SU867311A3 - Method of preparing d-7-/alpha-(4-oxy-6-methylnicotinamido)-alpha-4-oxyphenyl)-acetamido/-3-(1-methyltetrazol-5-ylthiometyl-3-cephem-4-carboxalic acid - Google Patents

Abstract

PURPOSE:D-7-[alpha-(4-hydroxy-6-methylnicotinamido)-4-hydroxyphenylace tamido]-3-(1-methyltetrazol-5-yl)-thiomethyl- <3>-cephem-4-carboxylic acid and its salt.

Description

(54) METHOD OF OBTAINING 0-7-HA- (4-OXI-6-METHYLNIKOTINAMIDO) -A- (4-OXYPHENYL) ACETAMIDOSE-3- (1-METYLETETRAZOL-5-ILTIOMETHYL) -3-DI-CHA-4-A-4-CVT-Z-THF-5-

.-. one .

This invention relates to a process for the preparation of a new cephalosporin antibiotic series, namely, 0-g-foL - (4-hydroxy-6-methyl nicotinamndo) -cLJH

| SS CONH- CH- COIfH HiC tf

as well as its salts or hydrates, which expand the arsenal of therapeutic agents / especially those that can treat infections, including those caused by pathogenic microorganisms that are resistant to chemotherapeutic agents.

A known method of producing 7-acnlamido-3-cephem-4-carboxylic acid derivatives of the formula

H COffH-CH-COtlH-iГ

 , about 1 (yut

- (4-hydroxyphenyl) acetamido-3-: (1-methyltetrazol-5-ylthiomethyl) -3-ts fem-4 - carboxylic acid form 15 ly

N

CHfSSUN

CH,

where R is free or substituted 15 are symmetric or asi1 "4-triazine, 2 - hydroxypyridine, or 2-hydroxyquinoline radical;

R is a hydrogen atom, a lower alkanoyloxymethyl: free or substituted pyridinomethylene,

interaction, respectively. 3-substituted D-7-r i-aMH4o- i- (4-hydroxyphenyl) -3-cephem-4-carboxylic acid with a reactive 25 carboxylic acid derivative of the formula

