic phase is separated and the aqueous phase is separated by 1000 m! shake again with chloroform. The combined chloroform extract was washed with dilute aqueous ammonium hydroxide solution and the solvent was distilled off. The residue was crystallized from 4000 ml of diethyl ether to give 467 g of 6-acetylamino-2- (4-acetyl-1-piperazinyl) -3-fluoro-pyridine, m.p. 178-179.5 ° C after recrystallization from ethyl acetate. C.

A suspension of 255 g of 6-acetylamino-2- (4-acetyl) -piperazinyl) -3-fluoropyridine in 332 ml of 10% hydrochloric acid and 1700 ml of methanol is refluxed for 2 hours and then cooled and make it slightly acidic. The methanol was then evaporated and the residue basified with aqueous sodium bicarbonate solution and extracted with chloroform. The extract was washed, dried and evaporated, and the residue was recrystallized from ethyl acetate. 194 g of 6-amino-2- (4-acetyl-1-piperazinyl) -3-fluoropyridine are obtained, m.p. 116-117 ° C after recrystallization from ethyl acetate.

To a stirred mixture of 6- (4-acetyl-l-piperazinyl) -2-amino-5-fluoropyridine, 23.8 g and 18.6 g of ethoxymethylene acetecetsa ^v heated -ethyl ester 100 to 110 ° C for 1 and 100 ml of ethanol are added to the resulting solution. That's when

184,827 precipitates were collected by filtration to give 34.4 g of ethyl α- (N- {6- (4-acetyl-1-piperazinyl) -5-fluoro-2-pyridyl) aminomethylene> acetic acid, m.p. 162-163 ° C after recrystallization.

Λ 10 g of Dowtherm (obtained from Dow Chemical Co., USA) are obtained as the solvent from the previous step, and 100 g as the solvent; composition, for example, in The Codensed Chemical Dictionary. 4th Edition, published by Reinhold Publishing Corporation of New York and Maruzen Company Limited in Tokyo, page 412, the mixture is heated at gentle reflux for 1 hour and then at about 60 ° C. cooled and n-hexane (200 mL) was added. The precipitate was filtered off to give 6.47 g of 3-acetyl-7- (4-acetyl-1-piperazinyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine, m.p. 300 ° C. above.

While stirring, 6.0 g of 3-acetyl-7- (4-acetyl-1-piperazulyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine, 50 ml of dimethylformamide and 5.0 g of The potassium carbonate mixture was heated at 60 ° C for 15 minutes and then 4.3 ml of ethyl iodide was added. The reaction mixture was then refluxed for 1 hour and evaporated to dryness under reduced pressure. The residue was dissolved in water and the aqueous solution was extracted with chloroform. The extract was washed with water, dried and evaporated to give a crystalline residue. Recrystallization of the latter from ethanol gave 4.58 g of 3-acetyl-7- (4-acetyl-1-piperazinyl) -1-ethyl-6-fluoro-1,4-dihydro-4-oxo, m.p. 225-226 ° C. 1,8-naphthyridine is obtained.

Example 1

While stirring at room temperature, 1.44 g of 3-acetyl-7- (4-acetyl-1-piperazinyl) -1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine in 20 ml of water and 20 ml of To a suspension of 2% sodium hypochlorite solution is added 4 ml of 2N sodium hydroxide solution. After stirring for 6 hours, the reaction mixture was neutralized with acetic acid and the precipitate was collected and then recrystallized from chloroform / ethanol. 28 g of 7- (4-acetyl-1-piperazinyl) -, m.p. ethyl 6-fluoro-3-carboxy-1,4-dihydro-4-oxo-1,8-naphthyridine is obtained.

10 g of 5% sodium hydroxide solution are added to 1 g of the product obtained, and the resulting solution is heated in a water bath for 30 minutes. The solution was then neutralized with acetic acid under ice-cooling and the precipitate was collected and then recrystallized from ethanol / chloroform. Thus 0.7 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-carboxy-7- (1-piperazinyl) -1,8-naphthyridine, m.p. m.p.

Dissolve 0.2 g of the compound of formula I in 5% hydrochloric acid with heating and evaporate to dryness under reduced pressure. The crystalline residue is filtered off and recrystallized from water to give 0.21 g of the title compound having a melting point above 300 ° C. hydrochloride salt.

0.2 g of the compound of formula I are dissolved in 7% methanesulfonic acid aqueous solution while heating, and ethanol is added to the resulting solution. A precipitate formed which was collected by filtration and recrystallized from water / methanol. 0.22 g of the corresponding methanesulfonate salt having a melting point above 30 ° C are obtained.

0.2 g of the compound of formula I are dissolved in ethanol with heating, and 0.2 ml of acetic acid is added to the resulting solution. The reaction mixture was cooled and the precipitate was filtered off and recrystallized from ethanol. 0.18 g of the corresponding acetate salt of m.p. 228-229 ° C are obtained.

