CS269501B1 - Process for preparing 3-acetoxymethyl7- [2- / 2-amino-4-thiazolyl] -2-methoxyiminoacetamido-3-cephem-4-carboxylic acid - Google Patents

Abstract

The solution relates to a method for preparing 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid by deblocking the chloroacetyl group with thiourea under controlled pH reaction.

Description

The invention relates to a method for the preparation of 3-acetoxymethyl-7-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido-3-cephem-4-carboxylic acid, syn isomer, formula I

/1/ as well as its salts with alkali metals, ammonia or substituted ammonia of the formula in which r, r2, r3 independently of the other represent H, alkyl or cycloalkyl.

The compound of formula I is used as an intermediate for the preparation of a broad-spectrum antibiotic for gram-positive bacteria and especially gram-negative bacteria.

In earlier applications, a process for preparing the title compounds of formula I is described by reacting 3-acetoxymethyl-7-(2-(2-chloroacefemido-4-thiazolyl)-2-methoxyiminoacetamido-3-cephem-4-carboxylic acid, the syn isomer and its oleate, with thiourea.

German Patent Specification No. 271 327 2 discloses the preparation of compounds of formula I by reacting 3-acetoxymethyl-7-[2-[2-chloroacetamido-4-thiazolyl]-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid, isomer syn and its salts with thiourea in water in the presence of potassium bicarbonate for 6 hours, with the result that a gum product is separated, which is further purified by evaporation.

German Patent No. 271 538 5 describes the preparation of the acid of formula I by reacting 3-acetoxymethyl-7-[2-[2-chloroacetamino-4-thiazolyl]-2-methoxyiminoacetamide-3-cephem-4-carboxylic acid, the isomer of syn and its salts with thiourea in dimethylacetamide for 17 hours and the product must be isolated and purified by chromatography on nonionic resins and lyophilized.

M. Ochiai et al. J. Antibiotics 34, 171 (1981) state that the 2-imino-4-thiazolidinone formed as a by-product in the reactions described above causes difficulties in the purification of the product of formula I and especially in carrying out the reaction on a larger scale due to the formation of products of a pasty consistency. These authors circumvent the above-mentioned shortcomings by using special reagents.

In the previously known processes, no attention was paid to the pH value of the reaction mixture, or rather, its change and subsequent control. Since no importance was attributed to the change in pH during the reaction, the disadvantage of the previous processes, in addition to those already mentioned, is that they lead to the formation of products that must be carefully and complexly purified, especially by chromatography, and subsequently isolated from the aqueous solution by laborious lyophilization or, in some cases, the necessity of using economically disadvantageous organic solvents for dissolving the starting acid 3-acetoxymethyl-7- [2- / 2-chloroacetamido-4-thiazolyl / -2-methoxyiminoacetamido -3-cephem-4-carboxylic acid, isomer syn.

The above-mentioned shortcomings are eliminated by the invention relating to the preparation of 7-[(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid, the syn isomer of formula I

N ^NH 2 S

CCONH---j—T-7S

N j—N EYES

OCR, 0 ^J CO H

CS 269501 Bl as well as its salts with alkali metals, ammonia or substituted ammonia of the formula τ o 7 1 2

R R R N, in which R R R independently represents H, C1-6 alkyl or C1-6 cycloalkyl by reacting 1 molar part of 3-acetoxymethyl-7-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid, the syn isomer of general formula II

C-CONH — N Λ \ ₀ · OCOCH, ci-c^co-nhXs? och _{3 c0m} ³ /11/, in which M represents hydrogen or an alkali metal ammonium cation or a substituted # * 1 2 λ 12^ ammonium cation RRRN, in which R ,R ,R independently represent H, C^ g alkyl or C^_g cycloalkyl β 1 to 5 molar parts of thiourea in an organic solvent miscible with water and/or in water, characterized in that the reaction mixture is maintained at a pH of 5.1 - 2, at a temperature of -10 to 45 °C and the resulting compound of formula I is isolated from the reaction mixture before or after its conversion into an alkali metal salt with ammonia or substituted ammonia of the formula R ³ 'R ² R ³ N in which R^,R ² ,R ³ independently represent H, C^g alkyl or Cj_g cycloalkyl.

The advantage of the preparation method according to the invention is the simple processing of the reaction mixture, the avoidance of separation and economically demanding operations, especially on an industrial scale, and the replacement of organic solvents. The process according to the invention is carried out by adding a salt of the general formula III to 1 molar part of the compound of formula I in water or its mixture with an organic solvent

MX /111/, in which X represents an anion of an acid whose acidity is less than or equal to that of the acid of formula II and M represents an alkali metal or ammonium cation. As salts of organic acids, for example, sodium hydrogen carbonate or tertiary sodium phosphate may be mentioned. As salts of organic acids, alkali salts of aliphatic linear or branched carboxylic acids containing preferably 2 to 10 carbon atoms, for example sodium or potassium acetate, or the sodium salt of 2-ethylhexanoic acid ¹ may be mentioned. The dissolution of the compound of formula I may also be achieved by the addition of ammonia or amines of general formula IV

R ^X R ² R ³ N /IV/,

12^ where R , R , R represent independently H, C 1-6 alkyl or C 1-6 cycloalkyl.