- R, -COOH,

where R ,, has the above values, in the medium of the solvent while cooling W in the presence of the catalyst fl. Known compounds are used as antibiotics. The purpose of the invention is to obtain new cephalosporin antibiotics that expand the arsenal of means of action on a living organism. This goal is achieved in that according to the proposed method for the preparation of compounds of the formula I, the compound of the formula HfN-CHCOt / Hyy, 1 4- is reacted with a compound of the formula H, cV or its active derivative in a solvent, preferably in the presence of a catalyst and / or when cooled. "The compound of formula 1t can be introduced into the reaction either in free form or in the form of its salt. Examples of the salt are salts of inorganic acids such as hydrochloric, sulfuric or phosphoric acid, salts of organic acids such as acetic acid or trifluoroacetic acid alkali metal salts such as sodium or potassium, etc. or salts with organic bases such as triethylamine, di-methylaniline or N-methylmorpholine. The compound of formula I1 can also be supplied to the reaction in a form in which the carboxyl group of this compound is protected by a benzhydryl ester, p-nitrobenzyl ester, 2.2, 2-triethylchloroethyl ester, tert-butyl ester, etc. in this case, the resulting product can be converted into the target compound by removing the „protective group after the reaction is complete. The reaction can use 4-C b-methyl-6-stinic acid of formula G II as such, but it is convenient to use it as an active derived from a carboxyl group. As the reactive derivative, its acid halide, azide, active ester, anhydride or active amide, and others are used. The reaction in the process is usually carried out in a solvent, in which water or organic solvent is used, such as chloroform, dichloromethane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric acid / triamide (AGMP). acetonitrile or ethyl formate. These organic solvents are used either individually or in combination with each other. In addition, those organic solvents that combine with water can be used in a mixture with it. In the case of the use of nicotinic acid of formula III as a free acid, the reaction is preferably carried out in the presence of a coupling agent, such as N, N-dicyclohexylcarbodiimide, diphenylphosphoryl azide, phosphorous trialkyl ester, phosphorus trichloride, phosgene or oxalic acid chloride. The compound of the formula G can be used as such, either as a salt or a hydrate. pharmacologically acceptable non-toxic salts, for example, alkali metal salts (sodium or potassium), ammonium salts, salts with organic compounds, such as dicyclohexylamine, cyclohexylamine, trimethylamine, triethylamine, ethanolamine, ornithine or lysine salts can be used as the compound salts. Salts of the compounds of the invention can be used for injections, in particular, sodium salt dissolves well in water and does not precipitate as crystals from solution upon standing. The proposed compound, its salts or hydrates can be administered orally or parenterally as antibiotics. The selected dosage is determined by the nature of the disease, the weight, the condition of the patient, etc., but is usually usually about 250 to 3000 mg / day per adult in two to four doses per day. Example 1. In 150 ml of a mixture of dichloromethane and dimethylformamide (1: 1 by volume) containing 15.5 ml of triethylamine, 23.8 g of 0-7-Gc. -Amino-CL- (4-hydroxyphenyl) acetamido -3 is dissolved - 11-methyltetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid. After cooling the solution to -30 ° C, 10.5 g of 4-hydroxy-6-methylnicotinoyl chloride and 1 ml of triethylamine are added to the solution and then the mixture is stirred for 2 hours at (-10) - (- 20) C. Then the mixture is stirred for 8 hours at a temperature from 0 to -5 s, after which it is concentrated under reduced pressure at a low temperature. 500 ml of sulfuric ether was added to the concentrate and acetone was added to the sticky precipitate, followed by stirring, to give a yellowish-orange powdery precipitate. This precipitate is separated by filtration, washed with a small amount of acetone and dissolved in 500 ml of cold water. With stirring and cooling with ice, the aqueous solution was adjusted to pH 2 by adding 6N. hydrochloric acid. A precipitate is formed. The precipitate is filtered off and dissolved in 1 liter of a mixture of acetone and water (2: 1 by volume). The resulting solution is terminated. Is triturated under reduced pressure. The initially formed yellowish-brown viscous precipitate is separated by decanting, and the supernatant is treated with activated charcoal to form a yellowish solution. The solution is concentrated under reduced pressure, removing the acetone, resulting in a light yellow precipitate. The latter is filtered off and, after adding 50 ml of acetone thereto, the mixture is stirred under heating to crystallize the product. To the resulting porous material, 100 ml of water are gradually added, after which it is stirred to precipitate a sufficient amount of crystals. ly filtered off, washed with 30% acetone and dried, obtaining 20.5 g of yellowish-white crystals of 0-7-G - (4-hydroxy-b-methyLnicotinamide) -ot- (4-hydroxyphenyl) acetamide J-3- (1-methyltetrazol -5-yl) thiomethyl-3-cephem-4-carboxylic acid. M.p. 213215 C (with decomposition). The structure of the product is confirmed by data IR and NMR spectra. The 4-hydroxy-6-methyl-nicotinoyl chloride used in the example is obtained by the following method. 