Example 2

1.26 g of 3-acetyl-7- (4-acetyl-1-piperazinyl) - 3-acetyl-7- (4-acetyl) -m.p. A mixture of ethyl ethyl fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine, 1.0 g elemental iodine and 5 ml pyridine was heated at 90-100 ° C for 1 hour with stirring. Pyridine is distilled off under reduced pressure. The residue was crystallized from water and the precipitated crystals were collected by filtration to give 7- (4-acetyl-1-piperazinyl) -1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine (1.4 g). Yielding -3-carbonylmethyl-pyridinium iodide, m.p. 238-239 ° C (dec.). 1.0 g of the latter compound is then added to a mixture of 10 ml of 1N sodium hydroxide solution and 40 ml of ethanol, and the resulting mixture is refluxed for 1 hour and then neutralized with acetic acid. The reaction mixture was then refluxed to remove ethanol and the aqueous residue was cooled. The precipitate was filtered off with 0.4 g of 7- (4-acetyl-1-piperazinyl) -1-ethyl-6-fluoro-3-carboxy-1,4-dihydro-4-oxo-1-ol, m.p. naphthyridine is obtained.

This compound was hydrolyzed as described in Example 1 to give 0.26 g of the compound of formula I.

Example 4

3.46 g of 7- (4-acetyl-1-piperazinyl) -1-ethyl-6-fluoro-3-formyl-1,4-dihydro-4-oxo-1,8-naphthyridine and 3.5 g of silver nitrate and a slurry of silver oxide (1.0 g) in sodium hydroxide in a mixture of 1 ml of water and 30 ml of ethanol were stirred at 10-20 ° C for 15 minutes at high intensity, and 5 ml of 1.5 g of sodium hydroxide was added dropwise. aqueous solution of sodium hydroxide containing xide. The reaction mixture was stirred at room temperature for 2 hours, then water (100 mL) was added and filtered to remove the precipitated silver. The filtrate was acidified with acetic acid and the precipitate was collected by evaporation to give 7- (4-acetyl-1-piperazinyl) -1-ethyl-6-fluoro-3-carboxy-1,4-dihydro-4,3 g (m.p. 300 ° C). -oxo-1,8-naphthyridine.

This compound was hydrolyzed as described in Example 1 to give 2.2 g of the compound of formula I.

Example 5

643.2 mg of the compound of formula I prepared in Example 1 are dissolved in 2 ml of 1 N aqueous sodium hydroxide solution and the resulting solution is evaporated to dryness under reduced pressure. This gives 648 mg of the corresponding sodium salt, m.p. 215-220 ° C (dec.).

Claims (5)

Patent claims A process for preparing 7- (1-piperazinyl) -1-ethylphloro-3-cassboxyl-1,4-dihydro-4-oxo-1,8-naphthindine and pharmaceutically acceptable salts thereof. a 1,8-naphthyridine derivative represented by the general formula (11) in the formula R 1 is hydrogen or a protecting group, preferably C 2 -C 5 acyl and L containing ₂ is hydrogen or C1-4 alkyl R represents an alkyl group is oxidized, optionally hydrolytically cleaving the _Rs protecting group from the resulting product, and if desired the resulting compound of formula 1 into a pharmaceutically acceptable salt in a suitable acid or with a base by one treatment. 2. A process according to claim 1, wherein the starting material is a compound of formula 11 wherein R ₂ is an alkyl group having 1 to 4 carbon atoms. í 3. The process according to claim 1 or 2, wherein the starting material is a compound of the formula II wherein R1 is a protecting group, preferably an acyl group having from 2 to 5 carbon atoms and an alkyl group containing R2 from _{1 to} 4 carbon atoms. 4. A process according to any one of claims 1 to 3, wherein the starting material is a compound of formula I wherein R _s is an acetyl group and R _{2 is a} lye methyl group. the oxidation product is hydrolyzed and optionally reacted with an acid. 5. A process according to claim 1, wherein the compound of formula IS, wherein R ₂ is hydrogen, is reacted as starting material. 4 Possible embodiment of the sixth of the first or claim 5 method, characterized in that as a starting material where Ri is védó'csoportot, preferably C2-5 acyl group and a hydrogen atom ₂ is 11 Compound R having the formula and the oxi5 photodegradation product was hydrolyzed . 7. A process according to claim 1 wherein the oxidizing agent is hypohalogenite. 8. Process according to claim 1, wherein a compound of formula II, wherein R 1 and R ₂ are as defined in claim 1, is reacted with a pyridine and iodine, and the resulting intermediate is treated with a base. 9. The method of claim 1, wherein: characterized in that silver iodide is used as the oxidizing agent.