The amount of salt of formula III or amine of formula IV is chosen such that their addition results in the dissolution of the acid of formula I, which means that at least a stoichiometric amount is preferably used. In some cases, it is advantageous to use an excess of from about 10% to 100%.

The concentration of the acid of formula I in water or in a mixture of water and an organic solvent is selected so as to form a 15 to 65% solution. The ratio between water and organic solvent in the mixture varies within a certain range, however, for the purpose of the advantageous course of the reaction, a ratio of 1 part water to 0.1 parts solvent up to 1 part water to 9 parts solvent can be used.

It has been found that C1-4 alcohols, water-miscible ketones, dimethylacetamide, dimethylformamide, tetrahydrofuran or dioxane can be used as solvents. Alternatively, the compound of formula I can be dissolved in an organic solvent and the salt of formula III or the amine of formula IV added during the reaction.

CS 269501 Bl

Subsequently, 1 to 5 molar parts of thiourea are added in aqueous solution or preferably in solid form. The desired pH value of the reaction mixture in the range of 7.1 to 3.1 is achieved by the addition of buffering agents such as sodium acetate or sodium bicarbonate or, in the case of using an excess of the salt of formula III or the amines of formula IV, for example acetic acid can be used as a buffering agent. It has been found that it is particularly advantageous to use the interval 0.1 to 2.0 pH values in the said range. For example, from 5.1 - 0.1 pH values to 5.1 - 2.0 pH values. The desired value can also be achieved by the use of buffers, which is also particularly advantageous for maintaining a constant pH value in the said range. It is clear that this value can be maintained by further addition of the salt of formula III or the amines of formula IV. It is particularly advantageous to use the salt* or the amine with the cation as was used to dissolve the acid of formula II. The reaction takes 0.5 to 6 hours to complete and can be carried out at temperatures of -10 to 45 °C. However, in order not to damage the desired substance and to prevent premature elimination from the reaction medium, it is preferably carried out at a temperature of 10 to 30 °C. The compound of formula I can be isolated in sufficient purity by adjusting the pH of the reaction mixture to a value of 1.2 to 3. The pH can be adjusted by using any suitable reagent, e.g. a mineral acid such as sulfuric acid or hydrochloric acid. The compound of formula I can be isolated by centrifugation or filtration or alternatively by extraction. Another possibility of isolating the compound I is salting out or precipitation by adding an organic solvent in which the compound of formula I is insoluble, e.g. dioxane, tetrahydrofuran. According to the latter method, this case is particularly suitable when using its salt such as iodine, potassium, etc.

The invention is further described in the examples. These examples describe in more detail some possibilities for preparing the compound of formula I and its salts without limiting the scope of the invention in any way.

Example 1

7-£2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido J -cephalosporanic acid, syn isomer. ’

10.57 g of 7-£2-(2-chloroacetamido-4-diazolyl)-2-methoxyiminoacetamido)-cephalosporanic acid are added to 40 ml of water and 5.7 ml of concentrated ammonia solution. 6 g of thiourea are added to the resulting solution. The reaction mixture is stirred at laboratory temperature for 3.5 hours, with the pH value being maintained at 5.1-0.5 by the addition of ammonia. After 1.5 hours, crystalline 2-imino-4-thiazolidinone precipitates. The reaction mixture is cooled to 5 °C, stirred for another 0.5 hour and filtered. The filtrate is decolorized with activated carbon and acidified by the addition of sulfuric acid. The precipitate is filtered off, washed with water, ethanol and dried under vacuum.

8.7 g of 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-cephalosporanic acid, syn isomer, are obtained. Purity confirmed by liquid chromatography.

Example 2

Diisopropylammonium salt* of 7-[2-(amino-4-thiazolyl)-2-methoxyiminoacetamide] acid

-cephalosporan, syn isomer.

2.63 g of 7-12-(2-chloroacetamido-4-thiazolyl) acid

-cephalosporan is dissolved in 15 ml of water and 5 ml of methanol by adding 0.55 g of diisopropylamine. The pH value is adjusted to 4.5 by adding acetic acid and then 1.5 g of thiourea is added. The reaction mixture is stirred for 3.5 hours while maintaining the above pH value by adding diisopropylamine. It is then cooled to 0 °C and

CS 269501 Bl is filtered. Ammonium sulfate is added to the filtrate until saturated and the mixture is left to crystallize. The precipitated product is filtered off, washed with acetone and dried under vacuum. 1.1 g of diisopropylammonium salt of 7-[2-[amino-4-thiazolyl]-2-methoxyiminoacetamido]-cephalosporanic acid, syn isomer, is obtained, the purity of which was confirmed by chromatography.