15.3 g of 4-hydroxy-6-methyl-nicottonic acid are suspended in 400 ml of dichloromethane and, after adding 14.7 ml of triethylamine, the mixture is stirred at room temperature, the solution is acid. The solution is cooled to -30 ° C and 7.6 MP of thionyl chloride is added dropwise with stirring and at the same temperature. When a precipitate began to precipitate from the clear solution, the solution was stirred for 1 hour at from 0 to and then for one hour at room temperature. The resulting precipitate was separated by filtration, washed with dichloromethane and dried Hssh with phosphoric anhydride under reduced pressure to give 4-hydroxy b-methi nicotinoyl chloride. Example 2. a) In 600 ml of a mixture of dichloromethane and dimethylformamide (2: 1 by volume) containing 45.4 ml: triethyl mIna, 73.5 g / O-7-rd is dissolved. -amino-ct- (4-hydroxypheyl) yl-acetamido-J-3- (1-methyltetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid To the solution, 56.3 N-oxysuccinimide ester 4- hydroxy-6-methylnicotinic acid p. The mixture immediately becomes a solution, and then crystals precipitate. After stirring the mixture for one hour at room temperature, 220 ml of chloromethane was added and then stirred for 30 minutes in order to obtain crystals. The crystals were filtered, followed by 300 ml of acetone, 200 ml of sulfuric ether and dried under reduced pressure. 90 g of white crystals of the triethylamine salt O-7-fA- (4-hydroxy-6-methyl-nicotinamide) (4-hydroxyphenyl) acetamido-3- (1-methyltetrazol-5-ylthiomethyl) -3-cephem 4-carboxylic acid are obtained. (yield 82%). Purity 97.1% (set by high-speed liquid chromatography). M.p. 171-173 C (with decomposition). IR absorption spectrum: cm; 1770 (beta lactam); 1655, 1510 (acid amide); 1605 (carboxylate). The structure of the product is also confirmed by the data of NMR spectrum. b) 60 g of the triethylamine salt obtained in step a is dissolved in 900 ml of water. The pH of the solution is up to 7 by adding 1 g of sodium bicarbonate. After filtration, 600 ml of acetone was added to the filtrate, and 600 ml of 6 ml were added to the mixture. hydrochloric acid to bring the pH to 2, the mixture being stirred. After stirring the mixture for about an hour while cooling with ice, the resulting crystals are filtered off, washed with 200 ml of 30% acetone and dried with an air stream. 48 g of white crystals of 0-7-G - (4-hydroxy-6-methyl nicotinamide) -d- (4-hydroxyphenyl) acetamido-3- (l-methyl-tetrazol-5-ylthiomethyl) -3-cephem-4 are obtained. -carboxylic acid (yield 92%). Purity 98.5% (determined by high-speed liquid chromatography. Mp. (With decomposition). IR absorption spectrum: cm: 1780 (beta-lactam); 1700 (carboxylic acid); 1660, 1510 (amide acid). X-ray Diffraction spectrum (X-Cook): 20 16.6 (d 5.34 X); 20.5 ° (d - 4.33 A); 21.2 ° (d. 4.19 A) Quantitative analysis of the content water was prepared by Karl Fischer method. Calculated, 5.55%, found 5.89%. N The structure of the product was confirmed by NMR spectrum data. Example Z. Dissolve 1ED g of 4-hydroxy-6-methyl-nicotine in 480 ml of dry methyl acid and amide. acid after adding to solution 17, 0 g of carbonyldiimidazole is stirred for 1 hour at room temperature, 47.7 g of D-7-ft-amino-fit- (4-hydroxyphenyl) acethimido3-3- (1-methyltetrazol-5-ylthioethyl) is added to the mixture. -Z-cephem-4-carboxylic acid 14.7 ml of triethylamine. After stirring the mixture for 2 hours at a comet temperature, 480 ml of dichloromethane was added to the mixture, followed by stirring for 1 hour at room temperature. The crystals formed were separated by filtration, sequentially washed with 200 ml of acetone, 130 ml of sulfuric ether and dried under reduced pressure. 56.6 g of yellowish trimethylamine salt of 0-7-HA- (4-hydroxy-6-methylnicotinamide) - .- {4-hydroxyphenyl) acetamido-3- (1j J COWH-CH-COA / HT) different compound are obtained. Formula II H, - CH-CONH X 1-cn, L, lh iH is reacted with a compound of formula III

-methyltetraeol-5-ylthiomethyl) -3-cephem-4-carboxylic acid.

The chemical and physical properties of the product are the same as those of the product of Example 2.

Claims (1)

Invention Formula The method of obtaining OV-fct- (4-hydroxy-6-methylnicotinamide) -A- (4-hydroxyphenyl) acetamido-3- (1-methyltetraeol-5-ylthiomethyl) -3-cephem-4-carboxylic acid of the formula I, Jr - or its active derivative in a solvent, if necessary in the presence of a catalyst and / or upon cooling. Sources of information taken into account in the examination 1. US patent 4041161, cl. 424/246, pub. 08.08.77