Example 3

7-[2-[2-amino-4-thiazolyl]-2-methoxylaminoacetamido]-cephalosporanic acid, syn isomer.

10.57 g of 7-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-cephalosporanic acid and 3.03 g of potassium carbonate are added to 160 ml of phosphate buffer (pH = 6.4). Subsequently, 4.2 g of thiourea are added and the reaction mixture is stirred for 2.5 hours. The precipitated crystalline 2-imino-4-thiazolidinone is filtered off. The filtrate is acidified by adding sulfuric acid to a pH of 2.85. The precipitate is filtered off, washed with water, isopropyl alcohol and dried under vacuum. 8.12 g of 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-cephalosporanic acid, syn isomer, are obtained.

Example 4

7- (2-[2-amino-4-thiazolyl]-2-methoxyiminoacetamido] -cephalosporanic acid, syn isomer.

°»53 g of 7-2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido-cephalosporanic acid are added to 5 ml of water and 0.2 ml of concentrated ammonia solution. Subsequently, 0.15 g of thiourea is added and the mixture is stirred at a pH of 6.2 to 5.8 until the precipitation of crystalline 2-imino-4-thiazolidinone occurs, which takes 1.5 hours. Subsequently, the mixture is stirred for another 2 hours and the reaction mixture is filtered. By working up as in Example 1, 0.38 g of 7-£2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamidoJ -cephalosporanic acid, syn isomer, is obtained.

Claims (3)

4 CS 269501 B1 is filtered. Ammonium sulphate was added to the filtrate and the mixture was allowed to crystallize. The precipitated product is filtered off, washed with acetone and dried under vacuum. 1.1 g of diisopropylammonium salt of 7- [2- (amino-4-thiazolyl) -2-methoxyiminoacetamido] -cephalosporanic acid, syn isomer, whose purity was confirmed by chromatography was obtained. EXAMPLE 3 7- [2- (2-Amino-4-thiazolyl) -2-methoxyiminoacetamido] -acephosphoric acid, synisomer. 10.57 g of 7- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido-3-cephalosporonic acid and 3.03 g of potassium carbonate are added to 160 ml of phosphate buffer (pH = 6.4). Thiourea (4.2 g) was then added and the reaction mixture was stirred for 2.5 hours. The precipitated crystalline 2-imino-4-thiazolidinone is filtered off. The filtrate was acidified by the addition of sulfuric acid to a pH of 2.85. The precipitate formed is filtered off, washed with water, isopropyl alcohol and dried under vacuum. 8.12 g of 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -cephalosporanic acid synisomer are obtained. Example 4 7- [2- (2-Amino-4-thiazolyl) -2-methoxyiminoacetamido] -cephalosporane, synisomer. 0.53 g of 7- 2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido-cephalosporanic acid is added to 5 ml of water and 0.2 ml of concentrated ammonia solution. stirring at a maintained pH of 6.2 to 5.8, excluding crystalline 2-imino-4-thiazolidinone, takes 1.5 hours. The subsequent mixture is stirred for a further 2 hours and the reaction mixture is filtered. Treatment as in Example 1 yields 0.38 g of 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamidojecalosporanic acid syn isomer. SUBJECT OF THE INVENTION 1. A process for preparing 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido-3-cephem-4-carboxylic acid, eyn isomer of formula (I) " ΝΝ ^ ^^^ΟΟΟΟΗ^ΟΟΟΟΗΟΟΟΟΗ 1 / / CO H H H H H H aj aj aj aj soli soli soli soli soli soli soli soli soli soli soli soli soli soli soli soli soli soli soli soli soli soli soli soli soli soli soli soli soli soli soli ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ g cycloalkyl by reacting 1 molar portion of 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacet-araido] -3-cephem-4-carboxylic acid, syn isomer of formula (II) CS 269501 B1 Cl-CH3CO- NH-C OCOCH, (11) in which M is hydrogen or an alkali metal cation of an ammonium or substituted ammonium cation of the type in which R5, R6, R6 independently of one another is H, C1-6 alkyl or C1-6 cycloalkyl of 1 to 5 molar thiourea in a water-miscible and / or water-miscible organic solvent, characterized in that the reaction mixture is maintained at a pH of 5.1-2 at -10 to 45 ° C and the resulting compound of formula (I) is reacted from the reaction mixture; the mixture is isolated prior to or after conversion to a salt of al-12 3 by quenching with metals, ammonia or substituted ammonia of the formula RR RN and in which R, R, R, independently of the other, represents H, C 1-6 alkyl or g cycloalkyl. 2. Process according to claim 1, characterized in that the pH of the reaction mixture is maintained by buffering agents at 5.1. 3. Process according to claim 1, characterized in that the compound of formula (I) is isolated from the reaction mixture by neutralization with inorganic or organic acidic agents and subsequent extraction with inert solvents or precipitation of the above-mentioned compound of formula (I) by acidification.